title: Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.
abstract: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Black
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Medicine, National Jewish Health, Denver, Colorado, USA;
authors.forename: Evgeny
authors.initials: E
authors.lastname: Berdyshev
authors.affiliation: PharmAkea Inc., San Diego, California, USA; and.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Flavia V
authors.initials: FV
authors.lastname: Castelino
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Shea
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Clemens K
authors.initials: CK
authors.lastname: Probst
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fontaine
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Medicine, National Jewish Health, Denver, Colorado, USA;
authors.forename: Irina
authors.initials: I
authors.lastname: Bronova
authors.affiliation: PharmAkea Inc., San Diego, California, USA; and.
authors.forename: Lance
authors.initials: L
authors.lastname: Goulet
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Neil
authors.initials: N
authors.lastname: Ahluwalia
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Knipe
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA;
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tager
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001565:Benzoates / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D005786:Gene Expression Regulation / Q000502:physiology; D008168:Lung / Q000378:metabolism*; D055370:Lung Injury / Q000139:chemically induced* / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D000099189:Lysophospholipase D
chemical_list: D000903:Antibiotics, Antineoplastic; D001565:Benzoates; D001761:Bleomycin; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C000621188:PAT-048; C032881:lysophosphatidic acid
keywords: bleomycin; ectonucleotide pyrophosphatase/phosphodiesterase 2; lysophosphatidylcholine; lysophospholipase D; mouse model