Prostaglandin [F.sup.2α] receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-β

[cPLA.sub.2] cleaves phospholipids in response to stimuli and releases arachidonic acid, which is metabolized by cyclooxygenase (COX) to produce prostaglandins and by 5-lipoxygenase to produce leukotrienes. Prostaglandins, including [PGD.sub.2], [PGE.sub.2], [...]
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function (1). Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed (1). Although transforming growth factor-β. (TGF-β) functions are crucial in fibrosis (2,3), antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely (4-7), indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase [A.sub.2] [(cPLA.sub.2)] suppresses bleomycin-induced pulmonary fibrosis (8), we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor (9-15). Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-β. stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-β. signaling additively decrease fibrosis. Furthermore, [PGF.sub.2α] is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-β These findings show that [PGF.sub.2α]-FP signaling facilitates pulmonary fibrosis independently of TGF-β and suggests this signaling pathway as a therapeutic target for IPF.