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

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 ectoapyrase (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. FASEB J. 23, 473‐482 (2009)