The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties

Abstract

Caveolin-1 (cav1) is a 22-kDa membrane protein essential to the formation of small invaginations in the plasma membrane, called caveolae. The cav1 gene is expressed primarily in adherent cells such as endothelial and smooth muscle cells and fibroblasts. Caveolae contain a variety of signaling receptors, and cav1 notably downregulates transforming growth factor (TGF)-β signal transduction. In pulmonary pathologies such as interstitial fibrosis or emphysema, altered mechanical properties of the lungs are often associated with abnormal ECM deposition. In this study, we examined the physiological functions and the deposition of ECM in cav1−/− mice at various ages (1–12 mo). Cav1−/− mice lack caveolae and by 3 mo of age have significant reduced lung compliance and increased elastance and airway resistance. Pulmonary extravasation of fluid, as part of the cav1−/− mouse phenotype, probably contributed to the alteration of compliance, which was compounded by a progressive increase in deposition of collagen fibrils in airways and parenchyma. We also found that the increased elastance was caused by abundant elastic fiber deposition primarily around airways in cav1−/− mice at least 3 mo old. These observed changes in the ECM composition probably also contribute to the increased airway resistance. The higher deposition of collagen and elastic fibers was associated with increased tropoelastin and col1α2 and col3α1 gene expression in lung tissues, which correlated tightly with increased TGF-β/Smad signal transduction. Our study illustrates that perturbation of cav1 function may contribute to several pulmonary pathologies as the result of the important role played by cav1, as part of the TGF-β signaling pathway, in the regulation of the pulmonary ECM.

Fibulin-1 Predicts Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

“…While much of the focus in the literature has centered on the importance of collagen to fi brosis, 21 it is possible that smaller ECM-connecting proteins, 22 like fi bulin-1 which binds to elastic fi bers, 12 can also act to alter the mechanical properties of the lung. 23 In this study, as the levels of tissue fi bulin-1 increased, the lung function of the patients decreased. Given that fi bulin-1 is a known modulator of the ECM during the progression of some diseases, 24 this fi nding is indicative of the potential importance of fi bulin-1 as a target during fi brogenesis.…”

Caveolin-1 knockout mice exhibit airway hyperreactivity

“…A single previous study that examined airway function in Cav1 KO mice (28) reported that, by 3 mo of age, lung compliance is significantly reduced whereas RL is increased. The reduced compliance was associated with increased deposition of collagen fibrils in the airways: a finding observed in the present study as well.…”

“…To this end we employed the mouse lacking caveolin-1 (Cav1 KO) as a model, with ovalbumin (OVA) sensitization and challenge as a model of allergic airway hyperresponsiveness to test our hypothesis. Cav1 KO mice are known to develop pulmonary fibrosis (9,15,60), and a single study showed that these mice have reduced lung compliance and increased elastance by 3 mo of age (28), with evidence of progressively greater deposition of collagen within airways and parenchyma. Whether such changes are associated with altered airway contractility and the specific role of ASM per se have not been examined.…”

Role of Growth Factors in the Pathogenesis of Tissue Fibrosis in Systemic Sclerosis

“…Numerous studies have supported this role of caveolin-1 in the development of tissue fibrosis [65][66][67][68]. For example, it was shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts and that caveolin-1 was reduced in affected SSc lungs and skin [66] and in lung tissues and fibroblasts from patients with idiopathic pulmonary fibrosis [67,68]. Increasing caveolin-1 expression markedly improved bleomycin-induced pulmonary fibrosis [67].…”

“…The localization of the TβRs in the EEA-1 positive compartment was responsible for downstream Smad activation, whereas their localization in caveolae lipid rafts caused recruitment of Smurf/Smad7 with subsequent receptor ubiquitination and rapid receptor degradation and turnover [63,64]. Numerous studies have supported this role of caveolin-1 in the development of tissue fibrosis [65][66][67][68]. For example, it was shown that caveolin-1 knockdown in vitro markedly increased collagen gene expression in normal human lung fibroblasts and that caveolin-1 was reduced in affected SSc lungs and skin [66] and in lung tissues and fibroblasts from patients with idiopathic pulmonary fibrosis [67,68].…”