Mechanisms of matrix metalloproteinase-9 upregulation and tissue destruction in various organs in influenza A virus infection

Severe influenza is characterized clinicopathologically by multiple organ failure, although the relationship amongst virus and host factors that influence this morbid out- come and the underlying mechanisms of action remain unclear. The present study identi- fied marked upregulation of matrix metalloproteinase (MMP)-9 and pro-inflammatory cy- tokine tumor necrosis factor alpha (TNF-) in various organs after intranasal infection of influenza A WSN virus. MMP-9 and TNF-were upregulated in the lung, the site of in- itial infection, as well as in the brain and heart. The infection-induced MMP-9 upregula- tion was inhibited by anti-TNF-antibodies and by anti-oxidative reagents pyrrolidine dithiocarbamate and N-acetyl-L-cysteine, which inhibit activation of nuclear factor kappa B( NF-B), as well as by nordihydroguaiaretic acid, which inhibits activation of activa- tor protein 1 (AP-1). In addition, MMP-9 upregulation via TNF-was also suppressed by inhibitors of mitogen-activated protein kinases (MAPKs), such as extracellular signal- regulated kinase 1/2 and p38, and partly by a c-Jun N-terminal kinase inhibitor. These re- sults indicated that the influenza-induced MMP-9 upregulation in various organs is me- diated through MAPK-NF-B- and/or AP-1-dependent mechanisms. Strategies that neu- tralize TNF-as well as inhibitors of MAPK-NF-B- and/or AP-1-dependent pathways may be useful for suppressing the MMP-9 effect and thus preventing multiple organ fail- ure in severe influenza. J. Med. Invest. 57 : 26-34, February, 2010