Eicosanoids: mediators and therapeutic targets in fibrotic lung disease

Abstract

Fibrosis is a common end-stage sequella of a number of acute and chronic lung diseases. Current concepts of pathogenesis implicate dysregulated interactions between epithelial cells and mesenchymal cells. Although investigative efforts have documented important roles for cytokines and growth factors in the pathogenesis of fibrotic lung diseases, these observations have not as yet been translated into efficacious therapies, and there is a pressing need for new pathogenetic insights and therapeutic approaches for these devastating disorders. Eicosanoids are lipid mediators derived from arachidonic acid, the most studied of which are the prostaglandins and leukotrienes. Although they are primarily known for their roles in asthma, pain, fever and vascular responses, present evidence indicates that eicosanoids exert relevant effects on immune/inflammatory, as well as structural, cells pertinent to fibrogenesis. In general, leukotrienes promote, whereas prostaglandin E(2) opposes, fibrogenic responses. An imbalance of eicosanoids also exists in pulmonary fibrosis, which favours the production of leukotrienes over prostaglandin E(2). This review highlights the role of this imbalance in the evolution of fibrotic lung disease, discusses the mechanisms by which it may arise and considers approaches for therapeutic targeting of eicosanoids in these conditions.

CD36, but not G2A, modulates efferocytosis, inflammation, and fibrosis following bleomycin-induced lung injury

“…Further studies are required to dissect the molecular and cellular pathways by which CD36 signaling regulates this cell type. In addition, other lipid-mediated mechanisms may account for the association between reduced efferocytosis and reduced fi brosis in CD36 Ϫ / Ϫ mice, including increased local generation of PGE2 by macrophages in response to increased numbers of apoptotic cells ( 56,57 ). Indeed, PGE2 produced as a result of the abnormal accumulation of apoptotic cells may act directly on myofi broblasts themselves to mediate antifi brotic effects ( 58,59 ).…”

Eicosanoid Lipid Mediators in Fibrotic Lung Diseases

“…Interestingly, eicosanoids can influence this balance and their synthesis/actions are influenced by it. Both LTB 4 and cysLTs have been shown to promote a polarized Th2 response in T cells, augmenting synthesis of IL-4, IL-5, and IL-13. 5 While PGE 2 favors Th2 responses in vitro, mounting evidence suggests the opposite effect in the lung in vivo.…”

“…Zileuton has been explored in a single-center study for the treatment of IPF, and the results are pending. New generation LT receptor antagonists as well as inhibitors of LT biosynthesis which target 5-LO, 5-LO activating protein, LTA 4 hydrolase, and LTC 4 synthase are currently under development, so it is likely that the available options for more potently and specifically targeting these mediators will continue to expand over the next decade. In order for anti-LT therapy to be intelligently applied in patients with fibrotic lung disease, remaining questions regarding the relative importance of cysLT1 vs. cysLT2 20 and of LTB 4 vs. cysLTs 30 in human pulmonary fibrosis need to be answered.…”

“…After release from membrane phospholipids by cytosolic phospholipase A 2 (Fig 1), arachidonate is further metabolized by the 5-lipoxygenase (5-LO) pathway into LTs, or by the cyclooxygenase (COX)-1/2 pathway into PGs. 3 LTs include both LTB 4 and the cysteinyl LTs (cysLTs) C 4 , D 4 , and E 4 , and are synthesized mainly by leukocytes. PGs, including PGE 2 , PGI 2 , PGD 2 , PGF 2α , and thromboxane A 2 , are synthesized by both leukocytes and structural cells.…”

Towards Systems Biology of Human Pulmonary Fibrosis

“…Studies using advanced molecular biology approaches, genetically modified animals, virally administered genes, and high-throughput transcriptional profiling approaches provided evidence for multiple pathways, molecules, and systems that may be involved in fibrosis. On the basis of these studies, it seems that pulmonary fibrosis, at least the form induced by bleomycin in the mouse lung, is in part dependent on intact tumor necrosis factor (TNF) pathways (2), intact transforming growth factor (TGF)-␤ activation and signaling pathways (3), angiogenesis, cell trafficking and recruitment (4), coagulation cascades (5), apoptosis (6), lipid mediator metabolisms (7), and expression of multiple regulatory molecules by the alveolar epithelium (8).…”