부산대학교 도서관

BACKGROUND: Hypoxia-inducible factor (HIF-1) is a master regulator of the cellular hypoxic response and has been implicated in the pathogenesis of inflammatory and fibrotic disease including IPF. AIMS: To study the role of hypoxia and HIF-1 activation in macrophages in the i.t. bleomycin-induced lung fibrosis model. METHODS: The i.t. bleomycin model was used to study the effect of HIF-1 manipulation in mice. The primary end-point was lung collagen content at day 24 post i.t. bleomycin instillation. The HIF-1α inducer dimethyloxallyl glycine (DMOG) was administered i.p. on days 14, 17 and 21. The role of myeloid-HIF-1 activity in lung fibrosis was determined using mice in which either HIF-1α or vHL (the dominant negative-regulator of HIF-1α) was selectively knocked out of lysosyme M expressing cells (LysM-Cre-Hif-1 and Cre-LysM-vHL). Lung tissue hypoxia was determined using Hypoxyprobe-1TM administered on day 24. Alternative activation status of HIF-1 null and vHL null macrophages was studied in bone-marrow derived cells from LysM-Cre-Hif-1 and Cre-LysM-vHL mice. RESULTS: Pharmacological induction of HIF-1 in the late period of the bleomycin model with i.p. dimethyloxallyl glycine (DMOG) resulted in significantly enhanced lung collagen (mean±s.e.mμg/lung) on day 24 compared to controls (193±15 vs 152±8, p<0.05, n>7 per gp). Hypoxyprobe-1 staining in the bleomycin-injured lung revealed hypoxic alveolar macrophages even in areas of lung distant to patches if severe fibrosis, implying a role for hypoxic/HIF-1 expressing alveolar macrophages in lung fibrosis. However, lung collagen content was identical in myeloid-cell Hif-1 null mice and wild-type litter-mate controls (276±23 vs 277±22, n=8 per gp). In contrast, myeloid-cell vHL-null mice exhibited significantly enhanced lung collagen deposition versus controls (373±36 vs 282±54, p<0.05, n>9 per gp). Isolated vHL-null macrophages exhibited enhanced expression of the alternative activation markers YM-1, mannose receptor, arginase-1 and FIZZ-1. CONCLUSIONS: vHL deletion in macrophages enhances alternative activation and promotes lung fibrosis independent of HIF-1.