Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice
Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice
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DOI：
10.1172/jci32730
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Perrella, Mark A.
中科院分区：
文献类型：
--
作者：
Chung, Su Wol;Liu, Xiaoli;Perrella, Mark A.
脓毒症的特征是对严重感染的全身反应。虽然脓毒症的炎症阶段有助于根除感染，但如果不加以控制，可能会产生有害的后果。针对脓毒症炎症介质的治疗几乎没有成功，并且有可能损害先天性抗菌防御。血红素加氧酶-1（HO-1）及其酶促反应产物CO具有有益和炎症特性，但对它们在微生物脓毒症中的作用知之甚少。在这里，我们已经证明，在微生物脓毒症，HO-1衍生的CO在抗菌过程中起着重要的作用，而不抑制炎症反应。HO-1缺陷型小鼠因多微生物败血症而遭受过度致死。将HO-1靶向血管和肠的SMC和肌成纤维细胞改善了与粪肠球菌感染相关的脓毒症诱导的死亡，但不是大肠杆菌感染。HO-1表达的增加并不抑制循环炎性细胞或其在损伤部位的积累，但确实通过增加吞噬作用和内源性抗菌反应来增强细菌清除。此外，注射CO释放分子到WT小鼠中增加了吞噬作用，并从败血症诱导的致死性中拯救了HO-1缺陷小鼠。这些数据主张HO-1衍生的CO作为宿主对脓毒症的防御反应的重要介质，并建议CO给药作为疾病的可能治疗。
Sepsis is characterized by a systemic response to severe infection. Although the inflammatory phase of sepsis helps eradicate the infection, it can have detrimental consequences if left unchecked. Therapy directed against inflammatory mediators of sepsis has shown little success and has the potential to impair innate antimicrobial defenses. Heme oxygenase-1 (HO-1) and the product of its enzymatic reaction, CO, have beneficial and inflammatory properties, but little is known about their effects on microbial sepsis. Here, we have demonstrated that during microbial sepsis, HO-1-derived CO plays an important role in the antimicrobial process without inhibiting the inflammatory response. HO-1-deficient mice suffered exaggerated lethality from polymicrobial sepsis. Targeting HO-1 to SMCs and myofibroblasts of blood vessels and bowel ameliorated sepsis-induced death associated with Enterococcus faecalis, but not Escherichia coli, infection. The increase in HO-1 expression did not suppress circulating inflammatory cells or their accumulation at the site of injury but did enhance bacterial clearance by increasing phagocytosis and the endogenous antimicrobial response. Furthermore, injection of a CO-releasing molecule into WT mice increased phagocytosis and rescued HO-1-deficient mice from sepsis-induced lethality. These data advocate HO-1-derived CO as an important mediator of the host defense response to sepsis and suggest CO administration as a possible treatment for the disease.