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Published ahead of print on October 7, 2004, doi:10.1165/rcmb.2004-0103OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 1, January 2005, 2-8

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Submitted on March 29, 2004
Revised on October 7, 2004

Synergy between A2B Adenosine Receptors and Hypoxia in Activating Human Lung Fibroblasts

Hongyan Zhong1, Luiz Belardinelli1, Tenning Maa1, and Dewan Zeng1*

1 Drug Research and Pharmacological Sciences, CV Therapeutics, Inc., Palo Alto, CA, USA

* To whom correspondence should be addressed. E-mail: dewan.zeng{at}cvt.com.

Chronic inflammatory airway diseases such as asthma, COPD and pulmonary fibrosis are associated with sub-epithelial fibroblast activation, myofibroblast hyperplasia, hypoxia and increase in interstitial adenosine concentrations. The goal of this study was to determine the effect of adenosine and its receptors on activation of human lung fibroblasts (HLFs) under normoxia (21% O2) and hypoxia (5% O2). Under the normoxic condition, adenosine and its stable analog, NECA, via activation of A2B adenosine receptors, increased the release of IL-6 by 14-fold and induced the differentiation of HLFs to myofibroblasts. This latter effect of NECA was abolished by an IL-6 neutralizing antibody. Hypoxia increased the release of IL-6 by 2.8-fold, and there was a synergy between hypoxia and activation of A2B adenosine receptors to increase the release of IL-6 and to induce differentiation of fibroblasts into myofibroblasts. Hypoxia increased the expression of A2B adenosine receptors by 3.4-fold. Altogether, these data suggest that hypoxia amplifies the effect of adenosine on the release of IL-6 and cell differentiation by upregulating the expression of A2B adenosine receptors. Our findings provide a novel mechanism whereby adenosine may participate in the remodeling process of inflammatory lung diseases.




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