Reactive oxygen species-dependent RhoA activation mediates collagen synthesis in hyperoxic lung fibrosis

Dmitry Yuryevich Kondrikov, Ruth B Caldwell, Zheng Dong, Yunchao Su

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Lung fibrosis is an ultimate consequence of pulmonary oxygen toxicity in human and animal models. Excessive production and deposition of extracellular matrix proteins, e.g., collagen-I, is the most important feature of pulmonary fibrosis in hyperoxia-induced lung injury. In this study, we investigated the roles of RhoA and reactive oxygen species (ROS) in collagen-I synthesis in hyperoxic lung fibroblasts and in a mouse model of oxygen toxicity. Exposure of human lung fibroblasts to hyperoxia resulted in RhoA activation and an increase in collagen-I synthesis and cell proliferation. Inhibition of RhoA by C3 transferase CT-04, dominant-negative RhoA mutant T19N, or RhoA siRNA prevented hyperoxia-induced collagen-I synthesis. The constitutively active RhoA mutant Q63L mimicked the effect of hyperoxia on collagen-I expression. Moreover, the Rho kinase inhibitor Y27632 inhibited collagen-I synthesis in hyperoxic lung fibroblasts and fibrosis in mouse lungs after oxygen toxicity. Furthermore, the ROS scavenger tiron attenuated hyperoxia-induced increases in RhoA activation and collagen-I synthesis in lung fibroblasts and mouse lungs after oxygen toxicity. More importantly, we found that hyperoxia induced separation of guanine nucleotide dissociation inhibitor (GDI) from RhoA in lung fibroblasts and mouse lungs. Further, tiron prevented the separation of GDI from RhoA in hyperoxic lung fibroblasts and mouse lungs with oxygen toxicity. Together, these results indicate that ROS-induced separation of GDI from RhoA leads to RhoA activation with oxygen toxicity. ROS-dependent RhoA activation is responsible for the increase in collagen-I synthesis in hyperoxic lung fibroblasts and mouse lungs.

Original languageEnglish (US)
Pages (from-to)1689-1698
Number of pages10
JournalFree Radical Biology and Medicine
Volume50
Issue number11
DOIs
StatePublished - Jun 1 2011

Fingerprint

Fibroblasts
Reactive Oxygen Species
Fibrosis
Collagen
Chemical activation
Toxicity
Lung
Guanine Nucleotide Dissociation Inhibitors
Hyperoxia
Oxygen
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
rho-Associated Kinases
Extracellular Matrix Proteins
Cell proliferation
Transferases
Small Interfering RNA
Animals
Pulmonary Fibrosis
Lung Injury
Animal Models

Keywords

  • Collagen
  • Fibroblasts
  • Free radicals
  • Lung
  • Oxygen toxicity
  • Reactive oxygen species
  • RhoA

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Reactive oxygen species-dependent RhoA activation mediates collagen synthesis in hyperoxic lung fibrosis. / Kondrikov, Dmitry Yuryevich; Caldwell, Ruth B; Dong, Zheng; Su, Yunchao.

In: Free Radical Biology and Medicine, Vol. 50, No. 11, 01.06.2011, p. 1689-1698.

Research output: Contribution to journalArticle

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