Adenosine signaling and the regulation of chronic lung disease

Abstract

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and interstitial lung disease are characterized by inflammation and tissue remodeling processes that compromise pulmonary function. Adenosine is produced in the inflamed and damaged lung where it plays numerous roles in the regulation of inflammation and tissue remodeling. Extracellular adenosine serves as an autocrine and paracrine signaling molecule by engaging cell surface adenosine receptors. Preclinical and cellular studies suggest that adenosine plays an anti-inflammatory role in processes associated with acute lung disease, where activation of the A2AR and A2BR have promising implications for the treatment of these disorders. In contrast, there is growing evidence that adenosine signaling through the A1R, A2BR and A3R may serve pro-inflammatory and tissue remodeling functions in chronic lung diseases. This review discusses the current progress of research efforts and clinical trials aimed at understanding the complexities of this signaling pathway as they pertain to the development of treatment strategies for chronic lung diseases.

Adenosine A2B Receptor and Hyaluronan Modulate Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Disease

“…These differences can be explained by pointing out that in the Ada 2/2 model, elevated levels of adenosine promote the destruction of the airway, but may also contribute to the heightened airway resistance. Indeed, several studies showed elevated levels of adenosine in the exhale condensate of patients with asthma that were thought to be responsible for the increased airway hyperresponsiveness reported in these patients (26). In addition, Ada 2/2 mice also present with lung fibrosis (19), which can also contribute to the increases in resistance and elastance and the reduction in compliance (18) reported here.…”

“…One molecule that is generated under these conditions of chronic inflammation, emphysema, and hypoxia is the signaling molecule adenosine (22,35). Elements of the adenosinergic signaling system are known to be elevated in chronic lung diseases, including COPD and IPF (26,27). However, little is known of how adenosine is able to orchestrate the remodeling of the vasculature leading to PH in COPD.…”

“…Adenosine is largely generated in response to cell injury, where it exerts both protective and detrimental effects (18,19,25). In the context of chronic lung disease, the engagement of ADORA2B via elevated adenosine levels has been implicated in disease progression and tissue remodeling (19,26). Indeed, increased levels of ADORA2B transcript levels are observed in lung samples from patients with COPD and IPF (27).…”

Special Consideration in Treating Patients of Overlap Between Asthma and COPD

“…Adenosine levels have been shown to increase in patients with asthma and COPD and in animal models having features of chronic airway disease (Zhou et al, 2009). Moreover, inhalation of adenosine induces bronchoconstriction in patients with asthma and COPD (Caruso et al, 2007).…”

“…Moreover, inhalation of adenosine induces bronchoconstriction in patients with asthma and COPD (Caruso et al, 2007). A non-selective adenosine receptor antagonist, theophylline, improves lung function and symptoms in asthma and COPD (Caruso et al, 2007;Zhou et al, 2009). Furthermore, adenosine receptors are expressed on most, if not all, inflammatory and stromal cell types involved in the pathogenesis of asthma and COPD.…”