A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis

Abstract

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.

Elevated levels of leukotriene B4 and leukotriene E4 in bronchoalveolar lavage fluid from patients with scleroderma lung disease

“…Important information supporting this therapeutic option comes from recent studies of mutant mice lacking the gene encoding for cytosolic phospholipase A 2 (cPLA 2 ), which is a crucial enzyme in the generation of arachidonic acid (44). Bleomycin-induced pulmonary fibrosis was significantly attenuated in cPLA 2 -null mice, together with a significant reduction in downstream products of arachidonic acid, such as thromboxanes and leukotrienes.…”

Low Molecular Weight Hyaluronan Activates Cytosolic Phospholipase A2α and Eicosanoid Production in Monocytes and Macrophages

“…cPLA 2 ␣ and its downstream metabolites can also directly modulate cellular function by altering intracellular transport (24) and regulating gene transcription (25,26). In experimental models of asthma (27), pulmonary fibrosis (28), ARDS (29), multiple sclerosis (30), and rheumatoid arthritis (31), cPLA 2 ␣ knock-out mice have reduced symptoms compared with wild-type mice (32). Moreover, cPLA 2 ␣ itself (33) or COX2-dependent synthesis of PGE 2 is known to participate in the development and progression of cancer (34).…”

Cytosolic Phospholipase A2-α Is Necessary for Platelet-activating Factor Biosynthesis, Efficient Neutrophil-mediated Bacterial Killing, and the Innate Immune Response to Pulmonary Infection

“…In addition, inactivation of the gene encoding cPLA 2 -α decreases the pulmonary dysfunction induced by acid aspiration or the intravenous infusion of lipopolysaccharide-zymosan and attenuates bleomycin-induced pulmonary fibrosis (17,18). Based on these studies, the inhibition of cPLA 2 -α has been proposed as a potential therapeutic strategy for the management of arthritis, bone resorption, and pulmonary inflammation.…”

“…Deletion of PLA 2 g4a, the gene that encodes cPLA 2 -α, attenuates the inflammatory response and lung injury associated with acid aspiration, intravenous infusion of lipopolysaccharidezymosan, and treatment with bleomycin (17,18). Based on these studies, which used the same PLA 2 g4a(−/−) mouse as the one employed in the current series of experiments, the inhibition of cPLA 2 -α was proposed as a potential therapeutic strategy for patients with acid aspiration or bleomycin-induced lung injury or pulmonary sepsis.…”