Adenosine and Inflammation: CD39 and CD73 Are Critical Mediators in LPS-induced PMN Trafficking Into the Lungs

FASEB J. 2009 Feb;23(2):473-82. doi: 10.1096/fj.08-119701. Epub 2008 Oct 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / deficiency
  • 5'-Nucleotidase / genetics
  • 5'-Nucleotidase / metabolism*
  • Adenosine / metabolism
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apyrase / deficiency
  • Apyrase / genetics
  • Apyrase / metabolism*
  • Cell Movement / drug effects*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lipopolysaccharides / pharmacology
  • Lung Diseases / chemically induced
  • Lung Diseases / genetics
  • Lung Diseases / metabolism*
  • Lung Diseases / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Neutrophils / cytology*
  • Neutrophils / drug effects*
  • Nucleotidases / metabolism
  • Phosphorylation / drug effects
  • Solubility
  • Transcription, Genetic / drug effects

Substances

  • Antigens, CD
  • Lipopolysaccharides
  • Nucleotidases
  • nucleotidase
  • 5'-Nucleotidase
  • Apyrase
  • CD39 antigen
  • Adenosine