International Journal of Immunopharmacology
Effect of endothelin-1 on α-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases
Introduction
Endothelin-1 (ET-1) has been implicated in fibrotic lung diseases, suggesting a pathophysiological role of ET-1 in fibrogenesis [3]. ET-1 is produced by a variety of cells in the human lung including airway epithelial cells, pulmonary vascular endothelial cells and pulmonary macrophages [10]. However, to the best of our knowledge, there are no data on ET-1 secretion by alveolar macrophages (AM) in interstitial lung diseases (ILD). Previous studies have demonstrated that ET-1 is a mitogen for vascular smooth muscle cells [19] and fibroblasts [22], and acts synergistically with other growth factors to increase fibroblasts proliferation [4]. However, the role of ET-1 in fibrotic lung diseases is not yet clear. Since one of the key events in the development of fibrotic lesions in ILD is myofibroblast proliferation, we undertook this study to explore how ET-1 presence affects the pathogenesis of fibrotic manifestations in ILD.
Myofibroblasts were first described in granulation tissue during wound healing as having ultrastructural features typical of both fibroblasts and smooth muscle cells [16]. Their origin is controversial. Although connective tissue fibroblasts was suggested as a source, there is a possibility that myofibroblasts originate from pericytes or smooth muscle cells [6], [30]. Recent studies based on immunochemistry and immunophenotypic analysis demonstrated that myofibroblasts manifested different cytoskeletal protein compositions, in particular α-smooth muscle actin (α-SM actin), during cell development and pathologic processes [25], [32]. This heterogeneity in ultrastracture and immunohistochemical characteristics may influence the functional properties of myofibroblasts and may contribute to different clinical outcomes.
In the normal lung, the myofibroblasts are located within the alveolar septa, in the thick portion of the air–blood barrier [1]. During most ILD, inflammatory events result in some degree of myofibroblast proliferation within the alveolar interstitium wherein severe cases end with parenchymal destruction and loss of lung function. Myofibroblasts migrate through gaps in the epithelial basement membrane and proliferate in the intra-alveolar space [14], [15]. In order to elucidate some aspects of fibrogenesis in ILD, it is important to characterize the alveolar fibroblasts and investigate the relationship between those cells to the lung environment which contains increased amounts of inflammatory cells. In the present study, we focused on two interstitial lung diseases, idiopathic pulmonary fibrosis (IPF) and sarcoidosis (SA), which are representative of two major categories of interstitial lung diseases with unknown etiology. Most SA patients experience a spontaneous remission of the disease, while interstitial fibrosis is the final outcome only in severe cases. We assessed the secretion of ET-1 by alveolar macrophages recovered from bronchoalveolar lavage of patients with IPF and SA. We characterized the phenotype of alveolar fibroblasts in ILD and evaluated the effect of ET-1 on the fibroblasts’ mitogenesis and on their cytoskeletal phenotype.
Section snippets
Patients
The study group consisted of 36 patients, none of whom were smokers nor had they been receiving medication before being enrolled. All patients underwent CT-scanning and roentgenological evaluation in addition to trans-bronchial biopsy from 4–5 randomly selected affected anatomical regions. They were divided into three groups. The first group consisted of 16 patients with SA (6 men and 10 women, mean age±SD 41±6 years). According to the chest X-ray findings, five patients were classified as
BAL cell analysis
Cells recovered by BAL were cultured on tissue culture plates after removal of non-adherent cells. The adherent cell population contained more than 90% macrophages which were identified by nonspecific esterase staining. The analysis of the differential cell profile in BAL from the IPF (n=17), SA (n=16) and control groups (n=3) is shown in Fig. 1. The IPF group had a significantly higher percent of neutrophils (42.8%±14.8) and eosinophils (9.1%±6.7) than both the SA (neutrophils: 0.92%±0.86;
Discussion
In this study, we demonstrated for the first time a greater increase in secretion of ET-1 by AM recovered from patients with IPF as compared with SA patients and control subjects. That ET-1 secretion was found to be significantly elevated in IPF AM but to a lesser degree in SA and control AM raises the question as to its accelerating effect upon the development of fibrosing conditions in ILD. Previous studies reported increased expression of ET-1 in fibrotic lung tissue in patients with
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