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.

Keywords: 1-deoxy-1,6[[(3-iodophenyl)methyl]amino]-9H-purin-9yl-N-methyl-B-d-ribofuronamide; 1-propyl-8-p-sulfophenulxanthine; 2 hexynyl-5′-N ethylcarboxamidoadenosine; 2-(2-phenyl)ethynyl-N-ethylcarboxamido-adenosine; 2-CI-IB MECA; 2-chloro-N6-cyclopentyladenosine; 2-cloro-N6-(3-iodobenzyl)-adenosine-50-N methyluronamide; 2-methyl-6-phenyl-4-phenylethynyl-1,4-dihydro-pyridine-3,5-dicarboxylicacid-3-ethyl ester-5-(4-nitro-benzyl)ester; 2-p-(2-carboxyethyl) phenethylamino-50-N-ethyl-carboxamidoadenosine; 2-phenyl hydroxypropynyl-5′-N-ethylcarboxamido adenosine phosphoinositide 3; 3-ethyl-1-propyl-8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1H-purine-2,6(3H,7H)-dione; 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate; 3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate; 4-(2-[7-amino-2-(2-furyl)-{1,2,4}-triazolo{2,3-a}{1,3,5}triazin-5-ylamino]ethyl)pieno; 5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)pyra-zolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine; 7-methyl-[11C]-(E)-8-(3-bromostyryl)-3,7-dimethyl-1-propargylxanthin; 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-l,3-dipropylxanthine; 8-cyclopentyl-1,3-dipropylxanthine; 9-chloro-2-(2-furanyl)-5-[(phenylacetyl) amino] [1,2,4]-triazolo[1,5-c]quinazoline; 9-chloro-2-(2-furanyl)-[1,2,4]triazolo[1,5-c]quinazolin-5-amine; A(1)R; A(2A)R; A(2B)R; A(3)R; AB-MECA; ADA; ADO; ADORA 1 receptor; ADORA 2A receptor; ADORA 2B receptor; ADORA 3 receptor; ADP; AIP; AK; AMP; ARs; ATP; Adenosine; Adenosine receptors; Bleomycin; CCPA; CD39; CD73; CGS 15943; CGS21680; CHA; CNS; CNT-1; CNT-2; COP; COPD; CPA; CVT6883; DAG; DIP; DPCPX; E-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine; ECM; ENT-1; ENT-2; ET-1; FITC; HE-NECA; IB-MECA; IIPs; ILD; INO; IPF; Idiopathic pulmonary fibrosis; KF17837; LIP; Lung disease; MAP; MRE3008-F207; MRS 1191; MRS 1220; MRS 1334; MRS 1523; MRS 1754; N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide; N-ethylcarboxamido-adenosine; N6-(2-phenylisopropyl)adenosine; N6-(4-aminobenzyl)-adenosine-5′-N-methyluronamidedihydrochloride; N6-cyclohexyl adenosine; N6-cyclopentyladenosine; NECA; NSPI; PAH; PENECA; PHPNECA; PIA; PKC; PLA2; PLC; PLD; PSB1115; RB-ILD; ROS; SCH-58261; UIP; XAC; ZM 241385; [11C]BS-DMPX; [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine]; acute interstitial pneumonia; adenosine; adenosine deaminase; adenosine diphosphate; adenosine kinase; adenosine monophosphate; adenosine receptors; adenosine triphosphate; cAMP; central nervous system; chronic obstructive pulmonary diseases; concentrative nucleoside transporters-1; concentrative nucleoside transporters-2; cryptogenic organizing pneumonia; cyclic adenosine monophosphate; desquamative interstitial pneumonia; diacylglycerol; ecto-5′-nucleotidase; ectonucleoside triphosphate diphosphohydrolase; endothelin 1; equilibrative nucleoside transporters-1; equilibrative nucleoside transporters-2; extracellular matrix; fluorescein isothiocyanate; idiopathic interstitial pneumonias; idiopathic pulmonary fibrosis; inosine; interstitial lung disease; lymphocytic interstitial pneumonia; mitogen-activated protein; nonspecific interstitial pneumonia; phospholipase A2; phospholipase C; phospholipase D; protein kinase C; pulmonary arterial hypertension; reactive oxygen specie; respiratory bronchiolitis-associated interstitial lung disease; usual interstitial pneumonia.