Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone resulted in highly elevated lethality of septic peritonitis. ⋯ These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.
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In the present study, we investigated the signaling pathways involved in the inhibition of cyclooxygenase 2 (COX-2) and iNOS by moscatilin under LPS challenge in murine macrophage-derived cell line RAW264.7. The results showed that moscatilin (10-100 microM) had a significant inhibition in a concentration-dependent manner on proinflammatory enzymes (COX-2 and iNOS) expression and macrophage activation under LPS (100 ng/mL) treatment. Hypoxia-inducible factor 1 (HIF-1)alpha was reported to initiate inflammation under cytokine stimulation or hypoxic conditions. ⋯ Moreover, the results showed that moscatilin suppressed nuclear translocation of nuclear factor (NF)-kappaB subunits, p65 and p50, and NF-kappaB activity by inhibiting phosphorylation of inhibitor of kappaBalpha. Taken together, we demonstrated that moscatilin inhibited both COX-2 and iNOS expressions after LPS treatment in RAW264.7. Furthermore, the inhibition of moscatilin seemed to be dependent on the repression of HIF-1alpha accumulation and NF-kappaB activation.
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Neutrophil elastase plays an important role in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC) in sepsis. Sivelestat is a selective neutrophil elastase inhibitor. It is possible that sivelestat improves the outcome of septic patients associated with ARDS and DIC. ⋯ A stepwise multiple logistic-regression analysis showed the sivelestat administration to be an independent predictor of survival of the septic patients associated with both ARDS and DIC. The length of ICU stay of the sivelestat group was significantly shorter than that of the control group. In addition, sivelestat administration was found to be an independent predictor of survival of those patients.
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Crocetin, a constituent of saffron, has been shown not only to prevent reactive oxygen species-induced hepatotoxicity and genotoxicity but also to increase whole-body oxygen consumption and survival. The present study was to determine whether crocetin has beneficial effects on cardiac injury caused by hemorrhagic shock and resuscitation in rats. Anesthetized rats were bled to reduce mean arterial pressure (MAP) to 35 +/- 5 mmHg for 60 min and then resuscitated with their withdrawn shed blood and isotonic sodium chloride solution. ⋯ Myocardial nuclear factor-kappaB activity, iNOS activity, NO, malondialdehyde, TNF-alpha, and IL-6 were significantly elevated, whereas T-SOD activity was suppressed in the control group if compared with those of sham animals. These parameters tended to be normalized in rats administered crocetin. These results suggest that crocetin blocks inflammatory cascades by inhibiting reactive oxygen species production and preserving T-SOD activity to ameliorate the cardiac injury caused by hemorrhage/resuscitation.