Article Text

PDF

Inflammation: an important regulator of the fibrotic response
S124 Macrophage deletion of vHL results in alternative activation and enhanced lung fibrosis independent of HIF-1
  1. M A Gibbons1,
  2. P M Fitch1,
  3. A MacDuff1,
  4. A C Mackinnon1,
  5. S J Forbes1,
  6. V Aidinis2,
  7. R S Johnson3,
  8. T Sethi1,
  9. C Haslett1,
  10. A G Rossi1,
  11. A J Simpson1,
  12. S E M Howie1,
  13. N Hirani1
  1. 1University of Edinburgh/MRC Centre for Inflammation Research, Edinburgh, UK
  2. 2BSRC Flemming, Athens, Greece
  3. 3University of California, San Diego, USA

Abstract

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.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.