Prophylactic ALA Administration Attenuates Liver and Lung Injury in CLP-Induced Sepsis in Mice Through CSE/H2S Dependent Pathways

Sepsis is a life-threatening syndrome characterized by a dysregulated host immune response to infection. Sepsis development usually results in organ dysfunction and multiple organ failure, including the liver and lungs. Alpha-lipoic acid (ALA) is a well-known anti-inflammatory agent. However, its effects on the endogenous cystathionine γ-lyase/hydrogen sulfide (CSE/H2S) pathway during cecal ligation and puncture (CLP)-induced sepsis remain unclear. In this study, the protective effects of ALA in wild-type (WT) and CSE knockout (CSE−/−) mice were investigated. Mice were randomly divided into six experimental groups, including (a) WT sham (b) CSE−/− sham (c) WT CLP (d) CSE−/− CLP (e) WT CLP + ALA.P and (f) CSE−/− CLP + ALA.P (n = 8 in each group). ALA (100 mg/kg) was administered intraperitoneally one hour before CLP surgery. Eight hours after CLP induction, mice were euthanized, and blood, liver and lung tissues were collected. Body weight changes, proinflammatory cytokine and chemokine concentrations (including tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 alpha (MIP-2α), myeloperoxidase (MPO) activity, histopathological changes, plasma H2S concentrations, and CSE expression in the liver and lung were measured. Severe liver and lung damage was characterized by markedly increased levels of MCP-1, MIP-2 α, TNF-α, and myeloperoxidase (MPO) activity, compared to WT sham control and CSE−/− groups (p < 0.0001). WT CLP-induced septic mice showed liver and lung injury as evidenced by hepatocyte swelling and ballooning degeneration with liver sinusoidal congestion, as well as pulmonary intra-alveolar and interstitial edema associated with thickening of alveolar septa and leucocyte infiltration, as compared to WT sham control and CSE−/− groups (p < 0.001). The WT-CLP group also showed a significant increase in hepatic and pulmonary expression of the H2S-producing enzyme (CSE) with elevated levels of plasma H2S concentrations, as compared to the WT sham group (p < 0.0001). Prophylactic ALA administration markedly improved these changes in the WT group. ALA also significantly decreased plasma H2S concentrations and hepatic and pulmonary CSE expression as compared to the WT CLP group (p < 0.01). However, ALA administration did not confer additional significant protective effects in CSE−/− mice, which supports the hypothesis that the effects of ALA are mediated through the modulation of the CSE/H2S pathway. In conclusion, this is the first experimental evidence showing that ALA prevents sepsis-associated organ injury at least partly by the downregulation of hepatic and pulmonary cystathionine γ-lyase expression.