Critical Role of SerpinB1 in Regulating Inflammatory Responses in Pulmonary Influenza Infection
Critical Role of SerpinB1 in Regulating Inflammatory Responses in Pulmonary Influenza Infection
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DOI：
10.1093/infdis/jir352
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发表时间：
2011-08-15
影响因子：
6.4
通讯作者：
Remold-O'Donnell, Eileen
中科院分区：
文献类型：
--
作者：
Gong, Dapeng;Farley, Kalamo;Remold-O'Donnell, Eileen
背景。过度的炎症宿主反应增加了与季节性呼吸道流感相关的发病率和死亡率，高致病性病毒株的特征是单核细胞和/或巨噬细胞大量浸润，产生大量有害细胞因子。在这里，我们研究了 serpinB1 在呼吸道流感中的作用，serpinB1 是丝氨酸蛋白酶、弹性蛋白酶、组织蛋白酶 G 和蛋白酶 3 的内源性抑制剂，越来越多地被认为是炎症的调节因子。结果。在用高剂量表面活性剂蛋白-D (SP-D) 敏感流感 A/费城/82 (H3N2) 攻击后，serpinB1(-/-) 小鼠比野生型小鼠更早死亡，死亡数量也更多。亚致死感染的动物发病率增加，上皮损伤消退延迟，免疫细胞死亡增加。病毒清除和 SP-D/SP-A 上调未受影响，早期病毒诱导的细胞因子和趋化因子爆发以及大量中性粒细胞和单核细胞流入也未受影响。虽然野生型小鼠中最初的细胞因子和趋化因子迅速被清除，但在 serpinB1(-/-) 小鼠中，TNF-α、IL-6、KC/CXCL1、G-CSF、IL-17A 和 MCP-1/CCL2 仍然升高。单核细胞衍生的细胞是流感感染肺部的主要免疫细胞，而来自serpinB1(-/-)小鼠的细胞在离体测试时产生过量的IL-6和TNF-α。产生 IL-17A 的肺 γ δ T 细胞也有所增加。结论。由于病毒清除未受影响，因此该研究强调了 serpinB1 在流感感染中减轻炎症和限制促炎细胞因子产生的关键作用。
Background. Excessive inflammatory host response increases morbidity and mortality associated with seasonal respiratory influenza, and highly pathogenic virus strains are characterized by massive infiltration of monocytes and/or macrophages that produce a storm of injurious cytokines.Methods. Here, we examined the role in respiratory influenza of serpinB1, an endogenous inhibitor of the serine proteases elastase, cathepsin G, and proteinase-3, increasingly recognized as regulators of inflammation.Results. After challenge with high-dose surfactant protein-D (SP-D)-sensitive influenza A/Philadelphia/82 (H3N2), serpinB1(-/-) mice died earlier and in greater numbers than did wild-type mice. Sublethally infected animals suffered increased morbidity, delayed resolution of epithelial injury, and increased immune cell death. Viral clearance and SP-D/SP-A upregulation were unimpaired and so were early virus-induced cytokine and chemokine burst and influx of large numbers of neutrophils and monocytes. Whereas initial cytokines and chemokines rapidly cleared in wild-type mice, TNF-alpha, IL-6, KC/CXCL1, G-CSF, IL-17A, and MCP-1/CCL2 remained elevated in serpinB1(-/-) mice. Monocyte-derived cells were the dominant immune cells in influenza-infected lungs, and those from serpinB1(-/-) mice produced excessive IL-6 and TNF-alpha when tested ex vivo. Pulmonary gamma delta T-cells that produced IL-17A were also increased.Conclusions. Because viral clearance was unimpaired, the study highlights the critical role of serpinB1 in mitigating inflammation and restricting pro-inflammatory cytokine production in influenza infection.