Carbon Monoxide and Mitochondrial Quality Control in Sepsis-induced Lung Injury

急性肺损伤（ALI）和多器官功能障碍综合征（MODS）是ICU中脓毒症导致死亡的主要原因。最初存活的患者随后可能死于免疫麻痹，其特征在于对涉及抑制NF-κ B依赖性促炎细胞因子合成的反调节细胞因子的过度表达的机制知之甚少。脓毒症诱导血红素加氧酶-1（HO-1; Hmox 1），其具有特异性抗炎作用，例如通过一氧化碳（CO）介导的IL-10产生，并对线粒体生物合成的转录网络施加强有力的控制， 通过改善线粒体质量和促进受损细胞器的清除来保护能量代谢（线粒体自噬）。我们的初步数据表明，HO-1/CO上调细胞因子信号转导抑制因子-3（SOCS 3）、炎性小体抑制因子/抗凋亡蛋白BCIXL、DNA损伤调节自噬调节蛋白1（Drami）以及线粒体自噬基因NIX和BNIP 3。这些信息表明，H 0 -1/C 0系统通过涉及SOCS 3、BCIXL和Drami的机制将线粒体生物发生、线粒体自噬和抗炎联系起来。我们推测线粒体生物合成的转录网络通过HO-1/CO依赖的NFE 2 I2和NRF-1激活来调节抗炎反应，导致IL 10和SOCS 3的上调，线粒体自噬的激活。以及抑制炎性小体介导的IL-1 B产生和抑制细胞凋亡。 使用金黄色葡萄球菌（S.金黄色葡萄球菌）脓毒症和肺炎在小鼠和相关细胞模型中的两个机制分子目标，并通过第三个目标，我们将解决线粒体质量控制的这种整合过程如何减轻肺和肝脏炎症并加速脓毒症的解决。这些目标的完成和这一假设的成功测试将允许我们在实验和临床上对脓毒症诱导的器官衰竭的理解和方法的范式转变，以及临床前测试CO作为改善ALI和MODS中线粒体质量控制的一种方式。

Acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS) is a major cause of sepsis-induced mortality in the ICU. Patients who initially survive may subsequently die with immune paralysis characterized by poorly understood mechanisms involving the over-expression of counter-regulatory cytokines that suppress NF-KB-dependent pro-Inflammatory cytokine synthesis. Sepsis induces heme oxygenase-1 (HO-1; Hmox1), which has specific anti-inflammatory effects, e.g. via carbon monoxide (CO) mediated IL-10 producfion, and exerts powerful control over the transcriptional network of mitochondrial biogenesis, which safeguards energy metabolism by improving mitochondrial mass and promoting clearance of damaged organelles {mitophagy). Our preliminary data demonstrate that HO-1/CO up-regulates the suppressor of cytokine signaling-3 (S0CS3), the inflammasome inhibitor/anti-apoptotic protein BCIXL, DNA damage regulated autophagy modulator protein 1 (Drami), and the mitophagy genes NIX and BNIP3. This information suggests that the H0-1/C0 system links mitochondrial biogenesis, mitophagy, and counter inflammation through mechanisms involving S0CS3, BCIXL and Drami. We hypothesize that the transcriptional network of mitochondrial biogenesis regulates the anti-inflammatory response through HO-1/CO-dependent NFE2I2 and NRF-1 activation, leading to up-regulation of IL10 and S0CS3, activation of mitophagy. and suppression of inflammasome-mediated IL-1 B production and suppression of apoptosis. Using Staphylococcal aureus (S. aureus) sepsis and pneumonia in mice and relevant cell models in two mechanistic molecular Aims, and through a translafional third Aim, we will address how this integrated process of mitochondrial quality control mitigates lung and liver inflammation and hastens the resolution of sepsis. Completion of these Aims and a successful test of this hypothesis would allow a paradigm shift in our understanding and approach to sepsis-induced organ failure both experimentally and clinically, as well as test CO pre-clinically as a way to improve mitochondrial quality control in ALI and MODS.