Suppression of von hippel-lindau protein in fibroblasts protects against bleomycin-induced pulmonary fibrosis

Qiyuan Zhou, Tianji Chen, Wei Zhang, Melike Bozkanat, Yongchao Li, Lei Xiao, Richard B. Van Breemen, John W. Christman, Jacob I. Sznajder, Guofei Zhou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We generated heterozygous fibroblast-specific pVHL (Fsp-VHL) knockdown mice (Fsp-VHL1/2) and homozygous Fsp-VHL knockout mice (Fsp-VHL2/2) by crossbreeding vhlh 2-lox mice (VHLfl/fl) with Fsp-Cre recombinase mice. Our data show that Fsp-VHL2/2 mice, but not Fsp-VHL1/2 mice, have elevated red blood cell counts, hematocrit, hemoglobin content, and expression of hypoxia-inducible factor (HIF) targets, indicating HIF activation. To examine the role of pVHL in bleomycin-induced lung injury and fibrosis in vivo, we administered PBS or bleomycin to age-, sex-, and strain-matched 8-week-old VHLfl/fl, Fsp-VHL1/2, and Fsp-VHL2/2 mice. In Fsp-VHL1/2 and Fsp-VHL2/2 mice, bleomycin-induced collagen accumulation, fibroblast proliferation, differentiation, and matrix protein dysregulation were markedly attenuated. Suppression of pVHL also decreased bleomycin-induced Wnt signaling and prostaglandin E2 signaling but did not affect bleomycin-induced initial acute lung injury and lung inflammation. These results indicate that pVHL has a pivotal role in bleomycin-induced pulmonary fibrosis, possibly via an HIF-independent pathway. Paradoxically, pVHL does not affect bleomycin-induced lung injury and inflammation, indicating a separation of the mechanisms involved in injury/inflammation from those involved in pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)728-739
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume54
Issue number5
DOIs
StatePublished - May 2016

Keywords

  • Hypoxia-inducible factor
  • Inflammation
  • Lung injury
  • Pulmonary fibrosis
  • Von Hippel-Lindau protein

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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