INCREASED LEVELS OF ENDOTHELIN-1 IN BRONCHOALVEOLAR LAVAGE FLUID FROMPATIENTS WITH SYSTEMIC-SCLEROSIS CONTRIBUTE TO FIBROBLAST MITOGENIC ACTIVITY IN-VITRO

Pulmonary fibrosis is a major cause of morbidity and mortality in pati ents 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. E ndothelial and epithelial cells can release several mediators, includi ng endothelin-1 (ET-1). In this study, we investigated the levels of E T-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 di vided into those with evidence of pulmonary fibrosis, assessed by thin -section computed tomography (group I, n = 16), and those with a norma l scan (group II, n = 10). BALF from both groups of patients stimulate d fibroblast proliferation. Values expressed as median (range) percent age 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 recept or 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). We conclude that BALF from pa tients with SSc contains increased levels of ET-1 and that this contri butes to the fibroblast proliferation induced by these fluids. Since E T-1 levels were highest in patients with a normal computed tomography scan, measurement of ET-1 in BALF may be a potential marker of early l ung disease in patients with SSc.