Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells

Shilpa Vyas-Read, Philip W. Shaul, Ivan S. Yuhanna, Brigham C. Willis

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Patients with interstitial lung diseases, such as idiopathic pulmonary fibrosis (IPF) and bronchopulmonary dysplasia (BPD), suffer from lung fibrosis secondary to myofibroblast-mediated excessive ECM deposition and destruction of lung architecture. Transforming growth factor (TGF)-β1 induces epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) to myofibroblasts both in vitro and in vivo. Inhaled nitric oxide (NO) attenuates ECM accumulation, enhances lung growth, and decreases alveolar myofibroblast number in experimental models. We therefore hypothesized that NO attenuates TGF-β1-induced EMT in cultured AEC. Studies of the capacity for endogenous NO production in AEC revealed that endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) are expressed and active in AEC. Total NOS activity was 1.3 pmol·mg protein-1·min-1 with 67% derived from eNOS. TGF-β1 (50 pM) suppressed eNOS expression by more than 60% and activity by 83% but did not affect iNOS expression or activity. Inhibition of endogenous NOS with L-NAME led to spontaneous EMT, manifested by increased α-smooth muscle actin (α-SMA) expression and a fibroblast-like morphology. Provision of exogenous NO to TGF-β1-treated AEC decreased stress fiber-associated α-SMA expression and decreased collagen I expression by 80%. NO-treated AEC also retained an epithelial morphology and expressed increased lamellar protein, E-cadherin, and pro-surfactant protein B compared with those treated with TGF-β alone. These findings indicate that NO serves a critical role in preserving an epithelial phenotype and in attenuating EMT in AEC. NO-mediated regulation of AEC fate may have important implications in the pathophysiology and treatment of diseases such as IPF and BPD.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 2007

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Alveolar Epithelial Cells
Epithelial-Mesenchymal Transition
Nitric Oxide
Transforming Growth Factors
Myofibroblasts
Nitric Oxide Synthase Type III
Bronchopulmonary Dysplasia
Idiopathic Pulmonary Fibrosis
Nitric Oxide Synthase Type II
Lung
Stress Fibers
NG-Nitroarginine Methyl Ester
Interstitial Lung Diseases
Cadherins
Surface-Active Agents
Smooth Muscle
Actins
Cultured Cells
Proteins
Fibrosis

Keywords

  • Alveolar epithelium
  • Lung injury
  • Nitric oxide synthases
  • Pulmonary fibrosis
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells. / Vyas-Read, Shilpa; Shaul, Philip W.; Yuhanna, Ivan S.; Willis, Brigham C.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 293, No. 1, 07.2007.

Research output: Contribution to journalArticle

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