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Suppression of von Hippel-Lindau Protein in Fibroblasts Protects against
Bleomycin-Induced Pulmonary Fibrosis
#MMPMID26488390
Zhou Q
; Chen T
; Zhang W
; Bozkanat M
; Li Y
; Xiao L
; van Breemen RB
; Christman JW
; Sznajder JI
; Zhou G
Am J Respir Cell Mol Biol
2016[May]; 54
(5
): 728-39
PMID26488390
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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-VHL(+/-)) and homozygous Fsp-VHL knockout mice (Fsp-VHL(-/-)) by
crossbreeding vhlh 2-lox mice (VHL(fl/fl)) with Fsp-Cre recombinase mice. Our
data show that Fsp-VHL(-/-) mice, but not Fsp-VHL(+/-) 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
VHL(fl/fl), Fsp-VHL(+/-), and Fsp-VHL(-/-) mice. In Fsp-VHL(+/-) and Fsp-VHL(-/-)
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.
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