Chronic inflammatory airway diseases, such as
asthma,
chronic obstructive pulmonary disease and
pulmonary fibrosis, are associated with subepithelial 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 under normoxia (21% O2) and
hypoxia (5% O2). Under the normoxic condition,
adenosine and its stable analog, 5'-(N-ethylcarboxamido)-adenosine, via activation of A2B
adenosine receptors, increased the release of
interleukin (IL)-6 by 14-fold and induced the differentiation of human lung fibroblasts to myofibroblasts. This latter effect of 5'-(N-ethylcarboxamido)-adenosine 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 participates in the remodeling process of inflammatory
lung diseases.