Production of fibronectin by the human alveolar macrophage: mechanism for the recruitment of fibroblasts to sites of tissue injury in interstitial lung diseases.

Abstract

Because cells of the mononuclear phagocyte system are known to produce fibronectin and because alveolar macrophages are activated in many interstitial lung diseases, the present study was designed to evaluate a-role for the alveolar macrophage as a source ofthe increased levels offibronectin found in the lower respiratory tract in interstitial lung. diseases and to determine ifsuch fibronectin might contribute to the development of the fibrosis found in these disorders by beinga chemoattractant for human lung fibroblasts. Production of fibronectin by human alveolar. macrophages obtained by bronchoalveolar lavage and maintained in short-term culture in serum-free conditions was demonstrated; de novo synthesis was confirmed by the incorporation of ['4C]proline. This fibronectin had a monomer molecular weight of 220,000 and was antigenically similar to plasma fibronectin. Macrophages from patients with idiopathic pulmonary fibrosis produced fibronectin at a rate 20 times higher than did normal macrophages; macrophages from patients with pulmonary sarcoidosis produced fibronectin at 10 times the normal rate. Macrophages from 6 of 10 patients with various other interstitial disorders produced fibronectin at rates greater than the rate of highest normal control. Human alveolar macrophage fibronectin was chemotactic for human lung fibroblasts, suggesting a functional role for this fibronectin in the derangement of the alveolar structures that is characteristic of these disorders.Fibronectin, a large glycoprotein found in plasma and tissues, is thought to mediate cell-matrix interactions (1-4) through its ability to bind to cells (5, 6), collagen (7,8), and other connective tissue components and to attract cells by virtue of its chemotactic properties (9, 10). Several cell types are known to produce this macromolecule, including cells of the mononuclear phagocyte system (11,12). Together, these observations lead to the hypothesis that mononuclear phagocytes at sites oftissue injury produce increased amounts of fibronectin which, in turn, recruits fibroblasts to aid in the repair process.The lung is a common site of tissue injury and is one of the few sites where human tissue mononuclear phagocytes are readily available for study. In addition, recent studies have demonstrated increased levels of fibronectin in the lower respiratory tract of patients with interstitial lung diseases (13). In this context, the present study was designed to answer several questions, including (i) do human alveolar macrophages produce fibronectin? (ii) do alveolar macrophages from patients with chronic tissue injury produce increased amounts of fibronectin? and (iii) is the fibronectin produced by the human alveolar macrophage chemotactic for human lung fibroblasts? MATERIALS AND METHODSStudy Population. The study population consisted of 48 patients with interstitial lung disease and 7 normal volunteers. Patients were selected from consecutive patients evaluated for interstitial lung disease at the National Institutes of Health and f...

Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats.

“…It seems reasonable to postulate that TGFP produced by activated alveolar macrophages at alveolar duct bifurcations acts in a paracrine fashion to stimulate increased fibronectin production by interstitial fibroblasts. Alveolar macrophages are also capable of fibronectin production (Rennard et al, 1981), although the antibody we used apparently did not stain any of the macrophages associated with the developing lesions ( Figures 2C-2F).…”

RETRACTED: Discoidin Domain Receptor 1 Contributes to the Survival of Lung Fibroblast in Idiopathic Pulmonary Fibrosis

“…38 In fact, integrins, which are receptors of ECM proteins, regulate lung fibroblast migration across the basement membrane in IPF.…”

Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis

“…Overexpression of IL-12, by activated alveolar macrophages, results in enhanced Th-1 cell proliferation and activation, leading to the increased expression of the pro-inflammatory mediators IFN-c and TNF-a, and the secretion of cytokines and chemotactic factors that could, in turn, recruit and activate additional T-cells. Macrophages also produce profibrotic mediators, such as fibronectin [30], and transforming growth factorb [31] that contribute to fibrotic granuloma development. Collectively, these data suggest that IL-12 may be involved in both initiating and perpetuating granulomatous inflammation of sarcoidosis.…”