Role of the urokinase-fibrinolytic system in epithelial-mesenchymal transition during lung injury

Amarnath Satheesh Marudamuthu, Yashodhar Prabhakar Bhandary, Shwetha Kumari Shetty, Jian Fu, Venkatachalem Sathish, Y.s. Prakash, Sreerama Shetty

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Alveolar type II epithelial (ATII) cell injury precedes development of pulmonary fibrosis. Mice lacking urokinase-type plasminogen activator (uPA) are highly susceptible, whereas those deficient in plasminogen activator inhibitor (PAI-1) are resistant to lung injury and pulmonary fibrosis. Epithelial-mesenchymal transition (EMT) has been considered, at least in part, as a source of myofibroblast formation during fibrogenesis. However, the contribution of altered expression of major components of the uPA system on ATII cell EMT during lung injury is not well understood. To investigate whether changes in uPA and PAI-1 by ATII cells contribute to EMT, ATII cells from patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and mice with bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced lung injury were analyzed for uPA, PAI-1, and EMT markers. We found reduced expression of E-cadherin and zona occludens-1, whereas collagen-I and α-smooth muscle actin were increased in ATII cells isolated from injured lungs. These changes were associated with a parallel increase in PAI-1 and reduced uPA expression. Further, inhibition of Src kinase activity using caveolin-1 scaffolding domain peptide suppressed bleomycin-, transforming growth factor β-, or passive cigarette smoke-induced EMT and restored uPA expression while suppressing PAI-1. These studies show that induction of PAI-1 and inhibition of uPA during fibrosing lung injury lead to EMT in ATII cells.

Original languageEnglish (US)
Pages (from-to)55-68
Number of pages14
JournalAmerican Journal of Pathology
Volume185
Issue number1
DOIs
StatePublished - Jan 1 2015

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Epithelial-Mesenchymal Transition
Alveolar Epithelial Cells
Plasminogen Activator Inhibitor 1
Urokinase-Type Plasminogen Activator
Lung Injury
Pulmonary Fibrosis
Bleomycin
Transforming Growth Factors
Smoke
Tobacco Products
Idiopathic Pulmonary Fibrosis
Myofibroblasts
src-Family Kinases
Herpes Zoster
Cadherins
Chronic Obstructive Pulmonary Disease
Smooth Muscle
Actins
Collagen
Lung

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Role of the urokinase-fibrinolytic system in epithelial-mesenchymal transition during lung injury. / Marudamuthu, Amarnath Satheesh; Bhandary, Yashodhar Prabhakar; Shetty, Shwetha Kumari; Fu, Jian; Sathish, Venkatachalem; Prakash, Y.s.; Shetty, Sreerama.

In: American Journal of Pathology, Vol. 185, No. 1, 01.01.2015, p. 55-68.

Research output: Contribution to journalArticle

Marudamuthu, Amarnath Satheesh ; Bhandary, Yashodhar Prabhakar ; Shetty, Shwetha Kumari ; Fu, Jian ; Sathish, Venkatachalem ; Prakash, Y.s. ; Shetty, Sreerama. / Role of the urokinase-fibrinolytic system in epithelial-mesenchymal transition during lung injury. In: American Journal of Pathology. 2015 ; Vol. 185, No. 1. pp. 55-68.
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