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.
Keywords: Alveolar epithelial regeneration, combination therapy, influenza viral pneumonia, oseltamivir,
recombinant hepatocyte growth factor.
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