Journal
PHARMACOLOGICAL RESEARCH
Volume 113, Issue -, Pages 348-355Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2016.09.013
Keywords
Hydrogen sulfide; Thermal injury; Shock; Inflammation; Nitric oxide
Categories
Funding
- Shriners of North America [85800]
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Hydrogen sulfide (H2S) exerts beneficial as well as deleterious effects in various models of critical illness. Here we tested the effect of two different pharmacological interventions: (a) inhibition of H2S biosynthesis using the cystathionine-beta-synthase (CBS)/cystathionine-gamma-lyase (CSE) inhibitor aminooxyacetic acid (AOAA) and the mitochondrially targeted H2S donor [10-oxo-10-[4-(3-thioxo-3H-1,2-dithio1-5-yl)phenoxy]decylltriphenyl-phosphonium (AP39). A 30% body surface area burn injury was induced in anesthetized mice; animals were treated with vehicle, AOAA (10 mg/kg i.p. once or once a day for 6 days), or AP39 (0.3 mg/kg/day once or once a day for 6 days). In two separate groups, animals were sacrificed, at 24h post-burn or on Day 7 post-burn, blood and lungs were collected and the following parameters were evaluated: myeloperoxidase (MPO) and malondialdehyde (MDA) in lung homogenates, plasma cytokines (Luminex analysis) and circulating indicators of organ dysfunction (Vetscan analysis). Lung MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) were significantly increased in response to burn injury both at 24 h and at 7 days; both AOAA and AP39 attenuated these increases. From a panel of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, IL-10, MCP-1, MIP-2, VEGF and IFN gamma) in the plasma, IL-6 and IL-10 levels were markedly elevated at 24 h and VEGF was slightly elevated. IL-6 remained highly elevated at 7 days post-burn while IL-10 levels decreased, but remained slightly elevated over baseline 7 days post-burn. The changes in cytokine levels were attenuated both by AP39 and AOAA at both time points studied. The burn-induced increases in the organ injury markers ALP and ALT, amylase and creatinine were reduced by both AOAA and AP39. We conclude that both H2S biosynthesis inhibition (using AOAA) and H2S donation (using AP39) suppresses inflammatory mediator production and reduces multi-organ injury in a murine model of burn injury, both at an early time point (when systemic H2S levels are elevated) and at a later time point (at which time systemic H2S levels have returned to baseline). These findings point to the complex pathogenetic role of H2S in burns. (C) 2016 Elsevier Ltd. All rights reserved.
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