Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by fibroblast proliferation and excess deposition of extracellular matrix proteins in the lungs. As anti-inflammatory therapies such as steroids or immunosuppressive agents do not improve disease progression, targets to block fibrogenesis per se are needed. Mice lacking cytosolic phospholipase A2, a key enzyme triggering the production of arachidonic acid metabolites such as eicosanoids including prostanoids and leukotrienes, did not develop bleomycin-induced pulmonary fibrosis, indicating that arachidonic acid metabolites play an important role in the pathogenesis of pulmonary fibrosis. Previous reports indicated that leukotrienes have fibrogenic effects, and prostaglandins (PGs) E2 and I2 have antifibrogenic effects. We have reported that, using mice lacking each prostaglandin receptor, PGF2α and its receptor FP signaling facilitated bleomycin-induced pulmonary fibrosis through increased fibroblast proliferation and collagen deposition, independently of transforming growth factor (TGF)-β signaling. Furthermore, to evaluate the clinical significance of PGF2α in IPF, using the liquid chromatography-tandem mass spectrometry, the levels of 15-keto-dihydro PGF2α as well as PGF2α increased in the bronchoalveolar lavage fluid of patients with IPF to a greater extent than in patients with sarcoidosis. Thus, we have suggested PGF2α-FP signaling as a therapeutic target for IPF. Eicosanoids may be promising targets for novel treatments and management of IPF, in addition to TGF-β.
