Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis

Hong Xia, Deanna Diebold, Richard S Nho, David M Perlman, Jill Kleidon, Judy Kahm, Svetlana V Avdulov, Mark Peterson, John Nerva, Peter B Bitterman, Craig A Henke

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in which fibroblasts accumulate in the alveolar wall within a type I collagen - rich matrix. Although lung fibroblasts derived from patients with IPF display durable pathological alterations in proliferative function, the molecular mechanisms differentiating IPF fibroblasts from their normal counterparts remain unknown. Polymerized type I collagen normally inhibits fibroblast proliferation, providing a physiological mechanism to limit fibroproliferation after tissue injury. We demonstrate that β1 integrin interaction with polymerized collagen inhibits normal fibroblast proliferation by suppression of the phosphoinositide 3-kinase (PI3K) - Akt -S6K1 signal pathway due to maintenance of high phosphatase activity of the tumor suppressor phosphatase and tensin homologue (PTEN). In contrast, IPF fibroblasts eluded this restraint, displaying a pathological pattern of β1 integrin signaling in response to polymerized collagen that leads to aberrant activation of the PI3K - Akt - S6K1 signal pathway caused by inappropriately low PTEN activity. Mice deficient in PTEN showed a prolonged fibroproliferative response after tissue injury, and immunohistochemical analysis of IPF lung tissue demonstrates activation of Akt in cells within fibrotic foci. These results provide direct evidence for defective negative regulation of the proliferative pathway in IPF fibroblasts and support the theory that the pathogenesis of IPF involves an intrinsic fibroblast defect.

Original languageEnglish (US)
Pages (from-to)1659-1672
Number of pages14
JournalJournal of Experimental Medicine
Volume205
Issue number7
DOIs
StatePublished - Jul 7 2008

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Idiopathic Pulmonary Fibrosis
Integrins
Fibroblasts
Lung
Phosphoric Monoester Hydrolases
1-Phosphatidylinositol 4-Kinase
Collagen Type I
Signal Transduction
Collagen
Wounds and Injuries
Lung Diseases

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Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. / Xia, Hong; Diebold, Deanna; Nho, Richard S; Perlman, David M; Kleidon, Jill; Kahm, Judy; Avdulov, Svetlana V; Peterson, Mark; Nerva, John; Bitterman, Peter B; Henke, Craig A.

In: Journal of Experimental Medicine, Vol. 205, No. 7, 07.07.2008, p. 1659-1672.

Research output: Contribution to journalArticle

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abstract = "Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease in which fibroblasts accumulate in the alveolar wall within a type I collagen - rich matrix. Although lung fibroblasts derived from patients with IPF display durable pathological alterations in proliferative function, the molecular mechanisms differentiating IPF fibroblasts from their normal counterparts remain unknown. Polymerized type I collagen normally inhibits fibroblast proliferation, providing a physiological mechanism to limit fibroproliferation after tissue injury. We demonstrate that β1 integrin interaction with polymerized collagen inhibits normal fibroblast proliferation by suppression of the phosphoinositide 3-kinase (PI3K) - Akt -S6K1 signal pathway due to maintenance of high phosphatase activity of the tumor suppressor phosphatase and tensin homologue (PTEN). In contrast, IPF fibroblasts eluded this restraint, displaying a pathological pattern of β1 integrin signaling in response to polymerized collagen that leads to aberrant activation of the PI3K - Akt - S6K1 signal pathway caused by inappropriately low PTEN activity. Mice deficient in PTEN showed a prolonged fibroproliferative response after tissue injury, and immunohistochemical analysis of IPF lung tissue demonstrates activation of Akt in cells within fibrotic foci. These results provide direct evidence for defective negative regulation of the proliferative pathway in IPF fibroblasts and support the theory that the pathogenesis of IPF involves an intrinsic fibroblast defect.",
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AU - Avdulov, Svetlana V

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