Adenosine Signaling in Asthma and Chronic Obstructive Pulmonary Disease

Amir Mohsenin; Michael R. Blackburn

Curr Opin Pulm Med. 2006;12(1):54-59.

Abstract and Introduction

Abstract

Purpose of Review: The chronic lung diseases, asthma and chronic obstructive pulmonary disease, are pulmonary disorders in which persistent inflammation and alterations in lung structure contribute to a progressive loss of lung function. Although the exact type of inflammation and damage in each disease is distinct, they share the common feature that they are chronic in nature. Despite efforts, little is known about the cellular and molecular mechanisms that drive the chronicity of these two diseases. This review will summarize important findings regarding the role of adenosine, a signaling nucleoside implicated in the pathogenesis of these two disorders.
Recent Findings: Aerosolized adenosine induces bronchoconstriction in patients with asthma and chronic obstructive pulmonary disease primarily through the release of mast cell mediators. In this setting it can not only be used to aid in diagnosis but also to monitor patient responses to steroid therapy. Adenosine levels are elevated in the lungs of asthma patients, indicating greater flux through adenosine receptor signaling pathways. In-vitro studies have shown adenosine to access pathways leading to the genesis of chronic inflammation via the release of proinflammatory cytokines and chemokines. Animal studies demonstrate that merely elevating adenosine levels in the mouse is sufficient to induce a pulmonary phenotype with features of asthma and chronic obstructive pulmonary disease.
Summary: Identifying mediators regulating the chronic nature of asthma and chronic obstructive pulmonary disease is critical towards advancements in treatment options. Adenosine has been implicated in promoting the inflammation and airway remodeling seen in chronic lung disease and thus makes an attractive therapeutic target.

Introduction

The chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are pulmonary disorders in which persistent inflammation and alterations in lung structure contribute to a progressive loss of lung function. The inflammatory response involves the recruitment of multiple cell types and results in the release of numerous soluble mediators that drive inflammation. These mediators are composed, in part, of cytokines and chemokines that are involved in the injury and repair process, but due to aberrant regulatory mechanisms remain elevated and result in tissue destruction and remodeling.^[1,2,3] Although the exact type of inflammation and damage in each disease is distinct, they share the common feature that they are chronic in nature. Despite efforts, little is known about the cellular and molecular mechanisms that drive the chronicity of these two diseases.

Adenosine is a purine nucleoside and breakdown product of ATP. During times of cellular stress and damage when the demand for ATP is high, adenosine generation is increased through the actions of ATPases and nucleotidases, which cleave the high-energy phosphate bonds, producing the parent nucleoside. For example, adenosine levels have been shown to increase during hypoxia and sepsis.^[4,5] Once formed, adenosine is a potent signaling molecule and can exert a wide variety of effects through the engagement of specific G-protein-coupled receptors on cell surfaces. Four adenosine receptors have been identified, each with a unique affinity for the ligand, and are termed A₁AR, A_2AAR, A_2BAR and A₃AR.^[6] These receptors have a broad distribution in the body and can access multiple signaling pathways to elicit cellular responses.

Adenosine has well described antiinflammatory and tissue protective effects in situations such as ischemia-reperfusion injury and acute inflammation.^[7*] In chronic conditions, however, such as asthma and COPD, adenosine can play a proinflammatory and tissue-destructive role.^[8] The aim of this review is to assess the current literature with regards to adenosine's role in asthma and COPD while also examining adenosine's role in animal models of chronic lung disease.

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References

Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest
** of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 84).

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