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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 A2 (cPLA2) in pulmonary fibrosis using cPLA2-null mutant mice, as cPLA2 is a key enzyme in the generation of pro-inflammatory eicosanoids. Disruption of the gene encoding cPLA2 (Pla2g4a) attenuated IPF and inflammation induced by bleomycin administration. Bleomycin-induced overproduction of thromboxanes and leukotrienes in lung was significantly reduced in cPLA2-null mice. Our data suggest that cPLA2 has an important role in the pathogenesis of pulmonary fibrosis. The inhibition of cPLA2-initiated pathways might provide a novel therapeutic approach to pulmonary fibrosis, for which no pharmaceutical agents are currently available.

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Figure 1: Physiological roles of cPLA2 in IPF induced by bleomycin treatment.
Figure 2: Photomicrograph of lung tissues from wild-type and cPLA2-null mice 14 d after bleomycin administration.
Figure 3: Histopathological roles of cPLA2 in pulmonary fibrosis induced by bleomycin treatment.
Figure 4: Roles of cPLA2 in leukocyte infiltration associated with pulmonary fibrosis induced by bleomycin treatment.

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Acknowledgements

We thank Y. Tateno, R. Mitsuzono, M. Yoshino, C. Ohkawara, T. Sato, H. Shiozawa, Y. Matsumoto and M. Ito for technical assistance; and F. Takaku and T. Yokomizo for valuable suggestions. This work was supported in part by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, and grants from the Human Science Foundation.

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Correspondence to Takahide Nagase.

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Nagase, T., Uozumi, N., Ishii, S. et al. A pivotal role of cytosolic phospholipase A2 in bleomycin-induced pulmonary fibrosis. Nat Med 8, 480–484 (2002). https://doi.org/10.1038/nm0502-480

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