Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta.
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. 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. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) 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-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.
Oga
Toru
T
[Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan.
Matsuoka
Toshiyuki
T
Yao
Chengcan
C
Nonomura
Kimiko
K
Kitaoka
Shiho
S
Sakata
Daiji
D
Kita
Yoshihiro
Y
Tanizawa
Kiminobu
K
Taguchi
Yoshio
Y
Chin
Kazuo
K
Mishima
Michiaki
M
Shimizu
Takao
T
Narumiya
Shuh
S
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid; D006801:Humans; D051379:Mice; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D011982:Receptors, Prostaglandin; D016212:Transforming Growth Factor beta; C034671:prostaglandin F2alpha receptor; D001761:Bleomycin; D016718:Arachidonic Acid