No 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)

Fibrosing alveolitis may occur alone (CFA) or in association with systemic sclerosis (FASSc). FASSc was recently shown to have a prognostic advantage over CFA. Because interleukin-8 (IL-8) is likely to be a major determinant of neutrophil alveolitis, we evaluated IL-8 expression in patients with CFA and FASSc and compared it with that in normal individuals and sarcoidosis and systemic sclerosis patients without pulmonary involvement (SSc no FA). IL-8 protein in bronchoalveolar lavage fluid (BALF) was assessed by immunoassay, and IL-8 mRNA expression was assessed using Northern analysis and reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization of lung parenchyma. Compared with normal subjects, IL-8 concentration was significantly greater in both CFA (p < 0.001) and FASSc groups (p < 0.05) but no different in sarcoidosis. The IL-8 concentration in CFA was higher than in FASSc (p < 0.01) and was related to BAL % neutrophils (rs = 0.48, p < 0.01). IL-8 mRNA expression evaluated by Northern analysis was seen only in patients with CFA and FASSc and was related to BAL % neutrophils (rs = 0.63, p < 0.01). We suggest that IL-8 is a key factor in the pathogenesis of fibrosing alveolitis and that the poorer prognosis of CFA compared with FASSc is related to higher levels of IL-8 within the lower respiratory tract.

The chemokine "regulated on activation, normal T-cell expressed and secreted" (RANTES) is a potent eosinophil and lymphocyte attractant with particular preference for CD45RO+ T-cells and eosinophils. These cells accumulate in the lungs of patients with sarcoidosis and fibrosing alveolitis. The purpose of this study was to determine whether RANTES mediates the inflammatory cell influx in these diffuse lung diseases.Cell types and number of bronchoalveolar cells expressing RANTES protein were investigated by immunocytochemistry using lavage cells obtained from 22 patients and 11 control subjects. Subsequently, RANTES messenger ribonucleic acid (mRNA) was semiquantitated using reverse transcription polymerase chain reaction (RT-PCR) methodology in unseparated lavage cell pellets in 26 patients and 13 control subjects. Cells expressing RANTES mRNA were identified by in situ hybridization.RANTES protein expression in lower respiratory tract (LRT) cells was identified in all study groups. The percentage of RANTES+ lavage cells in sarcoidosis was higher than in controls. RANTES was localized in the cytoplasm, mainly in alveolar macrophages (CD68+ cells) in sarcoidosis, and both in alveolar macrophages and eosinophils in fibrosing alveolitis. The same cell types which expressed RANTES protein expressed RANTES mRNA, as assessed by in situ hybridization. Sarcoidosis patients had higher levels of RANTES mRNA than the other groups. RANTES protein was higher in individuals with abnormal lymphocyte numbers: RANTES protein and mRNA expression was significantly correlated with lavage CD45RO+ lymphocyte numbers.These results indicate that RANTES may mediate T-lymphocyte influx in diffuse lung disease, particularly sarcoidosis. Moreover, they suggest that the cellular source of RANTES is the alveolar macrophage in sarcoidosis, and both macrophages and eosinophils in fibrosing alveolitis.

1. Interstitial lung disease is a common complication of systemic sclerosis. The mechanism by which excess collagen is deposited in the lung is poorly understood, but is thought to involve release of mediators which activate lung fibroblasts. In this study we investigated and partially characterized the fibroblast proliferative activity of bronchoalveolar lavage fluid from 29 patients with systemic sclerosis, 19 with and 10 without evidence of lung disease assessed by thin-section computed tomography. 2. Bronchoalveolar lavage fluid from both groups of patients stimulated fibroblast proliferation compared with control subjects: systemic sclerosis with normal computed tomography, 27.7 (range 10.5-57.9)% above control; systemic sclerosis with abnormal computed tomography, 26.7 (range 5.0-47.8)% above control, P < 0.02 in both cases. 3. The activity was reduced by about one-third by neutralizing antibodies to insulin-like growth factor-1 but not platelet-derived growth factor. Levels of insulin-like growth factor-1 of bronchoalveolar fluid were increased in patients with systemic sclerosis [2.10 (range 1.10-3.48) ng/ml of bronchoalveolar lavage fluid] compared with controls [1.45 (range 1.10-2.05) ng/ml; P < 0.01]. When patients were subdivided into those with abnormal computed tomography [2.10 (range 1.20-3.48) ng/ml] and those with normal computed tomography [1.85 (range 1.10-2.90) ng/ml] only the values for the group with evidence of lung disease were increased compared with control subjects (P < 0.02). Platelet-derived growth factor could not be detected in bronchoalveolar lavage fluid from any group. Fractionation of bronchoalveolar lavage fluid demonstrated activity in several fractions consistent with the molecular masses of insulin-like growth factor-1 associated with binding proteins.(ABSTRACT TRUNCATED AT 250 WORDS)