The role of the adenosinergic system in lung fibrosis
ABSTRACT Adenosine (ADO) is a retaliatory metabolite that is expressed in conditions of injury or stress. During these conditions ATP is released at the extracellular level and is metabolized to adenosine. For this reason, adenosine is defined as a "danger signal" for cells and organs, in addition to its important role as homeostatic regulator. Its physiological functions are mediated through interaction with four specific transmembrane receptors called ADORA1, ADORA2A, ADORA2B and ADORA3. In the lungs of mice and humans all four adenosine receptors are expressed with different roles, having pro- and anti-inflammatory roles, determining bronchoconstriction and regulating lung inflammation and airway remodeling. Adenosine receptors can also promote differentiation of lung fibroblasts into myofibroblasts, typical of the fibrotic event. This last function suggests a potential involvement of adenosine in the fibrotic lung disease processes, which are characterized by different degrees of inflammation and fibrosis. Idiopathic pulmonary fibrosis (IPF) is the pathology with the highest degree of fibrosis and is of unknown etiology and burdened by lack of effective treatments in humans.
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ABSTRACT: 1 The airway response to the inhaled nucleosides, adenosine (6.7 × 10-4-6.7 mg/ml) and guanosine (7.3 × 10-4-1.4 mg/ml) was studied in normal and asthmatic subjects. Airway response, measured in the body plethysmograph, was expressed as percentage change in specific airway conductance (sGaw) from baseline.2 Inhaled adenosine caused no change in sGaw in normal subjects but produced a dose-dependent reduction in sGaw in both allergic and non-allergic asthmatic subjects (76 and 62% reduction respectively at 6.7 mg/ml).3 Kinetics of adenosine induced bronchoconstriction were studied in 12 asthmatic subjects who inhaled a single concentration of adenosine. Bronchoconstriction was maximal within 5 min (42% reduction in sGaw) with partial recovery by 30 min.4 The related nucleoside guanosine caused no change in sGaw in normal or asthmatic subjects.5 Adenosine, but not guanosine, is a potent bronchoconstrictor in asthma suggesting that it may have a specific pharmacological effect.British Journal of Clinical Pharmacology 03/1983; 15(2):161-5. DOI:10.1111/j.1365-2125.2004.02285.x · 3.69 Impact Factor
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ABSTRACT: Recent data from several investigators, including our unit, have provided additional information on the etiology of radiation-induced lung damage. These data suggest that there are two quite separate and distinct mechanisms involved: (a) classical radiation pneumonitis, which ultimately leads to pulmonary fibrosis is primarily due to radiation-induced local cytokine production confined to the field of irradiation; and (b) sporadic radiation pneumonitis, which is an immunologically mediated process resulting in a bilateral lymphocytic alveolitis that results in an "out-of-field" response to localized pulmonary irradiation. Both animal experiments and human studies show that classical radiation pneumonitis has a threshold dose and a narrow sigmoid dose-response curve with increasing morbidity and mortality over a very small dose range. Clinical pneumonitis rarely causes death, whereas in the animal and human studies of classical radiation pneumonitis, all subjects will eventually suffer irreversible pulmonary damage and death. The description of classical radiation pneumonitis is that of an acute inflammatory response to lung irradiation, which is confined to the area of irradiation. Recent studies have also shown that irradiation induces gene transcription and results in the induction and release of proinflammatory cytokines and fibroblast mitogens in a similar fashion to other chronic inflammatory states, and which ultimately results in pulmonary fibrosis. The description of classical radiation pneumonitis does not adequately explain the following observed clinical characteristics: (a) the unpredictable and sporadic onset; (b) the occurrence in only a minority of patients; (c) the dyspnoea experienced, which is out of proportion to the volume of lung irradiated; and (d) the resolution of symptoms without sequelae in the majority of patients. We have demonstrated a bilateral lymphocytic alveolitis of activated T lymphocytes and a diffuse increase in gallium lung scan uptake in patients studied before and 4 to 6 weeks after strictly unilateral lung irradiation. This is suggestive of a hypersensitivity pneumonitis, which gives rise to an "out-of-field" response to localized lung irradiation and hence more accurately describes the clinical picture of radiation pneumonitis. Reevaluation of the mechanisms of pulmonary injury from irradiation suggest that (a) a new term, sporadic radiation pneumonitis, should be introduced to describe the clinical picture of radiation pneumonitis, which is not adequately explained by the classical description and is quite clearly an entirely different process; and (b) that the chronic response to localized lung irradiation that leads to pulmonary fibrosis is largely mediated through the induction and release of tissues cytokines.International Journal of Radiation OncologyBiologyPhysics 02/1995; 31(2):361-9. DOI:10.1016/0360-3016(94)00477-3 · 4.18 Impact Factor
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ABSTRACT: A series of 8-substituted derivatives of 3,7-dimethyl-1-propargylxanthine (DMPX) was synthesized and investigated as A2A adenosine receptor antagonists. Different synthetic strategies for the preparation of DMPX derivatives and analogues were explored. A recently developed synthetic procedure starting from 3-propargyl-5,6-diaminouracil proved to be the method of choice for the preparation of this type of xanthine derivatives. The novel compounds were investigated in radioligand binding studies at the high-affinity adenosine receptor subtypes A1 and A2A and compared with standard A2A adenosine receptor antagonists. Structure-activity relationships were analyzed in detail. 8-Styryl-substituted DMPX derivatives were identified that exhibit high affinity and selectivity for A2A adenosine receptors, including 8-(m-chlorostyryl)-DMPX (CS-DMPX, Ki A2A = 13 nM, 100-fold selective), 8-(m-bromostyryl)-DMPX (BS-DMPX, Ki A2A = 8 nM, 146-fold selective), and 8-(3,4-dimethoxystyryl)-DMPX (Ki A2A = 15 nM, 167-fold selective). These and other novel compounds are superior to the standard A2A adenosine receptor antagonists KF17837 (4) and CSC (5) with respect to A2A affinity and/or selectivity.Journal of Medicinal Chemistry 01/1998; 40(26):4396-405. DOI:10.1021/jm970515+ · 5.48 Impact Factor