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Titolo/Abstract/Parole chiave

ADENOSINE RECEPTORS IN RESPIRATORY DISORDERS AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MALIGNANT PLEURAL MESOTHELIOMA

Targa, Martina (2012) ADENOSINE RECEPTORS IN RESPIRATORY DISORDERS AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MALIGNANT PLEURAL MESOTHELIOMA. Tesi di Dottorato , Università degli studi di Ferrara.

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    Abstract

    Adenosine is a purine nucleoside that is commonly expressed in the body and involved in a wide range of physiological processes. The effects of adenosine are mediated through specific G-protein coupled cell surface receptors, named A1, A2A, A2B and A3 adenosine receptors (ARs). It is now well recognized that extracellular levels of adenosine markedly increase under metabolically stressful conditions and in the last two decades it has become clear that adenosine is a mediator involved in the pathogenesis of lung inflammatory disorders and in cancer. Indeed adenosine induces bronchoconstriction in animal models and in patients with airway diseases such as asthma and chronic obstructive pulmonary diseases (COPD). COPD is defined as an inflammatory respiratory disease, largely caused by exposure to tobacco smoke. The disease is characterized by a progressive and incompletely reversible airflow obstruction. The key elements of COPD are exposure to cigarette smoke, airway inflammation, and airflow obstruction that is not fully reversible. In addition, an high concentration of adenosine have been reported in cancer tissues, where it appears to be implicated in the growth of tumors, and in the regulation of cell death and proliferation. The development of pleural-based abnormalities such as malignant pleural mesothelioma (MPM), is caused by inhalation of asbestos fibers. To study the interaction between adenosine and pulmonary diseases, the presence and functionality of ARs were explored in human healthy subjects in comparison with COPD patients by using lung tissues and bronchoalveolar lavage (BAL). The aim of this study was to investigate the expression, affinity and density of ARs in peripheral lung parenchyma and in BAL from age-matched smokers with COPD and smokers with normal lung function. The data, obtained in lung samples from COPD patients, suggest a downregulation of A2BARs and an upregulation of A2A and A3ARs. A correlation among ARs expression and clinical parameters such as FEV1/FVC ratio, an established index of airflow obstruction, was observed. Moreover the subcellular location of A2BARs in BAL macrophages of patients with COPD and healthy smokers was investigated, revealing a significant decrease in A2BARs expression in BAL from COPD patients compared to an age-matched group of control smokers with normal lung function. This reduction was associated with a decrease in A2BARs mRNA expression, suggesting a regulation at the transcriptional level. ARs were also studied in MPM patients by using membranes or primary cultures from pleura of MPM patients in comparison with healthy tissues or cells. Furthermore, to better understand the interaction between adenosine and MPM, the presence and the functionality of ARs were explored in healthy mesothelial cells (HMC) and malignant mesothelioma cells (MMC). ARs were analyzed by using RT-PCR, western blotting and saturation binding assays. HMC were treated with crocidolite asbestos, which is the principal risk factor of MPM. The dual effect of ARs stimulation on healthy and cancer cell growth was studied by means of proliferation, apoptosis and cytotoxicity assays. The main result was that A3ARs were up-regulated in MPM when compared with healthy mesothelial pleura. Stimulation of A3ARs decreases proliferation and exerts cytotoxic and pro-apoptotic effect on MMC and on HMC exposed to asbestos and TNF-�, but not in control HMC. These data support the potential for modulating ARs function in pulmonary diseases such as inflammation and cancer. In particular, the modulation of A2BARs by using selective antagonists in alveolar macrophages as a new potential pharmacological tool could be used in the COPD disease. Moreover, the stimulation of A3ARs by selective agonists could be involved as novel pharmacological treatment for malignant pleural mesothelioma.

    Tipologia del documento:Tesi di Dottorato (Tesi di Dottorato)
    Data:8 Marzo 2012
    Relatore:Varani, Katia
    Coordinatore ciclo:Cuneo, Antonio
    Istituzione:Università degli studi di Ferrara
    Dottorato:XXIV Anno 2009 > FARMACOLOGIA E ONCOLOGIA MOLECOLARE
    Struttura:Dipartimento > Medicina clinica e sperimentale
    Soggetti:Area 05 - Scienze biologiche > BIO/14 Farmacologia
    Parole chiave:adenosine receptor, COPD, mesothelioma, BPCO, mesotelioma, cancro, infiammazione, adenosina
    Depositato il:19 Feb 2013 16:57

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