PATHOGENETIC AND CLINICAL-SIGNIFICANCE OF FIBROBLAST ACTIVATION IN SCLERODERMA LUNG-DISEASE

Fibrosing alveolitis (FA) is a major and often fatal complication of s ystemic sclerosis (SSC). The critical role of fibroblasts in the patho genesis of FA has long been recognized. Characterization of fibroblast activation in the lungs may improve our understanding and the managem ent of this disease. We analyzed bronchoalveolar lavage (BAL) fluid sa mples from 9 healthy controls and 43 patients with FA caused by lung i nvolvement form SSC. The chemoattractant activity (CAA) of cultured hu man fibroblasts elicited by native BAL fluid was measured in Boyden ch ambers. In addition, procollagen III peptide was measured in BAL fluid as a marker of collagen synthesis. CAA (expressed as percentage of th e chemoattractant effect of 0.25 ng/ml platelet-derived growth factor; PDGF) was elevated in the SSC patients compared with that of the cont rols (control: 12.6 +/- 4.0%; SSC: 68.8 +/- 15.2%; p < 0.01). A positi ve correlation was found between BAL total cell count and CAA (r = 0.6 0, p < 0.01). An inverse correlation existed between CAA and total lun g capacity (r = -0.55, p < 0.05). The patients were followed up for 13 .3 +/- 1.4 months (mean +/- SEM). Twenty-seven patients received immun osuppressive therapy, whereas 16 refused therapy. The patients were as signed to two groups according to their CAA being lower or higher than 36% of the PDGF response (= mean value of the controls + 2 SD). Durin g follow-up, patients in the high CAA group showed lung function deter ioration if untreated, whereas stabilization or improvement of lung fu nction occurred under immunosuppressive therapy; the differences betwe en untreated and treated patients were statistically significant for t he changes in vital capacity, total lung capacity and diffusing capaci ty (p < 0.05). In the low-CAA group, untreated and treated patients di d not differ significantly with respect to the change in lung function parameters. We conclude that CAA may serve as a marker of profibrotic activity within the epithelial lining fluid of patients with FA cause d by SSC. The results suggest that parameters reflecting activation of pulmonary fibroblasts provide relevant information about disease acti vity and may improve the management of FA in patients suffering from S SC.