Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection.

The acute lung injury (ALI) that occurs after the highly pathogenic avian influenza H5N1 virus infection is associated with an abnormal host innate immune response. Because the complement system plays a central role in innate immunity and because aberrant complement activation is associated with a variety of autoimmune and inflammatory diseases, we investigated the complement involvement in the pathogenesis of ALI induced by H5N1 virus infection. We showed that ALI in H5N1-infected mice was caused by excessive complement activation, as demonstrated by deposition of C3, C5b-9, and mannose-binding lectin (MBL)-C in lung tissue, and by up-regulation of MBL-associated serine protease-2 and the complement receptors C3aR and C5aR. Treatment of H5N1-infected mice with a C3aR antagonist led to significantly reduced inflammation in lungs, alleviating ALI. Furthermore, complement inhibition with an anti-C5a antibody or complement depletion with cobra venom factor after H5N1 challenge resulted in a similar level of protection to that seen in C3aR antagonist-treated mice. These results indicate that excessive complement activation plays an important role in mediating H5N1-induced ALI and that inhibition of complement may be an effective clinical intervention and adjunctive treatment for H5N1-induced ALI.

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