Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

被引:754
作者
Narasaraju, Teluguakula
Yang, Edwin
Samy, Ramar Perumal
Ng, Huey Hian
Poh, Wee Peng
Liew, Audrey-Ann
Phoon, Meng Chee
van Rooijen, Nico [2 ]
Chow, Vincent T. [1 ]
机构
[1] Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Infect Dis Program,Dept Microbiol, Singapore 117597, Singapore
[2] Vrije Univ Amsterdam, Fac Med, Dept Mol Cell Biol, Amsterdam, Netherlands
基金
英国医学研究理事会;
关键词
RESPIRATORY-DISTRESS-SYNDROME; A H5N1 VIRUS; INFECTION; MACROPHAGES; ANTIBODY; H1N1; ACTIVATION; VIRULENCE; SEVERITY; FAILURE;
D O I
10.1016/j.ajpath.2011.03.013
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-alpha, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolarcapillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophlls in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage. (Am J Pathol 2011, 179:199-210; DOI: 10.1016/j.ajpath.2011.03.013)
引用
收藏
页码:199 / 210
页数:12
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