Neutrophils and lung fibroblasts are thought to play a role in the pathogenesis of
pulmonary fibrosis. We reported previously that
heat shock protein 47 (HSP47), a
collagen-specific molecular chaperon, and collagen-1 synthesis were involved in
pulmonary fibrosis, and that plasma levels of
alpha-defensins (HNP; human neutrophil
peptide), cationic
proteins with antimicrobial and cytotoxic activity in neutrophils, were significantly higher in patients with
idiopathic pulmonary fibrosis than in control subjects. Here, we investigated the direct effect of
HNP-1 in vitro on the expression of HSP47 and collagen-1 in human lung fibroblasts (NHLF).
HNP-1 at 5 microg/ml induced fibroblast proliferation but at concentrations >50 microg/ml,
HNP-1 reduced cell viability. Incubation of NHLF with 10 to 25 microg/ml of
HNP-1 for 24-h increased the expression of HSP47 and collagen-1 mRNAs (p<0.05). The levels of HSP47
protein also increased significantly at 50 microg/ml, and those of collagen-1
protein increased
at 10 to 50 microg/ml of
HNP-1 (p<0.05). The
mitogen-activated protein kinase (MAPK) signaling pathway in NHLF was activated by
HNP-1 stimulation, but inhibitor of
MEK (
PD98059) did not block HNP-1-induced HSP47
protein production. Our results suggest that
alpha-defensin is a fibrogenic mediator that promotes
collagen synthesis through the upregulation of HSP47 and collagen-1 in lung fibroblasts and participates in the pathogenesis of neutrophil-induced
pulmonary fibrosis.