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1
Goswami, Manish, Deepak Sharma, Nazir M. Khan, Rahul Checker, Santosh Kumar Sandur, and Narendra Jawali. "Antioxidant supplementation enhances bacterial peritonitis in mice by inhibiting phagocytosis." Journal of Medical Microbiology 63, no. 3 (2014): 355–66. http://dx.doi.org/10.1099/jmm.0.067173-0.
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Antioxidants are known to exhibit numerous health benefits including anti-ageing, anti-apoptotic and immuno-stimulatory effects. However, we present the data showing counterproductive effects of therapeutically relevant antioxidants on bacterial clearance by the immune system in a murine peritonitic model. The antioxidants ascorbic acid, glutathione and N-acetylcysteine augmented morbidity and mortality in mice carrying Eshcerichia coli-induced acute bacterial peritonitis. Treatment of peritonitic mice with antioxidants significantly increased their bacterial load in the range of 0.3–2 logs. Antioxidant administration to peritonitic mice resulted in decreased numbers of macrophages, B-cells and dendritic cells at the primary site of infection and increased neutrophil infiltration. Serum TNF-α levels were also decreased in antioxidant-treated peritonitic mice. In vitro experiments showed that antioxidants reduced the phagocytic efficacy of peritoneal macrophages by ~60–75 % and also decreased E. coli-induced oxidative burst in macrophages cells. Taken together, our data indicate that the antioxidants increased the severity of peritonitis by decreasing the phagocytic efficiency, oxidative burst, and TNF-α production, and increasing neutrophil infiltration. Based on these results, we propose that antioxidant supplementation during the course of bacterial infection is not recommended as it could be detrimental for the host. In addition, the present study underlines the importance of timing and context of antioxidant administration rather than indiscriminate usage to gain the best possible therapeutic advantage of these redox compounds.
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Ishii, Yasuo, Tokihiko Sawada, Akira Shimizu, et al. "An experimental sclerosing encapsulating peritonitis model in mice." Nephrology Dialysis Transplantation 16, no. 6 (2001): 1262–66. http://dx.doi.org/10.1093/ndt/16.6.1262.
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Clark, Jessica A., Heng Gan, Alexandr J. Samocha, Amy C. Fox, Timothy G. Buchman, and Craig M. Coopersmith. "Enterocyte-specific epidermal growth factor prevents barrier dysfunction and improves mortality in murine peritonitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 3 (2009): G471—G479. http://dx.doi.org/10.1152/ajpgi.00012.2009.
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Systemic administration of epidermal growth factor (EGF) decreases mortality in a murine model of septic peritonitis. Although EGF can have direct healing effects on the intestinal mucosa, it is unknown whether the benefits of systemic EGF in peritonitis are mediated through the intestine. Here, we demonstrate that enterocyte-specific overexpression of EGF is sufficient to prevent intestinal barrier dysfunction and improve survival in peritonitis. Transgenic FVB/N mice that overexpress EGF exclusively in enterocytes ( IFABP-EGF) and wild-type (WT) mice were subjected to either sham laparotomy or cecal ligation and puncture (CLP). Intestinal permeability, expression of the tight junction proteins claudins-1, -2, -3, -4, -5, -7, and -8, occludin, and zonula occludens-1; villus length; intestinal epithelial proliferation; and epithelial apoptosis were evaluated. A separate cohort of mice was followed for survival. Peritonitis induced a threefold increase in intestinal permeability in WT mice. This was associated with increased claudin-2 expression and a change in subcellular localization. Permeability decreased to basal levels in IFABP-EGF septic mice, and claudin-2 expression and localization were similar to those of sham animals. Claudin-4 expression was decreased following CLP but was not different between WT septic mice and IFABP-EGF septic mice. Peritonitis-induced decreases in villus length and proliferation and increases in apoptosis seen in WT septic mice did not occur in IFABP-EGF septic mice. IFABP-EGF mice had improved 7-day mortality compared with WT septic mice (6% vs. 64%). Since enterocyte-specific overexpression of EGF is sufficient to prevent peritonitis-induced intestinal barrier dysfunction and confers a survival advantage, the protective effects of systemic EGF in septic peritonitis appear to be mediated in an intestine-specific fashion.
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Ni, Jie, Yvette Cnops, Rachel M. McLoughlin, Nicholas Topley, and Olivier Devuyst. "Inhibition of Nitric Oxide Synthase Reverses Permeability Changes in a Mouse Model of Acute Peritonitis." Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 25, no. 3_suppl (2005): 11–14. http://dx.doi.org/10.1177/089686080502503s03.
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Acute peritonitis is the most frequent complication of peritoneal dialysis. Previous studies have suggested a major role for nitric oxide (NO) in the permeability changes and loss of ultrafiltration induced by acute peritonitis. In this study, we further investigated the potential role of NO in a mouse model of peritonitis induced by Escherichia coli lipopolysaccharide (LPS). A 2-hour peritoneal equilibration test was performed in control and LPS-treated mice using 7% glucose dialysate supplemented or not with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The levels of NO metabolites in the dialysate were maximal 18 hours after LPS injection. At that time, acute peritonitis induced by LPS was reflected by an increased recruitment of leukocytes, an increased intraperitoneal release of interleukin-6, a significant increase in the peritoneal permeability for small solutes, a loss of sodium sieving, and a loss of ultrafiltration in comparison with controls. Addition of L-NAME in LPS-treated mice significantly reversed permeability modifications and prevented the release of NO metabolites into the dialysate. These results confirm that increased NO mediates permeability modifications during acute peritonitis, and illustrate the potential of mouse models to investigate the molecular mechanisms regulating peritoneal permeability.
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Liu, Shaoguang, Shaotong Zhang, Yulong Sun, and Wence Zhou. "Transcriptomics Changes in the Peritoneum of Mice with Lipopolysaccharide-Induced Peritonitis." International Journal of Molecular Sciences 22, no. 23 (2021): 13008. http://dx.doi.org/10.3390/ijms222313008.
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Peritonitis caused by LPS is a severe clinical challenge, which causes organ damage and death. However, the mechanism of LPS-induced peritonitis has not been fully revealed yet. Here, we investigated the transcriptome profile of the peritoneal tissue of LPS-induced peritonitis in mice. A model of LPS-induced peritonitis in mice was established (LPS 10 mg/kg, i.p.), and the influence of TAK 242 (TLR4 inhibitor) on the level of inflammatory cytokines in mouse peritoneal lavage fluid was investigated by using an ELISA test. Next, the peritoneal tissues of the three groups of mice (Control, LPS, and LPS+TAK 242) (n = 6) were isolated and subjected to RNA-seq, followed by a series of bioinformatics analyses, including differentially expressed genes (DEGs), enrichment pathway, protein-protein interaction, and transcription factor pathway. Then, qPCR verified-hub genes that may interact with TAK 242 were obtained. Subsequently, the three-dimensional structure of hub proteins was obtained by using homology modeling and molecular dynamics optimization (300 ns). Finally, the virtual docking between TAK 242 and hub proteins was analyzed. Our results showed that TAK 242 significantly inhibited the production of inflammatory cytokines in the peritoneal lavage fluid of mice with peritonitis, including IL-6, IFN-γ, IL-1β, NO, and TNF-α. Compared with the Control group, LPS treatment induced 4201 DEGs (2442 down-regulated DEGs and 1759 up-regulated DEGs). Compared with the LPS group, 30 DEGs were affected by TAK 242 (8 down-regulated DEGs and 22 up-regulated DEGs). A total of 10 TAK 242-triggered hub genes were obtained, and the possible docking modes between TAK 242 and hub proteins were acquired. Overall, our data demonstrated that a large number of DEGs were affected in LPS-triggered peritonitis mice. Moreover, the TLR4 inhibitor TAK 242 is capable of suppressing the inflammatory response of LPS-induced peritonitis. Our work provides clues for understanding the pathogenesis of LPS-induced peritonitis in mice.
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Steinhauser, Matthew L., Cory M. Hogaboam, Nickolas W. Lukacs, Robert M. Strieter, and Steven L. Kunkel. "Multiple Roles for IL-12 in a Model of Acute Septic Peritonitis." Journal of Immunology 162, no. 9 (1999): 5437–43. http://dx.doi.org/10.4049/jimmunol.162.9.5437.
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Abstract The present study addressed the role of IL-12 in a murine model of septic peritonitis, induced by cecal ligation and puncture (CLP). Although CLP surgery induced IL-12 production at 6 and 24 h after surgery, IL-12 immunoneutralization was clearly deleterious in this model: 54% of CLP mice receiving preimmune serum survived, whereas mice administered IL-12 antisera prior to CLP experienced a 25% survival rate. IL-12 immunoneutralization not only led to increased mortality, but also appeared to promote a shift away from IL-12 and IFN-γ, in favor of IL-10. This cytokine shift corresponded to changes in bacterial load, as CLP mice receiving IL-12 antiserum yielded more CFUs from the peritoneal cavity at 24 h after CLP. To address the role of bacterial infection in IL-12 antiserum-induced mortality following CLP, antibiotics were administered for 4 days after surgery. Despite regular antibiotic administration, IL-12 immunoneutralization still reduced survival in CLP mice. Furthermore, histology of the ceca revealed that mice administered IL-12 antisera failed to show typical organization of the damaged cecum wall. Accordingly, Gram staining revealed bacteria within peritoneal fluids from these mice, while peritoneal fluids from CLP mice that received preimmune serum and antibiotics were free of bacteria. Altogether, these data suggested multiple important roles for IL-12 in the evolution of murine septic peritonitis.
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Lan, Jing, Hong Zhang, Hui Zhao, et al. "Cord Blood Natural Killer Cells Inhibit Sepsis Caused by Feces-Induced Acute Peritonitis via Increasing Endothelium Integrity." Cell Transplantation 31 (January 2022): 096368972210902. http://dx.doi.org/10.1177/09636897221090257.
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Sepsis is associated with acute peritonitis, which can be induced by lipopolysaccharide exposure and feces. Generally, lipopolysaccharide induces mono-microbial peritonitis, whereas feces cause poly-microbial peritonitis; the latter is a more complicated and closer to the clinical diseases. Although several reports have discussed the mechanism of immune response in peritonitis-induced sepsis, however, the role of natural killer (NK) cells in sepsis, especially the relationship between NK cells and stabilization of the vascular endothelial barrier, is still unclear. Accordingly, in this study, we assessed the roles of NK cells in an acute sepsis model in mice. NK cells were injected via the tail vein into mice with acute sepsis, and nitric oxide (NO), anti-inflammatory cytokine, and angiogenic factors were tested to explore the effects of NK cells on sepsis. The survival rate of septic model mice infused with NK cells was significantly improved compared with the control group. Interestingly, the levels of NO, interleukin-10, and vascular endothelial growth factor (VEGF) decreased in NK cells therapy group. After the injection of NK cells, CD31 positive endothelial cells significantly increased in the kidneys and liver, although the expression of VEGF, ANGPT-1, and ET-1 was downregulated. Consistent with our hypothesis, the transfusion of NK cells into mice with sepsis blocked inflammation and increased endothelium integrity. Overall, these findings suggest that NK cells may block sepsis by modulating the VEGF pathway.
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Kang, Xu-Qi, Yue Qiao, Xiao-Yang Lu, et al. "Tocopherol polyethylene glycol succinate-modified hollow silver nanoparticles for combating bacteria-resistance." Biomaterials Science 7, no. 6 (2019): 2520–32. http://dx.doi.org/10.1039/c9bm00343f.
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Diedrich, Stephan, Julia van der Linde, Michael Nielson, et al. "The MRI Sepsis Score: An Innovative Tool for the Evaluation of Septic Peritonitis in Mice Using 7-Tesla Small Animal MRI." European Surgical Research 59, no. 3-4 (2018): 126–42. http://dx.doi.org/10.1159/000490663.
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Background: Magnetic resonance imaging (MRI) techniques are rarely used in the context of abdominal sepsis and in sepsis research. This study investigates the impact of MRI for monitoring septic peritonitis in an animal model (colon ascendens stent-induced peritonitis, CASP). The CASP model closely mimics that of human disease and is highly standardized. The most frequently employed readout parameter in mouse CASP studies is prolonged or decreased rate of survival. Monitoring the progression of peritonitis via MRI could provide a helpful tool in the evaluation of severity. The use of alternative readout systems could very well reduce the number of research animals. Perspectively, clinical improvement after certain treatment could be classified. Methods: This study describes for the first time MRI findings following the induction of septic peritonitis in mice using the CASP model. Two sublethal groups of mice with septic peritonitis were investigated. Each had received one of two differing stent diameters in order to control the leakage of feces into the abdominal cavity. Each mouse served as its own control. Imaging and analyses were performed blinded. Gut diameters, stomach volume, abdominal organ wall diameters, and volume of the adrenal glands were measured. Serum corticosterone levels were detected using ELISA. Serum IL-6, TNF-α, IL-1β, and IL-10 levels were screened by cytometric bead array. Statistical analysis was performed using the Mann-Whitney U test for nonparametric probes and the Kruskal-Wallis and t tests. Results: Using a 7-tesla MRI scanner 24 and 48 h after induction of septic peritonitis, interenteric fluid, organ swelling of spleen and adrenal glands, as well as dilatation of the stomach were compared to nonseptic conditions. Swelling of adrenal glands resulted in an increased serum corticosterone level. In addition, the wall of the intestine bowel was thickened. Based upon these findings, an MRI score (MRI sepsis score, MSS) for abdominal sepsis in mice was established. Reduced stent sizes led to reduced severity of the abdominal sepsis, which could be reproduced in the MSS, which is described here for the first time. Conclusions: Intraabdominal variations during septic peritonitis are detectable by MRI techniques. MRI methods should become a more important tool for the evaluation of abdominal peritonitis. MSS could provide an interesting tool for the evaluation of therapeutic strategies.
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Zantl, N., C.-D. Heidecke, B. Holzmann, and K. Pfeffer. "COLON ASCENDENS STENT PERITONITIS: A NOVEL SURGICAL MODEL FOR THE INDUCTION OF BACTERIAL PERITONITIS/SEPSIS IN MICE." Shock 7, Supplement (1997): 137. http://dx.doi.org/10.1097/00024382-199703001-00556.
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Woods, Dustin R., Susan Heffley, James C. Peyton, and William G. Cheadle. "Antibiotic Modulation in a Clinically Relevant Model of Chronic Intraabdominal Infection." American Surgeon 72, no. 7 (2006): 655–60. http://dx.doi.org/10.1177/000313480607200717.
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Continuous and twice-daily cefoxitin dosing was used in a highly lethal model of acute peritonitis in mice using intraperitoneal (IP) Klebsiella pneumoniae (Kpn). The purpose was to use antibiotics to create a model of chronic infection. Male Balb/c mice (averaging 20 g body weight) were inoculated IP with 103 colony-forming units (CFU) Kpn serotype 2. Controls received subcutaneous saline either twice daily or continuously. Antibiotic groups received 300 mg/kg per day of cefoxitin either twice daily or continuously. Survival and daily weight losses were determined. Another group was inoculated with 103 Kpn given twice daily saline or cefoxitin and harvested at 24 hours. Leukocyte counts were performed on peritoneal exudate cells (PEC) and peripheral blood. Cultures determined Kpn counts in blood, lung, and PEC. By 24 hours, saline-treated animals had lost more weight than cefoxitin mice (1 g vs. 2 g, P < 0.05). Continuous cefoxitin showed significant advantage with 50 per cent mortality at 5 days. Kpn levels were not significantly altered by cefoxitin. Cefoxitin treatment extended chronicity by preventing weight loss and increasing survival in a highly lethal, monomicrobial peritonitis model. This model will allow future study of specific host defense mechanisms over a prolonged time period.
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Echtenacher, Bernd, Marina A. Freudenberg, Robert S. Jack, and Daniela N. Männel. "Differences in Innate Defense Mechanisms in Endotoxemia and Polymicrobial Septic Peritonitis." Infection and Immunity 69, no. 12 (2001): 7271–76. http://dx.doi.org/10.1128/iai.69.12.7172-7276.2001.
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ABSTRACT Loss, reduction, or enhancement of the ability to respond to bacterial lipopolysaccharide (LPS) has no influence on survival of mice in a model of postoperative polymicrobial septic peritonitis induced by cecal ligation and puncture (CLP). This was demonstrated by using either mice with a defective Tlr4 gene, which encodes the critical receptor molecule for LPS responses, or mice deficient for LPS binding protein (LBP) or mice sensitized to LPS byPropionibacterium acnes. Though interleukin-12 (IL-12) and gamma interferon (IFN-γ) play an important role in the sensitivity to LPS as well as in the resistance to several infections, loss of these cytokine pathways does not affect survival after CLP. Thus, neutralization of neither endogenous IL-12 nor IFN-γ altered mortality. In addition, IFN-γ receptor-deficient mice demonstrated the same sensitivity to CLP as mice with a functional IFN-γ receptor. However, administration of IFN-γ at the time of operation or pretreatment of both IFN-γ-sensitive and IFN-γ-resistant mice with IL-12 significantly enhanced mortality. This indicates that in the present infection model activation of innate defense mechanisms is not dependent on LPS recognition and does not require endogenous IL-12 or IFN-γ function. Indeed, exogenous application of these two mediators had deleterious effects.
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Cao, Shirong, Shu Li, Yating Wang, et al. "Acetylation of HMGB1 by JNK1 Signaling Promotes LPS-Induced Peritoneal Mesothelial Cells Apoptosis." BioMed Research International 2018 (November 12, 2018): 1–12. http://dx.doi.org/10.1155/2018/2649585.
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Increased high mobility group box 1 (HMGB1) in dialysis effluence is associated with the presence of peritoneal dialysis-related peritonitis in patients and peritoneal dysfunction in acute peritonitis mice model, but it remains unclear whether HMGB1 is involved in peritoneal mesothelial cell injury and functions via molecular posttranslational modifications by acetylation in this process. Here we first showed correlation between HMGB1 acetylation level in dialysis effluence of patients and occurrence of Gram-negative peritonitis. The increased level of acetylated HMGB1 was similarly observed under the lipopolysaccharides (LPS) treatment in both human peritoneal mesothelial cell line (HMrSV5) and mice visceral peritoneum tissue. Overexpression of wild-type, but not hypoacetylation mutant of HMGB1, enhanced LPS-induced apoptosis in HMrSV5 cells, which was accompanied by elevated protein levels of BAX and cleaved-caspase 3 compared to the control. Pretreatment of HMrSV5 cell with JNK inhibitor attenuated LPS-induced HMGB1 acetylation. Consistently, primary peritoneal mesothelial cells from Jnk1-/- mice showed a lower protein contents of acetylated HMGB1, fewer apoptosis, and decreased protein expression of BAX and cleaved-caspase3 after LPS exposure, as compared to those from wild-type mice. In conclusion, our data demonstrated HMGB1 promotes LPS-induced peritoneal mesothelial cells apoptosis, which is associated with JNK1-mediated upregulation of HMGB1 acetylation.
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Huang, Miao-Tzu, Karen Y. Larbi, Christoph Scheiermann, et al. "ICAM-2 mediates neutrophil transmigration in vivo: evidence for stimulus specificity and a role in PECAM-1–independent transmigration." Blood 107, no. 12 (2006): 4721–27. http://dx.doi.org/10.1182/blood-2005-11-4683.
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AbstractICAM-2 has been implicated in leukocyte transmigration in vitro, but there is little in vivo evidence to support this. To address this, neutrophil migration was investigated in ICAM-2–deficient mice (KO) and in wild-type (WT) mice treated with an anti–ICAM-2 blocking monoclonal antibody (mAb) (3C4). In a peritonitis model, IL-1β–induced accumulation of neutrophils was significantly reduced in mice treated with 3C4 (51% inhibition) and in KO mice (41% inhibition). In contrast, TNF-α– or thioglycolate-induced responses were not suppressed in KO mice. Analysis of IL-1β–induced leukocyte responses in cremasteric venules of KO animals by intravital microscopy indicated a defect in transmigration (44% inhibition) but not rolling or adhesion. As found before, TNF-α–induced leukocyte transmigration was unaltered in the KO mice. WT mice treated with the anti–ICAM-2 mAb also exhibited a selective reduction in leukocyte transmigration in response to IL-1β while an anti–ICAM-1 mAb inhibited both leukocyte adhesion and transmigration. Interestingly, mAb 3C4 significantly suppressed IL-1β–induced neutrophil transmigration in PE-CAM-1 KO animals in the peritonitis model but not in the cremaster muscle. The findings provide direct evidence for the involvement of ICAM-2 in neutrophil transmigration in vivo, though this role appears to be stimulus specific. Furthermore, ICAM-2 appears capable of mediating PECAM-1–independent leukocyte transmigration.
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Parameswaran, Narayanan, Babu Gonipeta, Sitaram Parvataneni, Nandakumar Packiriswamy та Deepika Sharma. "β-arrestin-1 negatively regulates inflammatory response to polymicrobial sepsis in mice (110.11)". Journal of Immunology 186, № 1_Supplement (2011): 110.11. http://dx.doi.org/10.4049/jimmunol.186.supp.110.11.
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Abstract β-arrestins are scaffolding proteins that regulate a number of receptor signaling pathways including Toll-like receptors. We recently demonstrated that mice lacking either β-arrestin-1 or β-arrestin-2 are protected from lipopolysaccharide-induced lethality and have a markedly reduced inflammatory response. To assess the role of β-arrestin-1 in a clinically relevant model of sepsis, we subjected wild type and β-arrestin-1 knockout mice to cecal-ligation and puncture (CLP) to mimick septic peritonitis and polymicrobial sepsis. Surprisingly, we found that, mortality of β-arrestin-1 knockout mice was significantly enhanced compared to the wild type mice after CLP. Consistent with lethality, β-arrestin-1 knockout mice had markedly elevated inflammatory cytokine levels in the plasma, peritoneal cavity, and bronchoalveolar fluid. Enhanced systemic inflammatory response of β-arrestin-1 knockout mice was associated with significantly enhanced infiltration of immune cells into the peritoneal cavity after induction of septic peritonitis. Together, these results demonstrate that, contrary to its role in lipolysaccharide-TLR4 signaling in vivo, β-arrestin-1 is a negative regulator of inflammation induced by polymicrobial sepsis and that the phenotype of the mice may be related to a potentially aberrant immune response from excess infiltration of immune cells. These results also suggest that the role of β-arrestin-1 in this model is likely independent of its role in TLR4 signaling in vivo.
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Shi, Zheng-Zheng, Bing Han, Geetha M. Habib, Martin M. Matzuk та Michael W. Lieberman. "Disruption of γ-Glutamyl Leukotrienase Results in Disruption of Leukotriene D4 Synthesis In Vivo and Attenuation of the Acute Inflammatory Response". Molecular and Cellular Biology 21, № 16 (2001): 5389–95. http://dx.doi.org/10.1128/mcb.21.16.5389-5395.2001.
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ABSTRACT To study the function of γ-glutamyl leukotrienase (GGL), a newly identified member of the γ-glutamyl transpeptidase (GGT) family, we generated null mutations in GGL (GGLtm1) and in both GGL and GGT (GGLtm1-GGTtm1) by a serial targeting strategy using embryonic stem cells. Mice homozygous for GGLtm1 show no obvious phenotypic changes. Mice deficient in both GGT and GGL have a phenotype similar to the GGT-deficient mice, but ∼70% of these mice die before 4 weeks of age, at least 2 months earlier than mice deficient only in GGT. These double-mutant mice are unable to cleave leukotriene C4 (LTC4) to LTD4, indicating that this conversion is completely dependent on the two enzymes, and in some organs (spleen and uterus) deletion of GGL alone abolished more than 90% of this activity. In an experimental model of peritonitis, GGL alone is responsible for the generation of peritoneal LTD4. Further, during the development of peritonitis, GGL-deficient mice show an attenuation in neutrophil recruitment but not of plasma protein influx. These findings demonstrate an important role for GGL in the inflammatory response and suggest that LTC4 and LTD4 have distinctly different functions in the inflammatory process.
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Hogaboam, Cory M., Matthew L. Steinhauser, Harold Schock, et al. "Therapeutic Effects of Nitric Oxide Inhibition during Experimental Fecal Peritonitis: Role of Interleukin-10 and Monocyte Chemoattractant Protein 1." Infection and Immunity 66, no. 2 (1998): 650–55. http://dx.doi.org/10.1128/iai.66.2.650-655.1998.
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ABSTRACT This study demonstrates that the therapeutic effect of a nitric oxide inhibitor in a murine model of fecal peritonitis is mediated in part by increased levels of interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1). Female CD1 mice were subjected to cecal ligation and puncture (CLP) with a 21-gauge needle and, immediately following surgery, were injected intraperitoneally with saline,N G-nitro-l-arginine methyl ester (l-NAME; 8 mg/kg), orN G-nitro-d-arginine methyl ester (d-NAME; 8 mg/kg). At 96 h after surgery and drug treatment, 20% of mice that received d-NAME had survived whereas 60% of mice that received l-NAME were alive. To elucidate the effect of l-NAME treatment on chemokine and cytokine production during fecal peritonitis, the levels of macrophage inflammatory protein 2 (MIP-2), IL-10, and MCP-1 were measured in peritoneal washings from additional groups of mice 24 h after the CLP surgery. Peritoneal fluids froml-NAME-treated mice contained significantly higher levels of IL-10 and MCP-1 than did those from d-NAME-treated mice. To elucidate the effect of nitric oxide inhibition on potential cellular sources of IL-10 and MCP-1 in the CLP model, cultured alveolar and peritoneal macrophages were activated with bacterial lipopolysaccharide in the presence of l-NAME; these macrophages produced significantly more MCP-1 than did similarly activated macrophages in the presence of d-NAME. In the CLP surgery model, immunoneutralization of IL-10 alone or IL-10 and MCP-1 together with polyclonal antibodies prior to surgery significantly reduced the survival rates in l-NAME-treated groups compared with l-NAME-treated groups that received preimmune serum. Taken together, these data demonstrate that the inhibition of nitric oxide following experimental CLP fecal peritonitis is therapeutic, in part through the modulatory effect of this treatment on the synthesis of IL-10 and MCP-1.
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Dou, Jiangli, Qingsong Xu, Chengyu Tan, et al. "Effects of chitosan oligosaccharides on neutrophils from glycogen-induced peritonitis mice model." Carbohydrate Polymers 75, no. 1 (2009): 119–24. http://dx.doi.org/10.1016/j.carbpol.2008.07.005.
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da Silva, Morgana Duarte, Giselle Guginski, Maria Fernanda de Paula Werner, Cristiane Hatsuko Baggio, Rodrigo Marcon, and Adair Roberto Soares Santos. "Involvement of Interleukin-10 in the Anti-Inflammatory Effect of Sanyinjiao (SP6) Acupuncture in a Mouse Model of Peritonitis." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–9. http://dx.doi.org/10.1093/ecam/neq036.
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In this study, we determined the anti-inflammatory effect of manual acupuncture at the Sanyinjiao or Spleen 6 (SP6) point on carrageenan-induced peritonitis in mice and investigated mechanisms that may underlie this effect. In the first set of experiments, male Swiss mice were allocated into five groups: the control (sterile saline), dexamethasone (DEXA), invasive sham-acupuncture (non-acupoint), SP6 acupuncture and carrageenan-treated groups. Ten minutes after needle retention or 30 min after DEXA treatment, mice received an intraperitoneal injection of carrageenan (750 μg/mouse). After 4 h, total leukocyte and differential cell counts (neutrophils and mononuclear), myeloperoxidase (MPO) activity, vascular permeability and cytokine levels were evaluated. In another set of experiments, adrenalectomized (ADX) mice were used to study the involvement of the adrenal gland on the therapeutic effects of acupuncture. Mice were allocated into two groups: the ADX and sham-operated animals (Sham ADX) that were subdivided into four subgroups each: the control (sterile saline), DEXA, SP6 acupuncture and carrageenan-treated groups. The SP6 and DEXA treatments inhibited the inflammatory cell infiltration, vascular permeability and MPO activity in carrageenan-injected mice. In addition, the SP6 treatment also increased interleukin (IL)-10 levels. In contrast, when the animals were adrenalectomized, the SP6 treatment failed to reduce total leukocyte and the plasma extravasation. In conclusion, this study clearly demonstrates the anti-inflammatory effect of SP6 acupuncture in a model of carrageenan-induced peritonitis. Our results demonstrated that SP6 acupuncture depends of the adrenal glands and increased IL-10 levels to produce its anti-inflammatory action.
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Lucena, Alessandra, Cássio Souza, Jéssica Jales, et al. "The Bisindole Alkaloid Caulerpin, from Seaweeds of the Genus Caulerpa, Attenuated Colon Damage in Murine Colitis Model." Marine Drugs 16, no. 9 (2018): 318. http://dx.doi.org/10.3390/md16090318.
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Caulerpin (CLP), an alkaloid from algae of the genus Caulerpa, has shown anti-inflammatory activity. Therefore, this study aimed to analyze the effect of CLP in the murine model of peritonitis and ulcerative colitis. Firstly, the mice were submitted to peritonitis to evaluate which dose of CLP (40, 4, or 0.4 mg/kg) could decrease the inflammatory infiltration in the peritoneum. The most effective doses were 40 and 4 mg/kg. Then, C57BL/6 mice were submitted to colitis development with 3% dextran sulfate sodium (DSS) and treated with CLP at doses of 40 and 4 mg/kg. The disease development was analyzed through the disease activity index (DAI); furthermore, colonic tissue samples were submitted to histological analysis, NFκB determination, and in vitro culture for cytokines assay. Therefore, CLP at 4 mg/kg presented the best results, triggering improvement of DAI and attenuating the colon shortening and damage. This dose was able to reduce the TNF-α, IFN-γ, IL-6, IL-17, and NFκB p65 levels, and increased the levels of IL-10 in the colon tissue. Thus, CLP mice treatment at a dose of 4 mg/kg showed promising results in ameliorating the damage observed in the ulcerative colitis.
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Pagano, Rosana L., Mario Mariano, and Renata Giorgi. "Neutrophilic Cell-Free Exudate Induces Antinociception Mediate by the Protein S100A9." Mediators of Inflammation 2006 (2006): 1–6. http://dx.doi.org/10.1155/mi/2006/36765.
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Calcium-binding protein S100A9 (MRP-14) induces antinociceptive effect in an experimental model of painful sensibility and participates of antinociception observed during neutrophilic peritonitis induced by glycogen or carrageenan in mice. In this study, the direct antinociceptive role of the protein S100A9 in neutrophilic cell-free exudates obtained of mice injected with glycogen was investigated. Mice were intraperitoneally injected with a glycogen solution, and after4,8,24, and48hours, either the pattern of cell migration of the peritoneal exudate or the nociceptive response of animals was evaluated. The glycogen-induced neutrophilic peritonitis evoked antinociception4and8hours after inoculation of the irritant. Peritoneal cell-free exudates, collected in different times after the irritant injection, were transferred to naive animals which were submitted to the nociceptive test. The transference of exudates also induced antinociceptive effect, and neutralization of S100A9 activity by anti-S100A9 monoclonal antibody totally reverted this response. This effect was not observed when experiments were made24or48hours after glycogen injection. These results clearly indicate that S100A9 is secreted during glycogen-induced neutrophilic peritonitis, and that this protein is responsible by antinociception observed in the initial phase of inflammatory reaction. Thus, these data reinforce the hypothesis that the calcium-binding protein S100A9 participates of the endogenous control of inflammatory pain.
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Fernandez-Boyanapalli, Ruby, S. Courtney Frasch, David W. H. Riches, R. William Vandivier, Peter M. Henson та Donna L. Bratton. "PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease". Blood 116, № 22 (2010): 4512–22. http://dx.doi.org/10.1182/blood-2010-02-272005.
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Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) activation during CGD inflammation is deficient, leading to altered macrophage programming and decreased efferocytosis, and that PPARγ agonism would enhance resolution. using the gp91phox−/− murine model of X-linked CGD in a well-characterized model of sterile, zymosan-induced peritonitis, it was demonstrated that PPARγ expression and activation in CGD macrophages were significantly deficient at baseline, and acquisition was delayed over the course of inflammation relative to that of wild-type. Efferocytosis by macrophages reflected PPARγ activation during peritonitis and was impaired in CGD mice (versus wild-type), leading to accumulation of apoptotic neutrophils. Importantly, provision of the PPARγ agonist, pioglitazone, either prophylactically or during inflammation, significantly enhanced macrophage PPARγ-mediated programming and efferocytosis, reduced accumulation of apoptotic neutrophils, and normalized the course of peritonitis in CGD mice. As such, PPARγ may be a therapeutic target for CGD, and possibly other inflammatory conditions where aberrant macrophage programming and impaired efferocytosis delay resolution of inflammation.
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Massa, Christine, Emma Braine, Jason Lenzo, et al. "The effect of tissue type-plasminogen activator deletion and associated fibrin(ogen) deposition on macrophage localization in peritoneal inflammation." Thrombosis and Haemostasis 95, no. 04 (2006): 659–67. http://dx.doi.org/10.1160/th05-06-0405.
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SummaryThere are two plasminogen activators (PAs), urokinase type-PA (u-PA) and tissue type-PA (t-PA). While u-PA is considered to be involved in cellular migration and tissue remodeling and t-PA in fibrinolysis, this distinction is not always clear-cut. With the use of u-PA and t-PA gene deficient mice (u-PA-/and t-PA-/mice, respectively) we have assessed the role of each PA in acute peritonitis. The cellular infiltrate in both thioglycolateand antigen-induced peritoneal exudates was unaffected in u-PA-/mice; in contrast, in t-PA-/mice, the macrophage numbers, particularly of the Mac-1hi population, in the peritoneal cavity by day4 were significantly reduced compared to wild-type mice. However, examination of the peritoneal wall revealed in fact increased numbers of macrophages adhering on/in the cavity lining at all time points studied; in addition, increased fibrin(ogen) staining was observed for these mice. The reduced macrophage numbers in the peritoneal cavities of t-PA-/mice could be increased by administration of plasmin or t-PA prior to harvesting the thioglycolate-elicited exudates. These results suggest that t-PA and not u-PA is the PA controlling fibrinolysis in murine peritonitis. In its absence macrophages adhere to the accumulated fibrin(ogen) on/in the cavity wall lining, most likely via Mac-1 binding, thus affecting migration into and/or out of the peritoneal cavity. They also highlight the need to examine both the peritoneal cavity and wall in order to monitor accurately the extent of a peritoneal inflammatory reaction. Peritoneal inflammation in t-PA-/mice represents a useful model to study the progression of intra-abdominal adhesions during surgery and clinical peritonitis.
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Chan, Goldia, Christopher Fry, and Jean Nemzek. "Impact of thermoneutral acclimation on a murine model of polymicrobial peritonitis." PLOS One 20, no. 5 (2025): e0322855. https://doi.org/10.1371/journal.pone.0322855.
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To examine the effects of ambient temperature on the reproducibility and translation of a murine sepsis model, we hypothesized that acclimation of mice in temperatures within their thermoneutral zone would alter immune responses and outcomes compared to standard housing temperatures. Mice housed for one week in thermoneutral (30°C) as compared to standard (22°C) conditions displayed lower counts of circulating neutrophils (0.52 ± 0.20 vs. 1.10 ± 0.54 x103/μL; p = 0.011) and peritoneal macrophages (0.80 ± 0.57 vs. 1.62 ± 0.62 x 105/μL; p = 0.002) as well as reduced in vitro production of IFN-γ by stimulated splenocytes (0.38 ± 0.68 vs 2.55 ± 0.76 x104 pg/mL, respectively, p = 0.004). After one week of temperature acclimation followed by CLP, the 7-day mortality was significantly lower under thermoneutral as compared to standard temperatures (80% vs 30%, respectively; p = 0.012), although core body temperature was preserved (average for 24 hours: 36.4 ± 1.3°C vs 31.7 ± 4.7°C; p < 0.0001). The lower survival was accompanied by increased systemic IL-6 levels (3.8 ± 3.3 vs 1.9 ± 1.3 x103 pg/mL; p = 0.04) and less robust influx of neutrophils into the peritoneum (1.68 ± 1.07 vs. 4.20 ± 2.46 x105/μL, respectively; p = 0.0003). Overall, thermoneutral temperatures impacted innate immune parameters before and after CLP, producing distinctly different outcomes. Therefore, ambient temperature is an important variable that could impact model reproducibility and should be reported for the acclimation period and experimentation phases of murine sepsis studies.
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Rodgers, Kathleen, Shiquan Xiong, Theresa Espinoza, Norma Roda, Sonia Maldonado, and Gere S. diZerega. "Angiotensin II Increases Host Resistance to Peritonitis." Clinical Diagnostic Laboratory Immunology 7, no. 4 (2000): 635–40. http://dx.doi.org/10.1128/cdli.7.4.635-640.2000.
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ABSTRACT Studies by other laboratories have shown that angiotensin II (AII) can affect the function of cells which comprise the immune system. In the present study, the effect of AII on the function of peritoneal macrophages and peripheral blood monocytes was assessed. In vitro exposure (4 h prior to assay) of peritoneal macrophages from mice and rats to AII increased the percentage of cells that phagocytosed opsonized yeast and the number of yeast per macrophage. Furthermore, AII increased the respiratory burst capacity of peritoneal macrophages from mice and rats and peripheral blood mononuclear cells from humans. Because of these observations, the effect of AII on host resistance to bacterial infection was assessed. Intraperitoneal administration of AII was shown to increase host resistance (reduced abscess formation) in an animal model of bacterial peritonitis. Studies were then conducted to assess whether parenteral administration of AII, a clinically relevant route, could affect peritoneal host resistance in a manner similar to that observed after peritoneal administration. These studies showed that subcutaneous administration of AII throughout the postinfection interval increased the level of host resistance to bacterial peritonitis. Furthermore, in a study which compared AII and Neupogen, an agent approved for use for the reduction of febrile neutropenia after myeloablative therapy, daily subcutaneous administration of AII reduced abscess size and incidence, whereas Neupogen did not have any therapeutic benefit in this model. These data suggest that AII may be of therapeutic benefit as an immunomodulatory agent.
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Larmann, Jan, Tim Frenzel, Anke Hahnenkamp, et al. "In Vivo Fluorescence-mediated Tomography for Quantification of Urokinase Receptor-dependent Leukocyte Trafficking in Inflammation." Anesthesiology 113, no. 3 (2010): 610–18. http://dx.doi.org/10.1097/aln.0b013e3181e99bfc.
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Background Inflammation is characterized by leukocyte recruitment. Macrophages and neutrophils contribute to tissue damage and organ dysfunction. Modulating leukocyte invasion can protect from these adverse effects. Leukocyte recruitment critically depends on the urokinase-type plasminogen activator receptor (u-PAR). We here use a novel technique to longitudinally quantify cell trafficking in inflammatory models in live animals. Methods Near-infrared fluorophore-labeled leukocytes were adoptively transferred to mice with thioglycollate peritonitis to study leukocyte trafficking to sites of inflammation. Macrophage and neutrophil trafficking was followed with three-dimensional fluorescence-mediated-tomography. u-PAR-/- and wild-type macrophage recruitment was studied by cross-over adoptive cell transfer to elucidate the role of leukocytic versus u-PAR expressed on other cells. Endotoxic shock-induced pulmonary inflammation was used to study u-PARs role for pulmonary neutrophil recruitment. Results Mice experiencing peritonitis showed a significant increase in mean fluorescence intensity because of enhanced macrophage (315%, n=9-10), P&lt;0.05) or neutrophil (194%, n=6, P&lt;0.02) recruitment. Fluorescence-mediated-tomography uncovered a macrophage recruitment defect in the peritonitis model for u-PAR-/- mice (147% of baseline) compared with control mice (335% of baseline, n=8-9, P&lt;0.05). When u-PAR-/--macrophages were transferred to wild-type mice fluorescence intensity increased to 145% while wild-type macrophage transfer into u-PAR-/- resulted in 192% increase compared with baseline (n=6, P&lt;0.05). Reduced neutrophil recruitment in pulmonary inflammation in u-PAR-/- mice was accompanied by improved pulmonary gas exchange. Conclusion Using noninvasive in vivo fluorescence-mediated tomography to image leukocyte recruitment in inflammatory mouse models, we describe a novel macrophage recruitment defect in u-PAR-/- mice. Targeting u-PAR for modulation of leukocyte recruitment is a promising therapeutic strategy to ameliorate leukocyte induced tissue damage.
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Huang, Yuqing, Yi Ning, Zhiwei Chen, et al. "A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease." Molecules 29, no. 8 (2024): 1803. http://dx.doi.org/10.3390/molecules29081803.
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IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.
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Steinhauser, M. L., C. M. Hogaboam, A. Matsukawa, N. W. Lukacs, R. M. Strieter, and S. L. Kunkel. "Chemokine C10 Promotes Disease Resolution and Survival in an Experimental Model of Bacterial Sepsis." Infection and Immunity 68, no. 11 (2000): 6108–14. http://dx.doi.org/10.1128/iai.68.11.6108-6114.2000.
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ABSTRACT Previous studies have suggested that the C-C chemokine C10 is involved in the chronic stages of host defense reactions. The present study addressed the role of C10 in a murine model of septic peritonitis, induced by cecal ligation and puncture (CLP). Unlike other C-C chemokines, C10 levels in the peritoneal wash were increased approximately 30-fold above baseline levels at 48 h after CLP surgery. Immunoneutralization of peritoneal C10 levels with polyclonal anti-C10 antiserum during CLP-induced peritonitis negatively impacted mouse survival over 4 days. In contrast, when 500 ng of recombinant murine C10 was administered immediately after CLP surgery, the 4-day survival rate increased from 20% to over 60%. The C10 therapy appeared to facilitate a rapid and significant enhancement of the levels of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and a later increase in interleukin-13 (IL-13) levels in the peritoneal cavity. In vitro studies showed that the combination of IL-1β and C10 markedly augmented TNF-α synthesis by peritoneal macrophages and that C10 synthesis was induced in these cells following their exposure to IL-13. At 24 h after CLP surgery, only 25% of C10-treated mice were bacteremic versus 85% of the control group that exhibited dissemination of bacteria into the circulation. The lack of bacteremia in C10-treated mice appeared to be related, in part, to in vitro evidence that C10 significantly enhanced the bacterial phagocytic activity of peritoneal macrophages. In addition, in vivo evidence suggested that C10 therapy significantly reduced the amount of material that leaked from the damaged gut. Taken together, the results of this study demonstrate that the C10 chemokine rapidly promotes disease resolution in the CLP model through its direct effects on the cellular events critically involved in host defense during septic peritonitis.
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Wellmer, Andreas, Joachim Gerber, Jasmin Ragheb, et al. "Effect of Deficiency of Tumor Necrosis Factor Alpha or Both of Its Receptors on Streptococcus pneumoniae Central Nervous System Infection and Peritonitis." Infection and Immunity 69, no. 11 (2001): 6881–86. http://dx.doi.org/10.1128/iai.69.11.6881-6886.2001.
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ABSTRACT Tumor necrosis factor alpha (TNF-α) and TNF-β are key mediators in bacterial inflammation. We therefore examined the role of TNF-α and its two receptors in murine pneumococcal central nervous system infection. TNF-α knockout mice and age- and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-α-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-α deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55- and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-α or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 102 CFU of S. pneumoniaeproduced fatal peritonitis in TNF-α-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-α-deficient mice. The lack of TNF-α or its receptors renders mice more susceptible to S. pneumoniae infections.
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Stolarski, Allan E., Jiann-Jyh Lai, Jiyoun Kim, Kenneth L. Rock, and Daniel Remick. "GENETIC ABLATION OF THE C-TYPE LECTIN RECEPTOR CLEC2D INCREASES PERITONITIS MORTALITY, INFLAMMATION, AND PHYSIOLOGY WITHOUT DIMINISHING ORGAN INJURY." Shock 62, no. 3 (2024): 437–46. http://dx.doi.org/10.1097/shk.0000000000002413.
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ABSTRACT Background: Sepsis accounts for substantial morbidity and mortality motivating investigators to continue the search for pathways and molecules driving the pathogenesis of the disease. The current study examined if the novel C-type lectin receptor (CLR), Clec2d, plays a significant role in the pathogenesis of sepsis. Methods: Clec2d knockout (KO) mice were fully backcrossed onto the C57/BL6 background. Acute endotoxemia was induced with an intraperitoneal injection of lipopolysaccharide (LPS). Sepsis was induced in two different models, cecal ligation and puncture (CLP) and Pseudomonas aeruginosa pneumonia. Both models were treated with antibiotics and fluid resuscitation. In the sepsis models, physiologic and hematologic measurements were measured at 24 h by collecting a small sample of peripheral blood. Mortality was followed for 14 days. Results: A total of 197 mice were studied, 58 wild type (WT) and 54 knock-out (KO) in the LPS model; 27 wild type and 21 KO mice in the CLP model; and 22 WT and 15 KO mice in the pneumonia model. Clec2d KO mice had greater mortality in the LPS and CLP studies but not the pneumonia model. There were significant differences in multiple parameters determined 24 h post sepsis between mice who subsequently died and those lived. Consistent with previous reports in the CLP model, higher concentrations of IL-6, increased numbers of peripheral blood lymphocytes and greater renal injury were found in the dying mice. In contrast, in the pneumonia model, IL-6 was higher in the surviving mice; however, the IL-6 levels in the pneumonia model (0.6 ± 0.3 ng/mL mean ± SEM) were less than 2% of the IL-6 levels of mice that died in the CLP model (41 ± 9 ng/mL, mean ± SEM). There were no differences in the lymphocyte count or renal injury between living and dying mice in the pneumonia model. In both sepsis models, dying mice had lower heart rates, respiratory rates, and body temperatures. These values were also lower in the KO mice compared to the WT in CLP, but the breath rate and body temperature were increased in the KO pneumonia mice. Conclusion: The C-type lectin receptor Clec2d plays a complicated role in the pathogenesis of sepsis, which varies with source of infection as demonstrated in the models used to study the disease. These data highlight the heterogeneity of the responses to sepsis and provide further evidence that a single common pathway driving sepsis organ injury and death likely does not exist.
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An, Xiaoyu, Kaixia Lian, Jia Zheng, Fei Jian, Henry Li та Tao Yang. "724 Evaluation of an anti-human IL-1β antibody in monosodium urate crystals-induced peritonitis model in hIL-1β HuGEMM™ mice". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (2021): A753. http://dx.doi.org/10.1136/jitc-2021-sitc2021.724.
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BackgroundGout is a chronic inflammatory disease featuring the deposition of monosodium urate (MSU) crystals in the synovial fluid of patients, followed by NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome activation and bioactive IL-1β release, which recruits neutrophils to the local inflammation sites. Blocking IL-1β function is becoming a a potent therapeutic approach for gout and gouty arthritis. Conventional MSU-induced peritonitis in C57BL/6 mice provides a simple and rapid evaluation of therapeutics targeting inflammasome activation. However, this murine model has limitations when it comes to the evaluation of human-specific antibodies, for example, anti-human IL-1β (anti-hIL-1β) monoclonal antibodies (mAb). Thus, a murine model to assess the efficacy of anti-hIL-1β mAb is needed. We have developed a hIL-1β knock-in mouse model (hIL-1β HuGEMM™), which is able to facilitate the pre-clinical evaluation of drugs targeting specific human biological molecules especially when mouse ortholog is not available. Therefore, an MSU crystals induced peritonitis model using hIL-1β HuGEMM™ mice provides a robust model to evaluate therapies targeting hIL-1β.MethodsMSU crystals were injected intraperitoneally into human IL-1β (hIL-1β) knock-in mice, where the coding sequence of mouse IL-1β was replaced by hIL-1β. Prior to MSU crystal administration, mice received treatment of either vehicle or anti-hIL-1β antibody. Six hours facilitate post MSU crystal injection, serum and lavage flushed with PBS were collected. Subsequently, cytokine protein levels in the serum were determined by MSD, and the population of polymorphonuclear leukocytes (PMNs) (live CD11b+ Ly-6GHi cells) in the lavage was analysed by flow cytometry.ResultsThe vehicle treatment group showed a dramatic increase in hIL-1β secretion and PMN leukocytes, in comparison to the group that did not receive MSU, which suggests a successful induction of acute inflammatory response in the peritoneal cavity. In contrast, mice that received a single administration of anti-hIL-1β antibody 24 hours prior to MSU injection exhibited a significantly lower level of hIL-1β when compared to the vehicle treatment group, which implies that the anti-hIL-1β mAb efficaciously neutralized hIL-1β secretion. In addition, TNF-α and IL-6, two further cytokines downstream of IL-1β, were significantly reduced in the anti-hIL-1β mAb treatment group. However, the PMN leukocyte infiltration in the anti-hIL-1β mAb treatment group did not change in comparison to the vehicle group.ConclusionsIn this study, an MSU crystals-induced peritonitis model was successfully established in hIL-1β HuGEMM mice, which has the potential to evaluate immune therapeutics with anti-hIL-1β blockades.
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Khadagwanshi, Dipika, Sonkia Trivedi, Preeti Patel, and Megha Jha. "Effect of Phaseolus vulgaris on E. coli induced peritonitis and bacteraemia in mice." Journal of Drug Delivery and Therapeutics 9, no. 4-s (2019): 310–14. http://dx.doi.org/10.22270/jddt.v9i4-s.3323.
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Infectious or non-infectious peritonitis leads to systemic inflammation due to violation of the peritoneum which is often fatal. Evidences suggest that common bean (Phaseolus vulgaris L.) is a source of nutrients and contains phenolic compounds having antioxidant activity and its consumption has been linked with improved health benefits. The aim of the present investigation was evaluate the in vitro antibacterial, antioxidant activity and protective potential of the methanolic extract of P. vulgaris in E. coli induced model of peritonitis in albino wistar rats. Rats were pre-treated with 200 mg/kg and 400 mg/kg/bwt dose for 3 days and fourth day with E. coli (1×108 CFU/ml) strain and consecutively 3 days treatment. Mortality was monitored for 14 days. After the death of rats or completion of the experiment rats were sacrifice and kidney were used for our protocol. Colonies were count and statically analysis was done. Results showed dose dependent antibacterial activity. Thus the methanolic extract of P. vulgaris exhibited significant protection against E. coli induced peritonitis in normal rats. It significantly reduced the viable cells of E. coli when inoculated in rats. Activity is attributed to flavonoids and phenolic compounds. The present study thus suggests that methanolic extract of P. vulgaris significantly reverses peritoneal infection by E. coli in rats. It can be suggest that this medicinal formulation will be used as herbal medicine with no side effects. The high content of phenolic compounds, antioxidant activity and antibacterial activity of P. vulgaris indicate that they may impart health benefits when consumed and should be regarded as a valuable source of antioxidants. Thus, consumption of P. vulgaris seed along with coats might be recommended to gaining better nutritive benefits.
 Keywords: P. vulgaris, Peritonitis, Antioxidant, Antibacterial, E. coli
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Zasłona, Zbigniew, Carlos H. Serezani, Katsuhide Okunishi, David M. Aronoff, and Marc Peters-Golden. "Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling." Blood 119, no. 10 (2012): 2358–67. http://dx.doi.org/10.1182/blood-2011-08-374207.
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Abstract Prostaglandin E2 (PGE2) is a lipid mediator that acts by ligating 4 distinct G protein–coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE2 in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE2 receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2-deficient (EP2−/−) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2−/− mice exhibited a higher percentage of F4/80high/CD11bhigh cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE2 analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2−/− mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE2/EP2/protein kinase A signaling in the suppression of macrophage maturation.
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Verma, Taru, Shamik Majumdar, Shikha Yadav, Syed Moiz Ahmed, Siva Umapathy, and Dipankar Nandi. "Cell-free hemoglobin is a marker of systemic inflammation in mouse models of sepsis: a Raman spectroscopic study." Analyst 146, no. 12 (2021): 4022–32. http://dx.doi.org/10.1039/d1an00066g.
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Dupont, Herve, Philippe Montravers, Jacqueline Mohler, and Claude Carbon. "Disparate Findings on the Role of Virulence Factors of Enterococcus faecalis in Mouse and Rat Models of Peritonitis." Infection and Immunity 66, no. 6 (1998): 2570–75. http://dx.doi.org/10.1128/iai.66.6.2570-2575.1998.
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ABSTRACT The role of Enterococcus faecalis in polymicrobial peritonitis is still debated. Virulence factors expressed in some enterococcal strains might be involved in the pathogenicity of these organisms. To clarify their role, three of these virulence factors (cytolysin, gelatinase, and aggregation substance) were studied in six isogenic strains of E. faecalis expressing various combinations of these factors. Since the pathogenic effects of enterococci are only moderate, the expression of their virulence might vary from one animal species to another and from one type of infection to another. Therefore, we evaluated these effects in two animal models, i.e., a systemic infection in mice in which we assessed the virulence of the strains in 50% lethal dose studies and a model of compartmentalized infection in rats in which the microbiologic and inflammatory effects of the strains were evaluated in monomicrobial or polymicrobial infection. In mice, significant differences were observed in the cumulative survival curves depending on the virulence factors (P < 0.0001 [log rank test]). In rats, monomicrobial infection induced only mild changes. In polymicrobial peritonitis, the virulence factors mainly increased the inflammatory response while the changes observed in the microbiologic response were minimal. The combination of two virulence factors did not significantly increase the severity of infection either in the mice model or the polymicrobial rat model. These data argue for species and model dependence of the role of the virulence factors studied here and suggest that other important factors may be involved in the pathogenicity of enterococci.
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Weber, Georg F., Sylvia Schlautkötter, Simone Kaiser-Moore, Felicitas Altmayr, Bernhard Holzmann, and Heike Weighardt. "Inhibition of Interleukin-22 Attenuates Bacterial Load and Organ Failure during Acute Polymicrobial Sepsis." Infection and Immunity 75, no. 4 (2007): 1690–97. http://dx.doi.org/10.1128/iai.01564-06.
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ABSTRACT Interleukin-22 (IL-22) is a recently discovered proinflammatory cytokine, structurally related to IL-10. Since IL-22 is induced by lipopolysaccharide in vivo, we studied the role of IL-22 in a model of polymicrobial peritonitis. Quantitative real-time reverse transcription-PCR analysis showed marked induction of IL-22 and IL-22 receptor in spleen and kidney during the course of sepsis. The biological activity of IL-22 is modulated by IL-22-binding protein (IL-22BP), which is considered a natural antagonist of IL-22. To further analyze the role of IL-22 during septic peritonitis, mice were treated with recombinant IL-22BP generated as Fcγ2a fusion protein. IL-22BP-Fc completely blocked IL-22-induced STAT3 activation in hepatocytes in vitro. Treatment of mice with IL-22BP-Fc 4 h before sepsis induction led to enhanced accumulation of neutrophils and mononuclear phagocytes and a reduced bacterial load at the site of infection. In addition, IL-22 blockade led to an enhanced bacterial clearance in liver and kidney and reduced kidney injury. These results imply an important proinflammatory role of IL-22 during septic peritonitis, contributing to bacterial spread and organ failure. IL-22 therefore appears to play an important role in the regulation of inflammatory processes in vivo.
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Ren, Yunjia, Li Hua, Xiuping Meng, et al. "Correlation of Surface Toll-Like Receptor 9 Expression with IL-17 Production in Neutrophils during Septic Peritonitis in Mice Induced byE. coli." Mediators of Inflammation 2016 (2016): 1–17. http://dx.doi.org/10.1155/2016/3296307.
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IL-17 is a proinflammatory cytokine produced by various immune cells. Polymorphonuclear neutrophils (PMNs) are the first line of defense in bacterial infection and express surface Toll-like receptor 9 (sTLR9). To study the relationship of sTLR9 and IL-17 in PMNs during bacterial infection, we infected mice withE. coliintraperitoneally to establish a septic peritonitis model for studying the PMNs response in peritoneal cavity. We found that PMNs and some of “giant cells” were massively accumulated in the peritoneal cavity of mice with fatal septic peritonitis induced byE. coli. Kinetically, the CD11b+PMNs were increased from 20–40% at 18 hours to >80% at 72 hours after infection. AfterE. coliinfection, sTLR9 expression on CD11b+and CD11b−PMNs and macrophages in the PLCs were increased at early stage and deceased at late stage; IL-17 expression was also increased in CD11b+PMNs, CD11b−PMNs, macrophages, and CD3+T cells. Using experiments ofin vitroblockage, qRT-PCR and cell sorting, we confirmed that PMNs in the PLCs did increase their IL-17 expression duringE. coliinfection. Interestingly, sTLR9−CD11b+Ly6G+PMNs, not sTLR9+CD11b+Ly6G+PMNs, were found to be able to increase their IL-17 expression. Together, the data may help understand novel roles of PMNs in septic peritonitis.
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Ishimaru, Naozumi, Kunihiro Otsuka, Takaaki Tsunematsu, Yuhji Taquahashi, and Jun Kanno. "149 Chronic Immunotoxicity of Multi-Walled Carbon Nanotubes on Macrophages via MMP-12." Annals of Work Exposures and Health 67, Supplement_1 (2023): i74. http://dx.doi.org/10.1093/annweh/wxac087.178.
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Abstract Background The toxicological effects of nanomaterials, such as multi-walled carbon nanotubes (MWCNTs), on the immune system are considerably understood. However, the precise relationship between long-term exposure to MWCNTs and chronic inflammation remains unclear. Methods and Finding In this study, exposure to Taquann-treated MWCNTs (T-CNTs) was performed using aerosols generated in an inhalation chamber. At 12 months after T-CNT exposure, alveolar inflammation with macrophage accumulation and hypertrophy of the alveolar walls were observed. The fibrotic lesions were enhanced by T-CNT exposure. The cell surface phenotype of macrophages in the bronchoalveolar lavage fluid was shifted to the M1 macrophage phenotype. In addition, the alveolar macrophages of T-CNT-exposed mice produced matrix metalloprotinase-12 (MMP-12). By contrast, a mouse model of chronic peritonitis was also established using intraperitoneal injection of T-CNTs with high dispersion efficiency. Chronic peritonitis with fibrosis was observed in T-CNT-injected mice, but not in Taquann-treated TiO2-injected mice. In vivo and in vitro experiments showed that MMP-12 of macrophages was upregulated by T-CNT to enhance fibroblast activation and profibrotic molecule expression in fibroblasts. In addition, T-CNT-induced peritonitis reduced MMP-12 expression in Nfκb1−/− mice, suggesting that MMP-12-producing macrophages play a key role in chronic inflammation due to T-CNT exposure though NF-κB activation. Conclusion These results using the two models suggest that T-MWCNT exposure promoted chronic inflammation and fibrotic lesion formation in profibrotic macrophages via MMP12 for prolonged periods. The results of this study could be helpful in understanding the molecular toxicity of nanomaterial and chronic inflammation.
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Tang, Hung-Jen, Wen-Chien Ko, Chi-Chung Chen, et al. "In Vitro and In Vivo Intracellular Killing Effects of Tigecycline against Clinical Nontyphoid Salmonella Isolates Using Ceftriaxone as a Comparator." Antimicrobial Agents and Chemotherapy 55, no. 6 (2011): 2755–59. http://dx.doi.org/10.1128/aac.01807-10.
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ABSTRACTSalmonellais an important, worldwide food-borne pathogen. Resistance to fluoroquinolones and cephalosporins has been increasingly reported, and new therapeutic agents are desperately needed. In this study, we evaluated thein vitroantimicrobial susceptibility of clinical nontyphoidalSalmonellaisolates to tigecycline. Antibacterial activity of tigecycline, ceftriaxone, and ciprofloxacin were investigated by time-kill studies and the murine peritonitis model. The MIC50/MIC90values of tigecycline, ceftriaxone, and ciprofloxacin against 76Salmonellaisolates were 0.25/0.5, 1/8, and 0.125/0.5 μg/ml, respectively. The intracellular inhibitory activity of tigecycline at 0.5 μg/ml (1× MIC) againstSalmonellaisolates in human peripheral blood mononuclear cells was sustained for 24 h. In a mouse peritonitis model, tigecycline reduced the extracellular and intracellular bacterial counts from 107CFU/ml and 105CFU/ml, respectively, to an undetectable level within 96 h. The results were similar to those obtained with ceftriaxone. The survival rate of mice exposed to tigecycline after being infected by an inoculum of 1 × 105CFU was 80%, and that of mice exposed to ceftriaxone was 100%. When the inoculum was increased to 1.3 × 106CFU, the survival rate of mice treated by tigecycline was 20%, and that of mice exposed to ceftriaxone was 0% (P= 0.2). When a ceftriaxone- and ciprofloxacin-resistant but tigecycline-susceptible isolate was tested, mice treated by tigecycline had a higher survival rate than those treated by ceftriaxone (15/20 [75%] versus 6/20 [30%];P= 0.011). Our results suggest that tigecycline is at least as effective as ceftriaxone for murineSalmonellainfections and warrants further clinical investigations to delineate its potential against humanSalmonellainfections.
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Morioka, Shin, Kiyomi Nigorikawa, Junko Sasaki, et al. "Myeloid cell-specific inositol polyphosphate-4-phosphatase type I knockout mice impair bacteria clearance in a murine peritonitis model." Innate Immunity 22, no. 6 (2016): 444–51. http://dx.doi.org/10.1177/1753425916652714.
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Phosphatidylinositol 3-kinase (PI3K)/Akt signaling has been implicated in the anti-inflammatory response in a mouse model of endotoxemia and sepsis. The present study focused on the role of inositol polyphosphate-4-phosphatase type I (Inpp4a), which dephosphorylates PtdIns(3,4)P2 to PtdIns(3)P, in bacterial infections. We prepared myeloid cell-specific Inpp4a-conditional knockout mice. Macrophages from these mice showed increased Akt phosphorylation and reduced production of inflammatory cytokines in response to LPS or Escherichia coli in vitro. The Inpp4a knockout mice survived for a shorter time than wild type mice after i.p. infection with E. coli, with less production of inflammatory cytokines. Additionally, E. coli clearance from blood and lung was significantly impaired in the knockout mice. A likely mechanism is that the Inpp4a-catalyzed dephosphorylation of PtdIns(3,4)P2 down-regulates Akt pathways, which, in turn, increases the production of inflammatory mediators. This mechanism at least fits the decreased E. coli clearance and short survival in the Inpp4a knockout mice.
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Ulyanova, Tatiana, Ena R. Banerjee, Gregory V. Priestley, Linda Scott, and Thalia Papayannopoulou. "Migration Defects of Leukocytes from Alpha4 or Beta2 Integrin-Deficient Mice during Aseptic Peritonitis." Blood 104, no. 11 (2004): 2387. http://dx.doi.org/10.1182/blood.v104.11.2387.2387.
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Abstract Leukocyte migration to the inflammatory sites involves a dynamic and coordinated sequence of adhesion/ migration events, in which the α4 and β2 integrins in leukocytes play critical roles. In a model of aseptic peritonitis, normal mice respond with an initial influx of neutrophils followed by later recruitment of mononuclear cells. Previous studies used antibodies to inhibit α4 integrins in this model and provided only early observations (up to 24 hrs). Events at later stages were not addressed. To clarify the role of α4 integrins in this process, we induced aseptic peritonitis in α4-ablated (α4−/ −) mice and compared the results to similarly treated wild type (WT), and β2 integrin-deficient (β2−/ −) animals. A 4, 16 and 96 hrs post thioglycollate injection, leukocytes, harvested from the peritoneal cavity, were counted and evaluated by FACS and by differentials in smears. 3-5 animals per time point per genotype were analyzed. Early neutrophil accumulation in the peritoneum was similar in WT and α4−/ − mice (Table 1). β2−/ − mice were slow to accumulate neutrophils, but at 16 hrs the peaks were not different from α4−/ − or WT animals. However at later times in both α4−/ − and β2−/ − mice neutrophils persisted longer, suggesting either increased survival or prolonged recruitment. At 16 hrs large numbers of monocyte/ macrophages accumulated in the peritoneum and they were similar in all groups of mice up to 96 hours. The cumulative number of leukocytes in the peritoneum was compared to the concurrent circulating pool of leukocytes in each mouse group. At the peak time (16 hrs) the fraction recovered in the WT represented 394±148%, while in the α4−/ − mice it was 98±33% and in the β2−/ − mice it was 40±19%. Thus, although sufficient numbers of leukocytes accumulated in the peritoneum of both integrin-deficient mice, migration in the WT mice was significantly higher than that observed in the other two genetic models, suggesting impairment in animals with either integrin deficiency. Furthermore, lymphocyte accumulation was dramatically decreased at all time points in the α4−/ − mice (Table 2). Preliminary data in a model of combined, α4- and β2-integrin deficiency, generated in our laboratory, showed that only 3±2% of circulating leukocytes migrated into the peritoneum. Taken together, our results indicate that (1) for migration into peritoneum, neutrophils and monocyte/ macrophages can use α4 and β2 integrins interchangeably, (2) for optimal migration both integrins are needed, and (3) lymphocytes have an absolute requirement of α4 integrins for migration. These data extend previous knowledge on kinetic changes of leukocytes accumulating in the aseptic peritonitis model. Whether different kinetic changes are seen in other inflammatory models using our integrin-deficient animals requires further studies. Accumulation of myeloid cells in peritoneum Neutrophils Monocyte/macrophages 4 hrs 16 hrs 96 hrs 4 hrs 16 hrs 96 hrs WT 5.5±0.5 9.8±7.4 0.2±0.04 3.1±0.6 17.7±3.9 11.0±5.2 β2−/ − 2.5±0.8 10.5±5.3 3.7±1.6 4.7±1.3 12.8±5.2 11.0±4.0 α4−/ − 5.2±2.1 9.8±7.4 0.8±0.4 4.6±1.1 11.0±5.2 12.6±5.1 Lymphocyte accumulation in peritoneum 4 hrs 16 hrs 96 hrs Cell number (x106) in peritoneum at various time points; in bold are the numbers that significantly differ from the WT for each time point (p&lt;0.05) WT 2.7±1.2 2.5±0.3 3.1±0.5 β2−/ − 6.7±1.7 4.7±1.2 3.3±1.0 α4−/ − 0.5±0.1 0.4±0.1 0.6±0.1
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Celik, Ilhan, Cordula Stover, Marina Botto, et al. "Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis." Infection and Immunity 69, no. 12 (2001): 7304–9. http://dx.doi.org/10.1128/iai.69.12.7304-7309.2001.
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ABSTRACT The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.
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Echtenacher, Bernd, Karin Weigl, Norbert Lehn, and Daniela N. Männel. "Tumor Necrosis Factor-Dependent Adhesions as a Major Protective Mechanism Early in Septic Peritonitis in Mice." Infection and Immunity 69, no. 6 (2001): 3550–55. http://dx.doi.org/10.1128/iai.69.6.3550-3555.2001.
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ABSTRACT The occurrence of peritoneal adhesions in surgical patients is positively correlated with tumor necrosis factor (TNF) levels. In a model of septic peritonitis—cecal ligation and puncture—TNF neutralization prevented formation of peritoneal adhesions and increased mortality, most likely because localization of the septic focus was prevented. To discriminate between the coagulation-independent protective TNF effect and a potential protective procoagulant TNF effect, formation of peritoneal adhesions after CLP was inhibited with heparin, hirudin, or urokinase. Each treatment increased mortality and increased the number of bacteria in the peritoneal lavage fluid, kidney, and liver to various degrees. Under these experimental conditions, antibiotics prevented death. In coagulation-compromised mice, lethality was further enhanced by additional TNF neutralization. These findings demonstrate that peritoneal adhesions early in septic peritonitis are an important mechanism of innate immunity that prevents increased spread of bacteria and reduces mortality.
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Bahrami, Maryam, Ali Ghazavi, Ali Ganji, and Ghasem Mosayebi. "Observing the Anti-oxidant and Anti-inflammatory Effect of Nigella Sativa Combined With Silybum Marianum Extracts on the Acute Peritonitis Mouse Model." Journal of Arak University Medical Sciences 24, no. 3 (2021): 372–85. http://dx.doi.org/10.32598/jams.24.3.6154.1.
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Background and Aim: In addition to free radicals such as Nitric Oxide (NO), inflammation is one of the most important pathophysiological causes of peritonitis. Over thousands of years, Nigella Sativa (NS) and Silybum Marianum (SM) are two plants known for their anti-oxidant and anti-inflammatory properties. However, the effect of its compound is unclear. Thus, in this study, we evaluated the anti-inflammatory effect of NS and SM extracts and their combination on inflammatory diseases like thioglycollate peritoneal. Methods & Materials: Alcoholic extracts of SM and NS were obtained by the soxhlet method. Male Balb/C mice were divided into 5 groups and gavage orally for 14 days with SM, NS, the mixture of extracts of these two, DMSO 30% as the control group, and dexamethasone as the positive control group. The safety profile and acute toxicity in mice were assessed. On day 10, acute peritonitis was induced by thioglycollate 3%. Finally, the total anti-oxidant power and NO concentration were measured by FRAP and Griess method, respectively, in the serum of treated mice. Ethical Considerations: All experimental process was performed following the guidelines according to the Animal Ethics Committee of Arak University of Medical Sciences (IR.ARAKMU.REC.1397.359). Results: Acute toxicity test showed no significant changes in weight and physical appearance of the mice. However, the extract and their mixture decreased NO level significantly (P=0.000) in serum. Also, the mixture significantly increased total anti-oxidant power (P=0.015). Conclusion: Results showed that the SM and NS extract mixture demonstrated anti-inflammatory activity, inhibiting inflammatory mediators such as NO and increasing anti-oxidant power, thus supporting its therapeutic potential in slowing down inflammatory processes in inflammation disorders.
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Mullins, Eric S., Maureen A. Shaw, Zhen Gao та Matthew J. Flick. "Plasmin-Mediated Fibrinolysis Enables Macrophage Migration Via Liberation from Fibrin-αMβ2 Interactions". Blood 132, Supplement 1 (2018): 136. http://dx.doi.org/10.1182/blood-2018-99-117018.
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Abstract Mounting evidence ties both fibrin(ogen) and plasmin(ogen) to inflammatory diseases. Indeed, both fibrin(ogen) and plasmin(ogen) have been linked to critical macrophage functions in multiple disease processes. Migration of macrophages to sites of sterile inflammation is, at least partially, dependent on plasmin(ogen). Mice lacking plasminogen, when challenged with sterile thioglycollate-induced peritonitis, have both diminished overall leukocyte migration and decreased macrophage migration. Additionally, macrophage migration defects have been identified in both mice lacking plasminogen and plasminogen receptors. Plasmin has many targets that may play a role in supporting macrophage migration. In addition to proteolysis of fibrin(ogen), plasmin activates matrix metalloprotease (MMP) 2 and MMP9 and cleaves collagen and laminin. Indeed, mice that lack MMP9 have a migration defect similar to mice that lack plasminogen, suggesting that MMP9 is a biologically relevant proteolytic target in this context. To further examine the targets of plasmin that regulate macrophage migration, we challenged animals that have individual and combined genetic deficiencies in fibrinogen and plasminogen with thioglycollate-induced peritonitis. We have found that mice that lack fibrinogen alone have a significantly increased migration of macrophages to the peritoneal cavity. Mice that lack plasminogen alone demonstrated the expected diminution in macrophage migration to the peritoneal cavity. However, mice that were deficient in both plasminogen and fibrinogen demonstrated macrophage migration that was indistinguishable from wildtype. These data suggest that fibrin(ogen) impedes macrophage migration to the peritoneal cavity. To further confirm this mechanism, we examined macrophage migration in a transwell assay in vitro. Here, a macrophage cell line (RAW 264.7 or BMDM) migration was examined in the absence and presence of fibrin matrices. Macrophages, in the presence of plasminogen, did demonstrate a modest, but statistically significant, increase in migration across the transwell membrane in the absence of fibrinogen. When a fibrin matrix was generated on the transwell membrane, macrophages were essentially unable to cross in the absence of plasminogen. These data further support the concept that macrophages require plasmin(ogen) to cross fibrin matrices. We further sought to determine if the fibrin-αMβ2 interaction was implicated in the macrophage migration phenotype. To do this, we first examined macrophage migration in vivo in mice expressing a form of fibrinogen that cannot interact with αMβ2, Fibγ390-396A mice. Similar to mice lacking fibrinogen, an increase in peritoneal macrophages was observed at 72 hours following a challenge with 4% thioglycollate. To confirm that this was related to the fibrin-αMβ2 interaction, and not due to abnormal factor XIII crosslinking, factor XIII deficient animals were also challenged with thioglycollate induced peritonitis. Mice lacking factor XIII exhibited no difference from wildtype in this model of peritonitis. We further confirmed in the in vitro transwell migration assay that macrophages were able to cross a fibrin barrier, derived from Fibγ390-396A mice, in the absence of plasminogen. Taken together, these data suggest that plasmin allows macrophage migration via liberation from the fibrin-αMβ2 interaction. Disclosures Mullins: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Lee, H. Thomas, Mihwa Kim, Jin Deok Joo, George Gallos, Jiang-Fan Chen, and Charles W. Emala. "A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 4 (2006): R959—R969. http://dx.doi.org/10.1152/ajpregu.00034.2006.
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The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-α 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5′ N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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Shi, Ming, XIAOJUN ZHANG, KAI FU, et al. "MARVELD1 promotes survival during septic shock in mice." Journal of Immunology 200, no. 1_Supplement (2018): 109.26. http://dx.doi.org/10.4049/jimmunol.200.supp.109.26.
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Abstract MARVELD1 is integral to the inflammatory response occurring during septic shock, although its precise function has yet to be determined. Here we show that compared with wildtype mice, listeria monocytogenes (LM)-induced septic shock in MARVELD1 knockout mice resulted in a heightened pro-inflammatory response and increased mortality. This observation was associated with impaired bacterial clearance related to marked inhibition of the macrophage phagocytic acitivity in MARVELD1 knockout mice. Consistently, the MARVELD1 knockout mice were more sensitive to a lethal endotoxin or LM challenge, while wildtype mice in the bacterial peritonitis model produced a significant survival benefit. These data highlight the crucial role of the MARVELD1 pathway in inducing an adequate macrophage response to polymicrobial sepsis, and both the therapeutic promise and potential risks of its modulation.
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Manuilov, M. B., A. V. Martynov, N. I. Sklyar, V. V. Minukhin, M. S. Biryukov, and A. M. Manuilov. "IOON ONE MED Device Generates Singlet Hydrogen and Active Chlorine to Exhibit Antimicrobial Activity – an Experimental Study." Mikrobiolohichnyi Zhurnal 86, no. 6 (2024): 42–54. https://doi.org/10.15407/microbiolj86.06.042.
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The aim of the study was to investigate the in vitro antimicrobial activity against museum and circulating strains of microorganisms and fungi of an aqueous solution generated by the IOON ONE MED device containing atomic hydrogen and atomic (active) chlorine at a concentration of 1 mg/L as active substances and in vivo on a standardized model of purulent peritonitis in two variants – prophylactic (neutralization of bacteria) and therapeutic (effect on advanced infection). Methods. Microbiological methods were used to study the antimicrobial activity of new substances in vitro on museum and circulating strains of microorganisms, as well as fungi. The ability of the generated solution to exhibit antibiofilm effects on intubation tubes infected with resistant microorganisms was studied separately. In vivo study of the efficacy of the generated solution on a model of purulent peritonitis in mice was also conducted in two ways – by using the solution as a prophylactic agent (mixing live bacteria with the solution and then immediately testing the ability of bacteria to induce peritonitis) and by therapeutic effect by injecting the solution 3 hours after infection of mice and determining the number of surviving mice. Results. The results showed that the solution produced by the device worked as well as 0.05 % chlorhexidine and 3 % hydrogen peroxide. From the in vivo studies, it can be concluded that the drug under investigation does not cause acute toxicity: the injection of 1 mL of the generated solution intraperitoneally did not lead to the death of any mice. It was found that mixing 1:1 of the solution generated by the IOON ONE MED device with a suspension of P. aeruginosa #2261 and subsequent intraperitoneal injection into mice ensured 100 % survival of animals compared to 100 % mortality in the control group. When the mice were injected with the intraperitoneal solution three hours after infection with a lethal dose of the resistant hospital strain of P. aeruginosa #2261, a 40 % survival rate was observed compared to 100% mortality in the control group. The difference between the control and experimental groups was statistically significant. Conclusions. The solution generated by the IOON ONE MED device, containing atomic hydrogen and atomic chlorine, when used in combination, has strong antiseptic properties and has promising application for surface disinfection, despite its short residence time in solution.
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Knudsen, Jenny Dahl, Kurt Fuursted, Susan Raber, Frank Espersen, and Niels Frimodt-Møller. "Pharmacodynamics of Glycopeptides in the Mouse Peritonitis Model of Streptococcus pneumoniae orStaphylococcus aureus Infection." Antimicrobial Agents and Chemotherapy 44, no. 5 (2000): 1247–54. http://dx.doi.org/10.1128/aac.44.5.1247-1254.2000.
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ABSTRACT The emergence of resistance to various antibiotics in pneumococci leaves the glycopeptides as the only antibiotics against which pneumococci have no resistance mechanism. This situation has led to a renewed interest in the use of glycopeptides. It has not yet been possible to conclude which one or more of the pharmacokinetic or pharmacodynamic (PK/PD) parameters are the most important and best predictors for the effects of treatment with glycopeptides in animal models or in humans. We used the mouse peritonitis model with immunocompetent mice and with Staphylococcus aureus and Streptococcus pneumoniae as infective organisms. A wide spectrum of different treatment regimens with vancomycin and teicoplanin was tested to study the pharmacodynamics of these drugs. In studies in which the single dose that protected 50% of lethally infected mice (ED50) was given as one dose or was divided into two doses, survival was significantly decreased when the dose was divided. The only statistically significant correlations between the percentage of survival of the mice after 6 days and each of the PK/PD parameters were for peak concentration (C max)/MIC and S. aureus and for the free fraction of C max(C max-free)/MIC and S. pneumoniae. For S. pneumoniae, the ED50 for different dosing regimens increased with the number of doses given; e.g., the single-dose ED50s for vancomycin and teicoplanin were 0.65 and 0.45 mg/kg, respectively, but the ED50s for dosing regimens with 2-h doses given for 48 h were 6.79 and 5.67 mg/kg, respectively. In experiments with 39 different vancomycin dosing regimens and 40 different teicoplanin dosing regimens against S. pneumoniae, the different PK/PD parameters were analyzed using logistic regression. The C max-free/MIC was one of two parameters that best explained the effect for both drugs; for vancomycin, the other important parameter was the AUC/MIC, and for teicoplanin, the other parameter was the time the free fraction of the drug is above the MIC. The effect analyzed as a function ofC max-free/MIC disclosed thresholds with shifts from almost no effect to full effect at ratios of five to six for vancomycin and two to three for teicoplanin.
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Aragão, Gislei Frota, Dayanne Terra Tenório Nonato, Edson Lopes da Ponta, et al. "Protective effects of ethanolic extract from the red algae Amansia multifida on experimental inflammation, nociception and seizure experimental models." Acta Scientiarum. Biological Sciences 38, no. 4 (2016): 465. http://dx.doi.org/10.4025/actascibiolsci.v38i4.32361.
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This study aimed to investigate the EEAm effect in mice models of nociception, inflammation and in behavioral tests evaluating the central nervous system. EEAm had inhibitory effects in the following tests: acetic acid-induced writhing (78%); formalin (62% - inflammatory phase); open field (46%). EEAm increased the nociceptive latency (56%) in tail flick test and increased the death-latency by 36% in the pentylenetetrazole-induced seizure model. Moreover, EEAm inhibited paw edema (82%) and peritonitis (45%) induced by carrageenan. In conclusion, EEAm presents antinociceptive, anti-inflammatory and anticonvulsant effects involving peripheral and central-acting mechanisms in mice.