Adenosine signaling and the regulation of chronic lung disease
Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, 6431 Fannin St., Houston, Texas, 77030, United States Pharmacology [?] Therapeutics
(Impact Factor: 9.72).
07/2009; 123(1):105-116. DOI: 10.1016/j.pharmthera.2009.04.003
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 has 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 these signaling pathway as they pertain to the development of treatment strategies for chronic lung diseases.
Available from: Benjamin Lopez
- "Chronic lung diseases are characterized by inflammation with dysregulated wound healing and tissue remodeling, although little is known about the underlying molecular mechanisms. Evidence from both clinical and animal studies demonstrates that adenosine signaling is involved in the regulation of chronic lung diseases (5-9). Adenosine levels are elevated in exhaled condensates and bronchoalveolar lavage fluid of patients with chronic lung diseases such as asthma and chronic obstructive pulmonary disease COPD (10, 11), whereas diminishing levels of adenosine in animal models of chronic lung disease results in resolution of airway inflammation and remodeling (5). "
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Caffeine is a nonspecific adenosine receptor antagonist used in premature neonates to treat apnea of prematurity. While its use may reduce the incidence of bronchopulmonary dysplasia (BPD), the precise mechanisms remain unknown. Evidence of increased adenosine levels are noted in chronic lung diseases including tracheal aspirates of infants with BPD. Utilizing a well characterized newborn mouse model of alveolar hypoplasia, we hypothesized that hyperoxia-induced alveolar inflammation and hypoplasia is associated with alterations in the adenosine signaling pathway.
Newborn murine pups were exposed to a 14-day period of hyperoxia and daily caffeine administration followed by a 14-day recovery period in room air. Lungs were collected at both time points for bronchoalveolar fluid (BAL) analysis as well as histopathology and mRNA and protein expression.
Caffeine treatment increased inflammation and worsened alveolar hypoplasia in hyperoxia exposed newborn mice. These changes were associated with decreased alveolar type II cell numbers, increased cell apoptosis, and decreased expression of A2A receptors. Following discontinuation of caffeine and hyperoxia, lung histology returned to baseline levels comparable to hyperoxia exposure alone.
Results of this study suggest a potentially adverse role of caffeine on alveolar development in a murine model of hyperoxia-induced alveolar hypoplasia.
Pediatric Research 12/2013; 75(3). DOI:10.1038/pr.2013.233 · 2.31 Impact Factor
Available from: Joel Pounds
- "Accumulating evidence has suggested that elevated adenosine levels in lung are associated with chronic lung diseases in both human and animal models  . An indepth understanding of the biological relevance of Ada in lung will benefit our general understanding of COPD. "
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ABSTRACT: Background. The availability of large complex data sets generated by high throughput technologies has enabled the recent proliferation of disease biomarker studies. However, a recurring problem in deriving biological information from large data sets is how to best incorporate expert knowledge into the biomarker selection process. Objective. To develop a generalizable framework that can incorporate expert knowledge into data-driven processes in a semiautomated way while providing a metric for optimization in a biomarker selection scheme. Methods. The framework was implemented as a pipeline consisting of five components for the identification of signatures from integrated clustering (ISIC). Expert knowledge was integrated into the biomarker identification process using the combination of two distinct approaches; a distance-based clustering approach and an expert knowledge-driven functional selection. Results. The utility of the developed framework ISIC was demonstrated on proteomics data from a study of chronic obstructive pulmonary disease (COPD). Biomarker candidates were identified in a mouse model using ISIC and validated in a study of a human cohort. Conclusions. Expert knowledge can be introduced into a biomarker discovery process in different ways to enhance the robustness of selected marker candidates. Developing strategies for extracting orthogonal and robust features from large data sets increases the chances of success in biomarker identification.
Disease markers 10/2013; 35(5):513-23. DOI:10.1155/2013/613529 · 1.56 Impact Factor
Available from: PubMed Central
- "One inflammatory mediator common to both airway diseases is adenosine, making its receptor signaling pathway a therapeutic target for asthma and COPD. Adenosine levels were increased in the plasma, lavage fluid, and exhaled breath condensate of patients with asthma and COPD, and in animal models that exhibited features of chronic airway disease.72 Moreover, the inhalation of adenosine induced bronchoconstriction in patients with asthma and COPD.73 "
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ABSTRACT: Asthma and chronic obstructive pulmonary disease (COPD) are traditionally recognized as distinct diseases, with some clearly separate characteristic. Asthma originates in childhood, is associated with allergies and eosinophils, and is best treated by targeting inflammation, whereas COPD occurs in adults who smoke, involves neutrophils, and is best treated with bronchodilators and the removal of risk factors. However, the distinction between the two is not always clear. Patients with severe asthma may present with fixed airway obstruction, and patients with COPD may have hyperresponsiveness and eosinophilia. Recognizing and understanding these overlapping features may offer new insight into the mechanisms and treatment of chronic airway inflammatory diseases.
Allergy, asthma & immunology research 10/2010; 2(4):209-14. DOI:10.4168/aair.2010.2.4.209 · 2.43 Impact Factor
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