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 outcome
and the underlying mechanisms of action remain unclear. The present study identified
marked upregulation of matrix metalloproteinase (MMP)-9 and pro-inflammatory cytokine
tumor necrosis factor alpha (TNF-α) in various organs after intranasal infection
of influenza A WSN virus. MMP-9 and TNF-α were upregulated in the lung, the site of initial
infection, as well as in the brain and heart. The infection-induced MMP-9 upregulation
was inhibited by anti-TNF-α antibodies and by anti-oxidative reagents pyrrolidine
dithiocarbamate and N-acetyl-L-cysteine, which inhibit activation of nuclear factor kappa
B (NF-χB), as well as by nordihydroguaiaretic acid, which inhibits activation of activator
protein 1 (AP-1). In addition, MMP-9 upregulation via TNF-α was also suppressed by
inhibitors of mitogen-activated protein kinases (MAPKs), such as extracellular signalregulated
kinase 1/2 and p38, and partly by a c-Jun N-terminal kinase inhibitor. These results
indicated that the influenza-induced MMP-9 upregulation in various organs is mediated
through MAPK-NF-χB- and/or AP-1-dependent mechanisms. Strategies that neutralize
TNF-α as well as inhibitors of MAPK-NF-χB- and/or AP-1-dependent pathways
may be useful for suppressing the MMP-9 effect and thus preventing multiple organ failure
in severe influenza.

The journal of medical investigation : http://medical.med.tokushima-u.ac.jp/jmi/index.html