Influenza virus-cytokine-protease cycles are principal mechanisms of multi-organ failure in severe influenza and therapeutic approaches

摘要

Severe influenza is characterized by cytokine storm and multi-organ failure (MOF). However, the relationship amongst factors, such as cytokines, hyper-vascular permeability, host-cellular factors, and metabolic disorders in severe influenza remain unclear. The aim of the present study was to define the pathogenic impact of cytokine storm in influenza A virus (IAV) infection, and the effects of transcriptional inhibitors on cytokine, trypsin, and matrix metalloprotease (MMP-9) expressions and viral replication were determined. Since up-regulation of these cytokines and host-cellular proteases is associated with activation of transcription factors nuclear factor-kappa B (NF-kappaB) and activator protein 1 (AP-1), we treated mice with transcriptional inhibitors of NF-kappaB [pyrrolidine dithiocarbamate (PDTC), N-acetyl-L-cysteine (NAC)] and AP-1 [nordihydroguaiaretic (NDGA)]. Here, we report that treatment with PDTC, NAC, and NDGA suppressed viral multiplication and induction of cytokines, trypsin, and MMP-9, with improved animal survival.