Hyperinduction of Cyclooxygenase‐2–Mediated Proinflammatory Cascade: A Mechanism for the Pathogenesis of Avian Influenza H5N1 Infection

Suki M. Y. Lee, Chung‐Yan Cheung, John M. Nicholls, Kenrie P. Y. Hui, Connie Y. H. Leung, Mongkol Uiprasertkul, George L. Tipoe, Yu‐Lung Lau, Leo L. M. Poon, Nancy Y. Ip, Yi Guan, J. S. Malik Peiris
2008 Journal of Infectious Diseases  
The mechanism for the pathogenesis of H5N1 infection in humans remains unclear. This study reveals that cyclooxygenase-2 (COX-2) was strongly induced in H5N1-infected macrophages in vitro and in epithelial cells of lung tissue samples obtained during autopsy of patients who died of H5N1 disease. Novel findings demonstrated that COX-2, along with tumor necrosis factor ␣ and other proinflammatory cytokines were hyperinduced in epithelial cells by secretory factors from H5N1-infected macrophages
more » ... ected macrophages in vitro. This amplification of the proinflammatory response is rapid, and the effects elicited by the H5N1-triggered proinflammatory cascade are broader than those arising from direct viral infection. Furthermore, selective COX-2 inhibitors suppress the hyperinduction of cytokines in the proinflammatory cascade, indicating a regulatory role for COX-2 in the H5N1hyperinduced host proinflammatory cascade. These data provide a basis for the possible development of novel therapeutic interventions for the treatment of H5N1 disease, as adjuncts to antiviral drugs. The emergence and spread of the highly pathogenic avian influenza viruses (H5N1) in poultry and wild birds with repeated zoonotic transmission to humans has raised widespread concern. Outbreaks of H5N1 infection among poultry have now been reported on 3 continents, and at the time this article was written, over 370 cases of infection among humans had been reported, with an overall case fatality rate of over 60% [1]. The H5N1 virus appears to have the capacity to cause severe disease in previously healthy young children and adults [2, 3] , and it is reminiscent of the strain that caused the 1918 influenza pandemic in this respect. The explanation for the severity of H5N1-induced lung pathology may include increased viral replication competence or enhanced inflammatory responses, and the relative importance of these remains to be elucidated [4 -6]. Although there is a paucity of autopsy investigation of patients with H5N1 disease, the available data has consistently found very few virus-infected lung epithelial cells, despite widespread histopathological damage [7] [8] [9] [10] , which supports the argument that host inflammatory responses are important, at least in maintaining ongoing lung pathology in these patients. We previously found that the H5N1 viruses hyperinduced proinflammatory cytokines and chemokines (by Ͼ10 fold) in macrophages and alveolar epithelial cells in vitro, compared with H1N1-infected cells [11, 12] , suggesting that this differential host response may contribute to the pathogenesis of infection with H5N1 viruses in humans. Recently, others have reported that H5N1 virus induces lower levels of type-1 interferon (IFN) from differentiated bronchial epithelium [13] . These differences
doi:10.1086/590499 pmid:18613795 fatcat:hnzwhm4nxja6tfsddykmpiwkby