Complement C5 inhibition attenuates lung inflammation in H1N1 influenza

Abstract

Background: Viral infection including pandemic influenza may be associated with severe acute respiratory distress syndrome (ARDS) characterised by rapidly developing alveolitis with dense neutrophil infiltration. Complement activation has been suggested as a trigger but until now evidence has been lacking. Here we show that blockade of the complement system at the C5 level substantially reduces the severe respiratory effects of H1N1 infection in a mouse model and that this inhibition is independent of the severity of the viral infection. Methods: BalbC mice were infected with a sub-lethal (104 PFU) or a lethal dose (106 PFU) of human H1N1 virus or sham infected. Severe respiratory infection developed within 4 days in low inoculum animals and more rapidly in the high inoculum group. Mice were injected intraperitoneally with coversin, a C5 antagonist, at the time of infection and daily thereafter. At Day 6 (low inoculum group) and Day 3 (high inoculum group) animals underwent broncholaveolar lavage (BAL) pre-sacrifice. BAL fluid was inspected for total cells, neutrophils, protein and cytokines. Results: Vehicle treated mice in both high and low inocula groups had significantly elevated total cells, protein, neutrophils and cytokines (IL-1b, IL-6 and CXCL2) compared to sham treated. Mice treated with coversin had significantly lower elevation of all inflammatory parameters. In particular there was 69% inhibition of the neutrophil response in the low inoculum group and 71% in the high inoculum group compared to vehicle. These differences were significant at 104 PFU (p < 0.01) and at 106 PFU (p < 0.001). Conclusions: Treatment of mice infected with H1N1 virus with a complement C5 inhibitor significantly attenuated respiratory inflammation. The alveolar inflammatory response and the inhibition appeared to be independent of the viral load. This suggests that the response is an all-or-none phenomenon which further supports the possibility that complement activation is involved.