Editors' ChoiceIdiopathic Pulmonary Fibrosis

A Key Role for Caveolin

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Science Translational Medicine  16 Jun 2010:
Vol. 2, Issue 36, pp. 36ec94
DOI: 10.1126/scitranslmed.3001354

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by abnormally increased propagation of fibroblast cells that fill the airspaces of the lung, thus causing loss of pulmonary function, coughing, and great difficulty in breathing. Despite a devastating high mortality rate, effective treatment is still elusive, mostly because the disease is difficult to diagnose and the mechanisms of pathogenesis are unknown. Growth of fibroblasts is normally controlled by matrix proteins such as polymerized type I collagen. However, IPF fibroblasts rapidly divide despite increased collagen deposition. High phosphatase activity of plasma membrane–associated phosphatase and tensin homolog (PTEN) inhibits enzymes such as phosphatidylinositol 3-kinase (PI3K) that promote cellular proliferation. Now, Xia et al., using immunohistochemistry and immunofluorescence on tissues obtained from the lungs of normal and IPF subjects, demonstrate that the uncontrolled growth of fibroblasts in IPF occurs because of loss of PTEN at the plasma membrane. They further demonstrate that the integral membrane protein caveolin-1 and PTEN colocalize; this interaction is required for membrane association and activation of PTEN. Caveolin-1 is decreased in the fibroblasts of IPF, and the authors demonstrate that this low expression level is the cause of reduced PTEN activity and the abnormal phenotype of the IPF fibroblasts. Overexpression of caveolin-1 in IPF fibroblasts restored PTEN expression and inhibited phosphorylation of Akt (a downstream target of PI3K) and fibroblast proliferation. Hence, this study not only provides a role for caveolin-1 in PTEN membrane localization and activation, it also confirms that caveolin-1 plays a critical role in the pathogenesis of IPF and could be an important alternative therapeutic target.

H. Xia et al., Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. Am. J. Pathol. 176, 2626–2637 (2010). [Abstract]

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