Lysophosphatidic acid (LPA) is an important mediator of
pulmonary fibrosis. In blood and multiple
tumor types, autotaxin produces LPA from
lysophosphatidylcholine (LPC) via
lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a
bleomycin mouse model. We found that
bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX
protein 17-fold. However, the LPA and LPC species that increase in BAL of
bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in
pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after
bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor
PAT-048 to
bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or
fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in
pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following
lung injury, but is not required for pulmonary
lysophosphatidic acid production or
fibrosis.