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Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS-induced PMN trafficking into the lungs

Jörg Reutershan^*, Irene Vollmer^*, Stefanie Stark^*, Rosalyn Wagner^*, Kristian-Christos Ngamsri^* and Holger K. Eltzschig^*,,1

^* Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany; and

Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Science Center, Denver, Colorado, USA

¹ Correspondence: Mucosal Inflammation Program, University of Colorado Denver, Department of Anesthesiology and Perioperative Medicine, 12700 E. 19th Ave., Mailstop B112, Research Complex 2, Room 7124, Aurora, CO 80045, USA. E-mail: holger.eltzschig{at}ucdenver.edu

Extracellular adenosine has been implicated as anti-inflammatory signaling molecule during acute lung injury (ALI). The main source of extracellular adenosine stems from a coordinated two-step enzymatic conversion of precursor nucleotides via the ecto-apyrase (CD39) and the ecto-5'-nucleotidase (CD73). In the present study, we hypothesized a critical role of CD39 and CD73 in mediating pulmonary neutrophil (PMN) transmigration during lipopolysaccharide (LPS) -induced lung injury. Initial studies revealed that pulmonary CD39 and CD73 transcript levels were elevated following LPS exposure in vivo. Moreover, LPS-induced accumulation of PMN into the lungs was enhanced in cd39^–/– or cd73^–/– mice, particularly into the interstitial and intra-alveolar compartment. Such increases in PMN trafficking were accompanied by corresponding changes in alveolar-capillary leakage. Similarly, inhibition of extracellular nucleotide phosphohydrolysis with the nonspecific ecto-nucleoside-triphosphate-diphosphohydrolases inhibitor POM-1 confirmed increased pulmonary PMN accumulation in wild-type, but not in gene-targeted mice for cd39 or cd73. Finally, treatment with apyrase or nucleotidase was associated with attenuated pulmonary neutrophil accumulation and pulmonary edema during LPS-induced lung injury. Taken together, these data reveal a previously unrecognized role for CD39 and CD73 in attenuating PMN trafficking into the lungs during LPS-induced lung injury and suggest treatment with their soluble compounds as a therapeutic strategy.—Reutershan, J., Vollmer, I., Stark, S., Wagner, R., Ngamsri, K.-C., Eltzschig, H. K. Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS-induced PMN trafficking into the lungs.

Key Words: acute lung injury • ARDS • neutrophil • PMN • migration • chemotaxis

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