Frequent outbreaks caused by influenza viruses pose considerable public health threats worldwide. Virus-inflicted alveolar damage represents a major contributor of
acute lung injury in
influenza. We have previously demonstrated that
hepatocyte growth factor (HGF) produced by macrophages enhances alveolar epithelial proliferation during
influenza infection. Here, we investigated the therapeutic efficacy of recombinant human HGF (rhHGF) and an
antiviral agent (
oseltamivir) alone or in combination to treat
influenza viral pneumonia in macrophage-depleted BALB/c mice. Combination
therapy of infected mice significantly reduced lung pathology and mortality compared to other animal groups that received either treatment alone. Combination treatment with rhHGF induced alveolar type II (AT2) epithelial
hyperplasia more prominently in the distal airways, evident by increased cells with double-positive staining for
surfactant protein-C and
proliferating cell nuclear antigen within the alveolar epithelial lining. Similarly, rhHGF supplementation also induced stem cell antigen-1 (SCA-1) transcriptional expression at 5 days post-
infection (dpi), but
mRNA levels of both SCA-1 and its receptor c-KIT were decreased by 10 dpi. Microarray and pathway analyses indicated that rhHGF administration may act by accelerating tissue repair and suppressing inflammatory processes to minimize damage by
infection and to restore lung function by earlier repair. These results reveal that transient administration of rhHGF may confer synergistic effects in enhancing pulmonary repair by promoting AT2 cell proliferation. Thus, the combination of rhHGF and
oseltamivir may represent a promising therapeutic option against
influenza pneumonia to improve existing
antiviral treatment regimens.