Pathogenetic and Clinical Significance of Fibroblast Activation in Scleroderma Lung Disease

Abstract

Fibrosing alveolitis (FA) is a major and often fatal complication of systemic sclerosis (SSC). The critical role of fibroblasts in the pathogenesis of FA has long been recognized. Characterization of fibroblast activation in the lungs may improve our understanding and the management of this disease. We analyzed bronchoalveolar lavage (BAL) fluid samples from 9 healthy controls and 43 patients with FA caused by lung involvement form SSC. The chemoattractant activity (CAA) of cultured human fibroblasts elicited by native BAL fluid was measured in Boyden chambers. In addition, procoUagen III peptide was measured in BAL fluid as a marker of collagen synthesis. CAA (expressed as percentage of the chemoattractant effect of 0.25 ng/ml platelet-derived growth factor; PDGF) was elevated in the SSC patients compared with that of the controls (control: 12.6 ± 4.0%; SSC: 68.8 ± 15.2%; p < 0.01). A positive correlation was found between BAL total cell count and CAA (r = 0.60, p < 0.01). An inverse correlation existed between CAA and total lung capacity (r = -0.55, p < 0.05). The patients were followed up for 13.3 ± 1.4 months (mean ± SEM). Twenty-seven patients received immunosuppressive therapy, whereas 16 refused therapy. The patients were assigned to two groups according to their CAA being lower or higher than 36% of the PDGF response (= mean value of the controls + 2 SD). During follow-up, patients in the high CAA group showed lung function deterioration if untreated, whereas stabilization or improvement of lung function occurred under immunosuppressive therapy; the differences between untreated and treated patients were statistically significant for the changes in vital capacity, total lung capacity and diffusing capacity (p < 0.05). In the low-CAA group, untreated and treated patients did 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 caused by SSC. The results suggest that parameters reflecting activation of pulmonary fibroblasts provide relevant information about disease activity and may improve the management of FA in patients suffering from SSC.

Increased Vitronectin and Endothelin-1 in the Breath Condensate of Patients with Fibrosing Lung Disease

“…Several fibrogenic mediators produced by activated alveolar macrophages and the pulmonary epithelium have already been described [2]. …”

Circulating Collagen Metabolites and the Enhanced Liver Fibrosis (ELF) Score as Fibrosis Markers in Systemic Sclerosis

“…Previous reports have documented a remarkable decrease in serum PIIINP after plasma exchange or immunosuppressive therapy in patients with SSc (Behr et al, 1995;Heickendorff et al, 1995;Cozzi et al, 2001). However, the clinical relevance of the serological changes remains elusive.…”