title: Reduction of influenza virus-induced lung inflammation and mortality in animals treated with a phosophodisestrase-4 inhibitor and a selective serotonin reuptake inhibitor.
abstract: Inflammatory responses contribute to the morbidity and mortality of severe influenza. Current antiviral therapy offers limited success in treating severe influenza infection with both H1N1 and H5N1 viruses. We evaluated the effect of a neuraminidase inhibitor in combination with immunomodulatory drugs in vitro and in a mouse model of influenza A H1N1 infection by determining survival rate, lung inflammation markers and histopathology. Sertraline and rolipram significantly improved survival in mice infected with a lethal dose of influenza A H1N1 virus. Prophylactic treatment resulted in survival rates of 40% (rolipram), 30% (oseltamivir), 0% (sertraline), 100% (rolipram/oseltamivir) and 70% (sertraline/oseltamivir). Treatment in a therapeutic setting (24 h post-infection) resulted in 80% (rolipram/oseltamivir) and 40% (sertraline/oseltamivir) survival. Sertraline and rolipram had no effect on virus replication in vitro and in vivo, but significantly reduced lung inflammation. A significant reduction in cellular infiltration (10-fold) along with inflammatory cytokines monocyte chemotactic protein-1 (10-fold), interleukin-6 (5-fold) and regulated on activation normal T cell expressed and secreted (5-fold) was observed in the animals treated with the combination compared to oseltamivir alone. Lung histopathology of mice treated with combinations revealed significantly reduced consolidation, infiltration and alveolitis compared to oseltamivir alone. Rolipram and sertraline reduced H1N1 virus-induced lung inflammation and mortality. These data support further development of immunomodulatory agents for severe influenza.
authors.affiliation: CombinatoRx-Singapore Pte. Ltd., 138667 Singapore ;
authors.forename: Geeta
authors.initials: G
authors.lastname: Sharma
authors.affiliation: CombinatoRx-Singapore Pte. Ltd., 138667 Singapore ;
authors.forename: Danilal
authors.initials: D
authors.lastname: Champalal Sharma
authors.affiliation: CombinatoRx-Singapore Pte. Ltd., 138667 Singapore ;
authors.forename: Leong
authors.initials: L
authors.lastname: Hwei Fen
authors.affiliation: Forma (Singapore) Therapeutics Pte. Ltd., 138667 Singapore ;
authors.forename: Mukta
authors.initials: M
authors.lastname: Pathak
authors.affiliation: Forma (Singapore) Therapeutics Pte. Ltd., 138667 Singapore ;
authors.forename: Nijaguna
authors.initials: N
authors.lastname: Bethur
authors.affiliation: CombinatoRx-Singapore Pte. Ltd., 138667 Singapore ;
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: Centre of Influenza Research, School of Public Health, The University of Hong Kong , Hong Kong, China.
authors.forename: Malik
authors.initials: M
authors.lastname: Peiris
authors.affiliation: CombinatoRx-Singapore Pte. Ltd., 138667 Singapore ; ; Unit for Anti-Infective Research, Institut Pasteur of Shanghai , Shanghai 200025, China.
authors.forename: Ralf
authors.initials: R
authors.lastname: Altmeyer
keywords: inflammation, influenza, oseltamivir, phospsphodiesterase-4, selective serotonin reuptake inhibitor, therapy