Mechanisms of Disease: leukotrienes and lipoxins in scleroderma lung disease--insights and potential therapeutic implications.
Scleroderma interstitial lung disease (SLD) is a leading cause of morbidity and mortality in patients with systemic sclerosis. Although the pathogenesis of SLD is not clear, excessive fibrosis and inflammatory cell infiltration are the main histologic features of this disorder. Leukotrienes and lipoxins are two functionally different classes of lipoxygenase-derived eicosanoids. Leukotrienes are potent proinflammatory mediators and directly and indirectly stimulate fibroblast chemotaxis, proliferation, and collagen synthesis. Lipoxins counter-regulate the proinflammatory actions of leukotrienes and activate resolution of the inflammatory response. In addition, lipoxins inhibit growth-factor-induced fibroblast proliferation and collagen synthesis. Studies using bronchoalveolar lavage have revealed that there is an overproduction of proinflammatory and profibrotic leukotrienes in the lungs of patients with SLD, and that leukotriene levels correlate with inflammatory indices within the lungs. Moreover, the increased levels of leukotrienes in these patients are not balanced by an upregulation of anti-inflammatory and antifibrotic lipoxins. Unopposed actions of leukotrienes might, therefore, induce chronic inflammation and fibrosis in the lungs of SLD patients. Accordingly, pharmacologic correction of a leukotriene-lipoxin imbalance using leukotriene inhibitors or lipoxin analogs might be a new approach to the treatment of SLD.
Kowal-Bielecka
Otylia
O
Department of Rheumatology and Internal Medicine, Medical University in Bialystok, Bialystok, Poland. otylia@amb.edu.pl
Kowal
Krzysztof
K
Distler
Oliver
O
Gay
Steffen
S
D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015289:Leukotrienes / Q000378:metabolism*; D044045:Lipoxins / Q000378:metabolism*; D017563:Lung Diseases, Interstitial / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000150:complications* / Q000378:metabolism
D015777:Eicosanoids; D015289:Leukotrienes; D044045:Lipoxins; D003094:Collagen