Research of heat shock protein 47 in lung fibtotic process

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Heat shock protein(HSP) 47 is involved in the synthesis/assembly of various collagens as a collagen-specific molecular chaperone. HSP 47 expression has been shown upregulated in liver cirrhosis and other fibrotic diseases. We have studied the effect of α-defensin, cationic proteins with antimicrobial and cytotoxic activity in the azurophil granule of neutrophils, on the production of HSP 47 and collagen using lung fibroblasts, and the relationship between HSP47 expression and fibrotic process in murine bleomycin-induced pulmonary fibrosis. At first, we investigated the direct effect of a-defensin (human neutrophil peptide(HNP)-1) on expression of HSP47 and collagen-1 in human lung fibroblasts. HNP-1 5 μg/ml induced fibroblast proliferation and concentrations >50 μg/ml of HNP-1 reduced the cell-viability. Expression of HSP 47 and collagen-1 mRNA was significantly increased by 10 to 25 μg/ml of HNP-1, whereas their protein release increased in dose-dependent manner. TGF-β also enhanced the expression of these mRNA and proteins, and pirfenidone inhibited these findings. In murine bleomycin-induced pulmonary fibrosis, a good correlation was also observed between the degree og pulmonary fibrosis and expression of HSP47 mRNA and proteins and pirfenidone reduced the ashcroft score and hydroxyproline content. It also attenuated expression of HSP 47, a-SMA and F4/80 in lung cells by immunohistochemical study. Our results suggest that α-defensin may promote directly fibrotic process through upregulation of HSP 47 and collagen-1 in human lung fibroblasts and play an important role in the pathogenesis of pulmonary fibrosis and HSP47 positive cells may have an ability of enhanced collagen synthesis and release. Pirfenidone inhibited these positive cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis. These findings suggest that HSP47 and α-defensin might be a new promising target for the treatment of IPF.