A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury

Abstract

Adenosine is a signaling nucleoside that has been implicated in the regulation of asthma and chronic obstructive pulmonary disease. Adenosine signaling can serve both pro-and anti-inflammatory functions in tissues and cells. In this study we examined the contribution of A 1 adenosine receptor (A 1 AR) signaling to the pulmonary inflammation and injury seen in adenosine deaminase-deficient (ADA-deficient) mice, which exhibit elevated adenosine levels. Experiments revealed that transcript levels for the A 1 AR were elevated in the lungs of ADA-deficient mice, in which expression was localized predominantly to alveolar macrophages. Genetic removal of the A 1 AR from ADA-deficient mice resulted in enhanced pulmonary inflammation along with increased mucus metaplasia and alveolar destruction. These changes were associated with the exaggerated expression of the Th2 cytokines IL-4 and IL-13 in the lungs, together with increased expression of chemokines and matrix metalloproteinases. These findings demonstrate that the A 1 AR plays an anti-inflammatory and/or protective role in the pulmonary phenotype seen in ADA-deficient mice, which suggests that A 1 AR signaling may serve to regulate the severity of pulmonary inflammation and remodeling seen in chronic lung diseases by controlling the levels of important mediators of pulmonary inflammation and damage.

Adenosine, an endogenous distress signal, modulates tissue damage and repair

“…72 By contrast, the adenosine A 1 receptor appears to play a protective role in adenosine-dependent pulmonary injury. 61 Thus, in the absence of A 1 receptors increased adenosine causes much more infiltration with eosinophils, neutrophils and lymphocytes. Furthermore, adenosine A 1 receptors were upregulated in the ADA-deficient lung; there were also changes in the other adenosine receptors.…”

“…However, two in vivo studies using A 1 k-o mice have provided evidence that A 1 receptors, probably on macrophages, play a protective role in inflammation. 60,61 Dendritic cells. The dendritic cells are antigen-presenting cells that function to activate T cells.…”

“…By contrast, there were no adaptive changes in the other adenosine receptors when A 1 receptors were knocked out. 39,61 This role of the A 1 receptor could not be easily predicted from the studies on isolated immune cells. It is, however, compatible with the results on a role of A 1 receptors in neuroinflammation related to multiple sclerosis.…”

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…Adenosine, acting at its receptors, promotes granulation tissue formation both directly and indirectly [14][15][16]. It has been shown that A 1 R and A 2A R hasten the resolution of acute inflammation by a variety of mechanisms [17][18][19]. All four adenosine receptor subtypes have also been implicated in revascularization although the A 2A R and A 2B R play the dominant roles in fibrosis.…”

Hyaluronan Fragments Promote Inflammation by Down-Regulating the Anti-Inflammatory A2a Receptor.

“…If adenosine deaminase is only partially knocked out, the mice accumulate adenosine slowly over time, and develop a progressive lung fibrosis with increased myofibroblasts and collagen deposition, presumably by overstimulation of the profibrotic A2bR (36,37). In these models, it is unclear which of the adenosine receptors are the culprits, although adenosine deaminase/ A1 double-knockout mice have increased inflammation (38). In addition, IL-13 transgenic mice, which have increased A1, A2b, and A3, but not the anti-inflammatory A2aR, have recently been shown to have high levels of lung adenosine and increased lung inflammation (39).…”