The adenosine A2a receptor inhibits matrix-induced inflammation in a novel fashion

Kara A. Scheibner, Sada Boodoo, Samuel Collins, Katharine E. Black, Yee Chan-Li, Paul Zarek, Jonathan D. Powell, Maureen R. Horton

Research output: Contribution to journalArticlepeer-review

Abstract

Endogenous mediators within the inflammatory milieu play a critical role in directing the scope, duration, and resolution of inflammation. High-molecular-weight extracellular matrix hyaluronan (HA) helps to maintain homeostasis. During inflammation, hyaluronan is broken down into fragments that induce chemokines and cytokines, thereby augmenting the inflammatory response. Tissue-derived adenosine, released during inflammation, inhibits inflammation via the anti-inflammatory A2 adenosine receptor (A2aR). We demonstrate that adenosine modulates HA-induced gene expression via the A2aR. A2aR stimulation inhibits HA fragment-induced pro-fibrotic genes TNF-α, keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-2, and MIP-1α while simultaneously synergizing with hyaluronan fragments to up-regulate the TH1 cytokine 1L-12. Interestingly, A2aR stimulation mediates these affects via the novel cAMP-activated guanine nucleotide exchange factor EPAC. In addition, A2aR-null mice are more susceptible to bleomycin-induced lung injury, consistent with a role for endogenous adenosine in inhibiting the inflammation that may lead to fibrosis. Indeed, the bleomycin treated A2aR-null mice demonstrate increased lung inflammation, HA accumulation, and histologic damage. Overall, our data elucidate the opposing roles of tissue-derived HA fragments and adenosine in regulating noninfectious lung inflammation and support the pursuit of A2aR agonists as a means of pharmacologically inhibiting inflammation that may lead to fibrosis.

Original languageEnglish (US)
Pages (from-to)251-259
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume40
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Keywords

  • Adenosine
  • Chemokines
  • Hyaluronan
  • Lung fibrosis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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