Opposing roles of leukotrienes and prostaglandins in fibrotic lung disease

Abstract

Lung fibrosis is a devastating disease that involves a variable degree of inflammation, alveolar epithelial injury, fibroblast hyperplasia and the deposition of extracellular matrix. Standard therapies that consist of corticosteroids and immunosuppressive agents offer little benefit and most patients experience a progressive deterioration in lung function which is ultimately fatal within 2–5 years of diagnosis. New pathogenetic insights and therapeutic approaches are badly needed. Eicosanoids are lipid mediators derived from arachidonic acid metabolism, the best studied of which are prostaglandins and leukotrienes. Although these mediators are primarily known for their roles in asthma, pain, fever and vascular responses, they also exert relevant effects on immune and inflammatory cells as well as structural cells such as epithelial cells and fibroblasts – cell types which participate in fibrogenesis. In general, leukotrienes promote while prostaglandin E2 opposes fibrogenic responses. Lung fibrosis is associated with increased production of leukotrienes and decreased production of prostaglandin E2. Furthermore, responses to prostaglandin E2 are altered in fibrotic conditions. This review highlights the role of this leukotriene/prostaglandin imbalance in the evolution of fibrotic lung disease, offers insights into the mechanisms that underlie the dysregulated responses and discusses approaches for therapeutic targeting of eicosanoids in these conditions.