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 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.
Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany.
Jörg
J
Reutershan
Irene
I
Vollmer
Stefanie
S
Stark
Rosalyn
R
Wagner
Kristian-Christos
KC
Ngamsri
Holger K
HK
Eltzschig
D015720:5'-Nucleotidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008171:Lung Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects*; D009708:Nucleotidases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012995:Solubility; D014158:Transcription, Genetic / Q000187:drug effects
D015703:Antigens, CD; D008070:Lipopolysaccharides; D009708:Nucleotidases; C030287:nucleotidase; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine