Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro.

Abstract

Pulmonary fibrosis is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). The pathogenesis of this condition is poorly understood, but one of the earliest pathologic features is endothelial and epithelial cell injury with subsequent regeneration. Endothelial and epithelial cells can release several mediators, including endothelin-1 (ET-1). In this study, we investigated the levels of ET-1 in bronchoalveolar lavage fluid (BALF) from patients with SSc and assessed the contribution of ET-1 to the fibroblast mitogenic activity induced by these fluids. A total of 26 patients were evaluated and divided into those with evidence of pulmonary fibrosis, assessed by thin-section computed tomography (group I, n = 16), and those with a normal scan (group II, n = 10). BALF from both groups of patients stimulated fibroblast proliferation. Values expressed as median (range) percentage increase above media controls were 25.5% (5.0 to 47.8%) and 27.6% (10.9 to 51.6%) for groups I and II, respectively (P < 0.02 in both cases). Mitogenic activity was inhibited by about 40% in the presence of either a neutralizing antibody to ET-1 or two synthetic ET-1 receptor ligands. Levels of ET-1 in BALF, expressed as medians (range) were 2.90 ng/mg albumin (0.68 to 5.75) in patients with SSc and 1.23 ng/mg albumin (0.84 to 2.0) in control patients (P < 0.02). Furthermore, ET-1 levels in BALF from patients in group II (3.83 ng/mg albumin, range 1.76 to 5.75) were elevated compared with those in group I (2.62 ng/mg albumin, range 0.68 to 3.81; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia reduces endothelin production by rat alveolar type II cells in primary culture

“…Immunoreactive ET could also be detected in other humans bronchial epithelial cells [19] and bronchial and tracheal epithelial cells have been shown to secrete irET-1 in culture [20]. Moreover, irET could be detected in the bronchoalveolar lavage fluid of normal subjects [21]. In the human lung, expression of irET-1 and preproET-1 mRNA by the hyperplastic alveolar epithelium appears to be a striking finding in interstitial pulmonary fibrosis with or without pulmonary hypertension [5,22], whereas normal human lung tissue expressed very little ET-1.…”

Blocking endothelin: breaking new ground

“…ET has been detected in the plasma of patients with IPF at significantly higher levels compared with matched controls (p,0.01) [11] and in patients with scleroderma, levels of ET in bronchoalveolar lavage fluid are higher in patients with lung fibrosis than in patients without lung involvement ( fig. 4) [12]. Importantly, biopsy studies have reported increased ET protein in the airway and alveolar epithelium of IPF patients, as well as in the vascular endothelium ( fig.…”

“…Moreover, ET has been found to stimulate pulmonary fibroblast proliferation [12] (fig. 6) and the addition of ET to primary normal lung fibroblasts induces the expression of a-smooth muscle actin, which is the hallmark of the differentiation of fibroblasts to myofibroblasts, which in turn aggregate to form myofibroblast foci, which are characteristic features of UIP/IPF.…”

“…Taken together, these in vitro experiments demonstrate that the use of bosentan favours a situation of reduced collagen deposition and all these effects of bosentan might be expected to be useful in the clinical management of patients with IPF. [11] (a) and [12] (b) with permission from the publishers.…”

Neutrophil Extracellular Traps - The Invisible Inflammatory Mediator in Fibrosis

“…This inflammatory environment activates effector cells (such as fibroblasts and myofibroblasts) resulting in the production of matrix proteins and subsequent fibrotic process (second and third phases) [2]. The fibrotic changes can occur in different tissues, and are mediated by common pathogenic signaling such as transforming growth factor-β (TGF-β) [3], platelet-derived growth factor (PDGF) [4], connective tissue growth factor (CCN2) [5], endothelin-1 [6], angiotensin II [7], integrins [8] extracellular matrix-driven pathways. Among the mechanisms involved in fibrosis, a cornerstone for the progression of the fibrotic process is the differentiation of fibroblasts towards activated cells, namely myofibroblasts, which contribute in the production of abundant amount of extracellular matrix [2].…”