Cytokine regulation of pulmonary fibrosis in scleroderma
Section snippets
Clinical overview of scleroderma
Scleroderma (systemic sclerosis) is an uncommon disease that is characterized by immune system activation and autoimmunity, a proliferative and obliterative small vessel vasculopathy, and fibrosis. There are two major categories of scleroderma, limited cutaneous scleroderma and diffuse cutaneous scleroderma. Limited cutaneous scleroderma is defined as skin involvement distal to the elbows and knees, with face and neck involvement allowed. Patients with the CREST syndrome of calcinosis,
Overview of lung pathology associated with pulmonary fibrosis in scleroderma
Pathologic studies of early lung disease in scleroderma show a mixed cellular infiltrate in the lung interstitium that spills into alveolar spaces (Fig. 1A), unaccompanied by immune complex deposition. With disease progression, thickening of alveolar walls and some loss of pulmonary architecture occurs. Inflammatory infiltrates may be less apparent in later stages of disease (Fig. 1B). End-stage disease can show nothing more than severe fibrosis and remodeling of the lung.
Alveolar macrophages
Aberrant fibroblasts responsiveness in scleroderma
Lung and dermal fibroblasts from scleroderma patients differ from normal fibroblasts. Scleroderma fibroblasts have an activated, profibrotic phenotype that persists during in vitro culture and are able to participate in an inflammatory response [66]. Fibroblast lines from scleroderma patients produce more collagen, fibronectin and glycosoaminoglycans than do normal fibroblast lines [67], [68], [69], [70]. Compared to normal fibroblasts, scleroderma fibroblasts proliferate faster and are more
Cytokines of pulmonary fibrosis in scleroderma
Levels of mRNA and proteins for a number of profibrotic cytokines are increased in the blood, tissues or BAL fluids from scleroderma patients with pulmonary fibrosis but not in other scleroderma patients or healthy controls [20], [24], [56], [93], [94], indicating a potential role for these molecules in the pathogenesis of pulmonary fibrosis in scleroderma. Support for the involvement of these profibrotic molecules in the pathogenesis of pulmonary fibrosis in scleroderma comes from studies of
Conclusion
Pulmonary fibrosis can be a debilitating and occasionally fatal complication of scleroderma, striking a subset of patients with limited cutaneous and diffuse cutaneous scleroderma. The profibrotic environment that has been identified in the lungs of scleroderma patients who are at risk for progressive pulmonary fibrosis shares certain characteristics with that found in pulmonary fibrosis in other human diseases and some animal models of fibrosis. These characteristics include epithelial cell
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