A pivotal role of cytosolic phospholipase A(2) in bleomycin-induced pulmonary fibrosis.
Pulmonary fibrosis is an interstitial disorder of the lung parenchyma whose mechanism is poorly understood. Potential mechanisms include the infiltration of inflammatory cells to the lungs and the generation of pro-inflammatory mediators. In particular, idiopathic pulmonary fibrosis is a progressive and fatal form of the disorder characterized by alveolar inflammation, fibroblast proliferation and collagen deposition. Here, we investigated the role of cytosolic phospholipase A(2) (cPLA(2)) in pulmonary fibrosis using cPLA(2)-null mutant mice, as cPLA(2) is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA(2) (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA(2)-null mice. Our data suggest that cPLA(2) has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA(2)-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.
Nagase
Takahide
T
Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. takahide-tky@umin.ac.jp
Uozumi
Naonori
N
Ishii
Satoshi
S
Kita
Yoshihiro
Y
Yamamoto
Hiroshi
H
Ohga
Eijiro
E
Ouchi
Yasuyoshi
Y
Shimizu
Takao
T
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003094:Collagen / Q000096:biosynthesis; D003600:Cytosol / Q000201:enzymology; D015777:Eicosanoids / Q000502:physiology; D006909:Hydroxyproline / Q000032:analysis; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D013931:Thromboxanes / Q000378:metabolism
D015777:Eicosanoids; D011506:Proteins; D013931:Thromboxanes; D001761:Bleomycin; D003094:Collagen; D010741:Phospholipases A; D006909:Hydroxyproline