• Gye Young Park, Yong Gyu Lee, Evgeny Berdyshev, Sharmilee Nyenhuis, Jian Du, Panfeng Fu, Irina A Gorshkova, Yongchao Li, Sangwoon Chung, Manjula Karpurapu, Jing Deng, Ravi Ranjan, Lei Xiao, H Ari Jaffe, Susan J Corbridge, Elizabeth A B Kelly, Nizar N Jarjour, Jerold Chun, Glenn D Prestwich, Eleanna Kaffe, Ioanna Ninou, Vassilis Aidinis, Andrew J Morris, Susan S Smyth, Steven J Ackerman, Viswanathan Natarajan, and John W Christman.
• 1 Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine.
• Am. J. Respir. Crit. Care Med.. 2013 Oct 15;188(8):928-40.

RationaleBioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis.ObjectivesTo define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation.MethodsWe investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice.Measurements And Main ResultsSubsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation.ConclusionsThe ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.

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