Inflammatory cytokine storm is a known cause for acute respiratory distress syndrome. In this study, we have investigated the role of IFN-γ in lethal lung inflammation using a mouse model of postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. To mimic the clinical scenario, animals were treated with antibiotics for effective bacterial control following MRSA superinfection. However, antibiotic therapy alone is not sufficient to improve survival of wild-type animals in this lethal acute respiratory distress syndrome model. In contrast, antibiotics induce effective protection in mice deficient in IFN-γ response. Mechanistically, we show that rather than inhibiting bacterial clearance, IFN-γ promotes proinflammatory cytokine response to cause lethal lung damage. Neutralization of IFN-γ after influenza prevents hyperproduction of TNF-α, and thereby protects against inflammatory lung damage and animal mortality. Taken together, the current study demonstrates that influenza-induced IFN-γ drives a stepwise propagation of inflammatory cytokine response, which ultimately results in fatal lung damage during secondary MRSA pneumonia, despite of antibiotic therapy.

炎症性细胞因子风暴是导致急性呼吸窘迫综合征的已知原因。在这项研究中，我们使用流感后耐甲氧西林金黄色葡萄球菌的小鼠模型研究了 IFN-γ 在致死性肺部炎症中的作用(MRSA) 肺炎。为了模拟临床情况，在 MRSA 双重感染后，动物接受了抗生素治疗以有效控制细菌。然而，在这种致命的急性呼吸窘迫综合征模型中，单独的抗生素治疗不足以提高野生型动物的存活率。相反，抗生素在缺乏 IFN-γ 反应的小鼠中诱导有效保护。从机制上讲，我们表明 IFN-γ 不是抑制细菌清除，而是促进促炎细胞因子反应，从而导致致命的肺损伤。流感后中和 IFN-γ 可防止 TNF-α 的过度产生，从而防止炎症性肺损伤和动物死亡。综上所述，目前的研究表明，流感诱导的 IFN-γ 驱动炎症细胞因子反应的逐步传播，