Chest
Volume 101, Issue 6, June 1992, Pages 1663-1673
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Clinical Implications of Basic Research
Fibronectin: A Versatile Matrix Protein with Roles in Thoracic Development, Repair and Infection

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Fibronectin, a dimeric cell-adhesive extracellular matrix glycoprotein, is secreted by mesenchymal cells and assembled into insoluble matrices which have important biological functions in embryologic development as well as in tissue response to injury. Fibronectin interacts with numerous cell types including mesenchymal cells and inflammatory cells which bear appropriate fibronectin receptors. In vitro, fibronectin serves as an adhesive substrate and promotes cell proliferation and cytodifferentiation. During development, fibronectin-rich matrices are deposited in specific location and regulate the directional migration of embryonic cells. In particular, fibronectin matrices appear to be of critical importance to normal cardiopulmonary development. Following embryologic development, the tissue expression of fibronectin is greatly reduced, but increases markedly following tissue injury, where newly expressed fibronectin matrices appear critical to tissue repair. Recent evidence has documented increased expression of fibronectin in numerous pulmonary conditions including the adult respiratory distress syndrome (ARDS), bronchiolitis obliterans organizing pneumonia (BOOP) and idiopathic pulmonary fibrosis (IPF). Additionally, fibronectin also interacts with a large number of microorganisms and therefore also is potentially important in microbial adherence to airway epithelium and subsequent infections of the respiratory system.

Section snippets

Fibronectin Biochemistry

Fibronectins are dimeric glycoproteins of approximately 500 kDa molecular weight which are derived from the variable splicing of a single gene product. Fibronectins are strikingly modular proteins composed of protease-resistant domains which retain their individual activities following cleavage and purification from the intact molecule (Fig. 1, top). These protease-resistant domains are in turn composed of smaller homologous motifs termed type I, II and III repeats which comprise the majority

Fibronectin Receptors

Cells interact with fibronectin via specific cell surface receptors (Fig. 1, bottom).1 Fibronectin receptors include members of the integrin family, a structurally related group of transmembrane heterodimeric glycoproteins conserved during evolution and responsible for cell binding to extracellular matrices or to other cells.17 Integrin receptors are composed of distinct a subunits that help confer ligand binding specificity and β subunits common to other integrins. Traditionally, integrins

Biological Actions of Fibronectin

The initial interaction of cells with immobilized fibronectin is the binding of cell surface fibronectin receptors to adhesive sequences contained within the fibronectin molecule. This binding event activates multiple intracellular processes responsible for cell adhesion and subsequent cell spreading. Many of these intracellular activities are mediated via the integrin VLA-5. Following binding to fibronectin, VLA-5 receptors aggregate or cluster into membrane structures termed adhesive plaques

Fibronectin in Thoracic Development

Human embryogenesis is characterized by remarkable morphologic changes resulting in the formation of specialized tissues. Intricate regulation of biologic events such as cell adhesion, migration, cytodifferentiation and proliferation is essential for the normal progression of organogenesis. As described earlier, fibronectin is highly expressed in embryonic tissues and has been shown to affect many of the cellular processes required for embryogenesis in vitro.4,25,30 It is therefore not

Fibronectin in Lung Repair and Fibrosis

Acute lung injury is characterized by interstitial edema, formation of alveolar exudates, disruption of basement membranes and tissue invasion by inflammatory cells.39 In general, regardless of the causative agent, the lung responds in a stereotypical manner. Pulmonary injury caused by such diverse agents as smoke, acid, drugs or multiorgan disease results in a generalized activation of counterreactive mechanisms responsible for ridding the lung of the injurious agents and effecting tissue

Fibronectin in Cardiopulmonary Infection

Adherence of microorganisms to host epithelial surfaces is necessary for the establishment of infection in the skin, urinary system and upper and lower respiratory tracts. Microorganisms have evolved widely varied mechanisms to attach to host epithelial cells including specialized structures such as pili and fimbriae. Recently, it has been found that some microbes also may exploit host adhesive proteins, such as fibronectin, to attach to epithelial surfaces. Following adhesion and local

Current and Future Research

Although much has been learned of fibronectin's structure, function and potential role in disease, several important topics provide the basis for ongoing investigation. The control of fibronectin expression continues to be an area of active research. Recent investigations have led to cloning of the fibronectin gene and promoter.71, 72 Study of these sequences will provide further insight into the control of fibronectin gene expression and may eventually lead to novel therapeutic approaches to

Summary

Fibronectin, a dimeric glycoprotein, utilizes its multidomained structure to interact with components of the extracellular matrix, microorganisms and mesenchymal, epithelial and inflammatory cells. Fibronectin interacts with these cells through specific cell surface receptors including members of the integrin family which mediate many of fibronectin's effects on cellular function such as promotion of cell adhesion, proliferation, migration and cytodifferentiation. These varied biologic

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    This work was supported in part by funds from the American Heart Association (Clinician-Scientist Award No. 91004230 to A.H.L.) and by a Minority Medical Faculty Development Award from The Robert Wood Jonnson Foundation (to Dr. Roman).

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