Hyper-induction of COX-2-medicated proinflammatory cascade: A mechanism for the pathogenesis of avian influenza H5N1 infection

Abstract

Highly pathogenic avian virus H5N1 continues to pose a serious threat to human health. It is therefore important to understand its pathogenesis and to explore novel therapeutic options. Recent studies have demonstrated that the intense proinflammatory response may be a major contributory factor to the pathogenesis of this virus. In this study, we found that COX-2 was strongly induced in H5N1-infected macrophages and in epithelial cells in autopsy lung-tissue from patients dying of H5N1 disease. COX-2, along with TNF-α and other proinflammatory cytokines, were found to be hyper-induced in epithelial cells by secretory factors from H5N1-infected human macrophages in vitro and contribute to the amplification of the proinflammatory response. This amplification is rapid, and the effects elicited by H5N1-triggered proinflammatory cascade are broader than those arising from direct viral infection. Furthermore, selective COX-2 inhibitors were able to suppress the hyper-induction of cytokines in the proinflammatory cascade, indicating a regulatory role for COX-2 in the H5N1 hyper-induced host proinflammatory cascade. Taken together, these results highlight the role of the host proinflammatory response in the pathogenesis of H5N1 infection and may indicate a novel therapeutic option for the treatment of H5N1 disease, as an adjunct to antiviral drugs.