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Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins

¹ Asthma and Allergy Research Institute, Nedlands, Western Australia, 6009
² Department of Medicine, University of Western Australia, Nedlands, Western Australia, 6009

*Author for correspondence (e-mail: dknight{at}cyllene.uwa.edu.au)

Accepted June 25, 2001

Myofibroblasts, characterised by high expression of -smooth muscle actin (-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via v and ß1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in -SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins v, ß1, vß3 and vß5 induced the expression of -SMA and its organization into stress fibers. Expression of -SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of -SMA. The expression and organization of -SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of -SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of -SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.

Key words: Extracellular matrix, Fibroblast, Asthma, Integrin, Remodeling, Fibroblast

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