Ahmad Akbar, Gerö Domokos, Olah Gabor, Szabo Csaba
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555‑1102, USA.
Int J Mol Med. 2016 Dec;38(6):1683-1692. doi: 10.3892/ijmm.2016.2771. Epub 2016 Oct 14.
Hydrogen sulfide (H2S) has been proposed to exert pro- as well as anti-inflammatory effects in various models of critical illness. In this study, we compared bacterial lipopolysaccharide (LPS)‑induced changes in inflammatory mediator production, indices of multiple organ injury and survival in wild‑type (WT) mice and in mice with reduced expression of one of the three H2S‑producing enzymes, cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) or 3-mercaptopyruvate sulfurtransferase (3MST). Mice were injected intraperitoneally (i.p.) with LPS (10 mg/kg). After 6 h, the animals were sacrificed, blood and organs were collected and the following parameters were evaluated: blood urea nitrogen (BUN) levels in blood, myeloperoxidase (MPO) and malondialdehyde (MDA) in the lung, cytokine levels in plasma and the expression of the three H2S‑producing enzymes (CBS, CSE and 3MST) in the spleen, lung, liver and kidney. LPS induced a tissue‑dependent upregulation of some of the H2S‑producing enzymes in WT mice (upregulation of CBS in the spleen, upregulation of 3MST in the liver and upregulation of CBS, CSE and 3MST in the lung). Moreover, LPS impaired glomerular function, as evidenced by increased BUN levels. Renal impairment was comparable in the CSE‑/‑ and Δ3MST mice after LPS challenge; however, it was attenuated in the CBS+/‑ mice. MPO levels (an index of neutrophil infiltration) and MDA levels (an index of oxidative stress) in lung homogenates were significantly increased in response to LPS; these effects were similar in the WT, CBS+/‑, CSE‑/‑ and Δ3MST mice; however, the MDA levels tended to be lower in the CBS+/‑ and CSE‑/‑ mice. LPS induced significant increases in the plasma levels of multiple cytokines [tumor necrosis factor (TNF)α, interleukin (IL)‑1β, IL‑6, IL‑10, IL‑12 and interferon (IFN)γ] in plasma; TNFα, IL‑10 and IL‑12 levels tended to be lower in all three groups of animals expressing lower levels of H2S‑producing enzymes. The survival rates after the LPS challenge did not show any significant differences between the four animal groups tested. Thus, the findings of this study indicate that a deficiency in 3MST does not significantly affect endotoxemia, while a deficiency in CBS or CSE slightly ameliorates the outcome of LPS-induced endotoxemia in vivo.
硫化氢（H₂S）在各种危重病模型中被认为具有促炎和抗炎作用。在本研究中，我们比较了细菌脂多糖（LPS）诱导的野生型（WT）小鼠以及三种产H₂S酶（胱硫醚-γ-裂解酶（CSE）、胱硫醚-β-合酶（CBS）或3-巯基丙酮酸硫转移酶（3MST））之一表达降低的小鼠炎症介质产生、多器官损伤指标和存活率的变化。小鼠腹腔注射（i.p.）LPS（10 mg/kg）。6小时后，处死动物，收集血液和器官，并评估以下参数：血液中的血尿素氮（BUN）水平、肺中的髓过氧化物酶（MPO）和丙二醛（MDA）、血浆中的细胞因子水平以及脾脏、肺、肝脏和肾脏中三种产H₂S酶（CBS、CSE和3MST）的表达。LPS诱导WT小鼠中一些产H₂S酶的组织依赖性上调（脾脏中CBS上调、肝脏中3MST上调以及肺中CBS、CSE和3MST上调）。此外，LPS损害肾小球功能，BUN水平升高证明了这一点。LPS攻击后，CSE⁻/⁻和Δ3MST小鼠的肾功能损害相当；然而，CBS⁺/⁻小鼠的肾功能损害有所减轻。肺匀浆中的MPO水平（中性粒细胞浸润指标）和MDA水平（氧化应激指标）因LPS而显著升高；这些作用在WT、CBS⁺/⁻、CSE⁻/⁻和Δ3MST小鼠中相似；然而，CBS⁺/⁻和CSE⁻/⁻小鼠中的MDA水平往往较低。LPS诱导血浆中多种细胞因子[肿瘤坏死因子（TNF）α、白细胞介素（IL）-1β、IL-6、IL-10、IL-12和干扰素（IFN）γ]水平显著升高；在所有三组产H₂S酶表达较低的动物中，TNFα、IL-10和IL-12水平往往较低。LPS攻击后的存活率在测试的四组动物之间没有显示出任何显著差异。因此，本研究结果表明，3MST缺乏不会显著影响内毒素血症，而CBS或CSE缺乏会在体内略微改善LPS诱导的内毒素血症的结果。
