TY - JOUR
T1 - Both the H2S biosynthesis inhibitor aminooxyacetic acid and the mitochondrially targeted H2S donor AP39 exert protective effects in a mouse model of burn injury
AU - Ahmad, Akbar
AU - Szabo, Csaba
N1 - Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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-dithiol-5-yl)phenoxy]decyl]triphenyl-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 24 h 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 (TNFα, IL-1β, IL-6, IL-10, MCP-1, MIP-2, VEGF and IFNγ) 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.
AB - 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-dithiol-5-yl)phenoxy]decyl]triphenyl-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 24 h 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 (TNFα, IL-1β, IL-6, IL-10, MCP-1, MIP-2, VEGF and IFNγ) 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.
KW - Hydrogen sulfide
KW - Inflammation
KW - Nitric oxide
KW - Shock
KW - Thermal injury
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U2 - 10.1016/j.phrs.2016.09.013
DO - 10.1016/j.phrs.2016.09.013
M3 - Article
C2 - 27639598
AN - SCOPUS:84987920198
SN - 1043-6618
VL - 113
SP - 348
EP - 355
JO - Pharmacological Research
JF - Pharmacological Research
ER -