A. K. Alencar, G. C. Montes, E. J. Barreiro, R. T. Sudo, and G. Zapata-sudo, Adenosine receptors as drug targets for treatment of pulmonary arterial hypertension, Front. Pharmacol, vol.8, p.858, 2017.

S. L. Archer, E. K. Weir, and M. R. Wilkins, Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies, Circulation, vol.121, pp.2045-2066, 2010.

J. Avouac, I. Konstantinova, C. Guignabert, S. Pezet, J. Sadoine et al., Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension, Ann. Rheum. Dis, vol.76, 1931.

J. Behr and J. H. Ryu, Pulmonary hypertension in interstitial lung disease, Eur. Respir. J, vol.31, pp.1357-1367, 2008.

Y. Bei, T. Hua-huy, S. Duong-quy, V. H. Nguyen, W. Chen et al., Long-term treatment with fasudil improves bleomycininduced pulmonary fibrosis and pulmonary hypertension via inhibition of Smad2/3 phosphorylation, Pulm. Pharmacol. Ther, vol.26, pp.635-643, 2013.

M. R. Blackburn, Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice, Trends Pharmacol. Sci, vol.24, pp.66-70, 2003.

M. R. Blackburn and R. E. Kellems, Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation, Adv. Immunol, vol.86, pp.1-41, 2005.

N. Y. Chen, S. Collum, F. Luo, T. Weng, T. T. Le et al., Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.311, pp.238-254, 2016.

J. L. Chunn, A. Mohsenin, H. W. Young, C. G. Lee, J. A. Elias et al., Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.290, pp.579-587, 2006.

L. Ciuclan, O. Bonneau, M. Hussey, N. Duggan, A. M. Holmes et al., A novel murine model of severe pulmonary arterial hypertension, Am. J. Respir. Crit. Care Med, vol.184, pp.1171-1182, 2011.

S. P. Colgan, H. K. Eltzschig, T. Eckle, and L. F. Thompson, Physiological roles for ecto-5 ? -nucleotidase (CD73), Purinergic Signal, vol.2, pp.351-360, 2006.

S. D. Collum, J. Amione-guerra, A. S. Cruz-solbes, A. Difrancesco, A. M. Hernandez et al., Pulmonary hypertension associated with idiopathic pulmonary fibrosis: current and future perspectives, Can. Respir. J, p.1430350, 2017.

S. D. Collum, N. Y. Chen, A. M. Hernandez, A. Hanmandlu, H. Sweeney et al., Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis, Br. J. Pharmacol, vol.174, pp.3284-3301, 2017.

J. Davies, H. Karmouty-quintana, T. T. Le, N. Y. Chen, T. Weng et al., Adenosine promotes vascular barrier function in hyperoxic lung injury, Physiol Rep, vol.2, p.12155, 2014.

T. R. Diraimondo, C. Klöck, R. Warburton, Z. Herrera, K. Penumatsa et al., Elevated transglutaminase 2 activity is associated with hypoxiainduced experimental pulmonary hypertension in mice, ACS Chem. Biol, vol.9, pp.266-275, 2014.

R. L. Eckert, M. T. Kaartinen, M. Nurminskaya, A. M. Belkin, G. Colak et al., Transglutaminase regulation of cell function, Physiol. Rev, vol.94, pp.383-417, 2014.

T. Eckle, L. Füllbier, M. Wehrmann, J. Khoury, M. Mittelbronn et al., Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury, J. Immunol, vol.178, pp.8127-8137, 2007.

T. Eckle, M. Koeppen, and H. K. Eltzschig, Role of extracellular adenosine in acute lung injury, Physiology, vol.24, pp.298-306, 2009.

H. K. Eltzschig, P. Abdulla, E. Hoffman, K. E. Hamilton, D. Daniels et al., HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia, J. Exp. Med, vol.202, pp.1493-1505, 2005.

L. Farkas, J. Gauldie, N. F. Voelkel, and M. Kolb, Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors, Am. J. Respir. Cell Mol. Biol, vol.45, pp.1-15, 2011.

C. D. Fell, Idiopathic pulmonary fibrosis: phenotypes and comorbidities, Clin. Chest Med, vol.33, pp.51-57, 2012.

D. Ferrari, R. Gambari, M. Idzko, T. Müller, C. Albanesi et al., Purinergic signaling in scarring, FASEB J, vol.30, pp.3-12, 2016.

B. B. Fredholm, Adenosine, an endogenous distress signal, modulates tissue damage and repair, Cell Death Differ, vol.14, pp.1315-1323, 2007.

B. B. Fredholm, A. P. Ijzerman, K. A. Jacobson, K. N. Klotz, and J. Linden, International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors, Pharmacol. Rev, vol.53, pp.527-552, 2001.

L. J. Garcia-morales, N. Y. Chen, T. Weng, F. Luo, J. Davies et al., Altered hypoxic-adenosine axis and metabolism in group III pulmonary hypertension, Am. J. Respir. Cell Mol. Biol, vol.54, pp.574-583, 2016.

H. Grasemann, R. Dhaliwal, J. Ivanovska, C. Kantores, P. J. Mcnamara et al., Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.308, 2015.

C. Guignabert, B. Raffestin, R. Benferhat, W. Raoul, P. Zadigue et al., Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats, Circulation, vol.111, pp.2812-2819, 2005.
URL : https://hal.archives-ouvertes.fr/inserm-00499643

S. Gundemir, G. Colak, J. Tucholski, J. , and G. V. , Transglutaminase 2: a molecular Swiss army knife, Biochim. Biophys. Acta, vol.1823, pp.406-419, 2012.

S. Hansdottir, D. J. Groskreutz, and B. K. Gehlbach, WHO's in second?: A practical review of World Health Organization group 2 pulmonary hypertension, Chest, vol.144, pp.638-650, 2013.

M. L. Hart, I. C. Gorzolla, J. Schittenhelm, S. C. Robson, and H. K. Eltzschig, SP1-dependent induction of CD39 facilitates hepatic ischemic preconditioning, J. Immunol, vol.184, pp.4017-4024, 2010.

A. R. Hemnes, A. Zaiman, and H. C. Champion, PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.294, pp.24-33, 2008.

R. H. Hübner, W. Gitter, N. E. El-mokhtari, M. Mathiak, M. Both et al., Standardized quantification of pulmonary fibrosis in histological samples, Biotechniques, vol.44, pp.514-507, 2008.

A. Huertas, L. Tu, R. Thuillet, M. Le-hiress, C. Phan et al., Leptin signalling system as a target for pulmonary arterial hypertension therapy, Eur. Respir. J, vol.45, pp.1066-1080, 2015.
URL : https://hal.archives-ouvertes.fr/inserm-02578446

E. P. Judge, A. Fabre, H. I. Adamali, and J. J. Egan, Acute exacerbations and pulmonary hypertension in advanced idiopathic pulmonary fibrosis, Eur. Respir. J, vol.40, pp.93-100, 2012.

H. Karmouty-quintana, K. Philip, L. F. Acero, N. Y. Chen, T. Weng et al., Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension, FASEB J, vol.29, pp.50-60, 2015.

H. Karmouty-quintana, T. Weng, L. J. Garcia-morales, N. Y. Chen, M. Pedroza et al., ADORA2B and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease, Am. J. Respir. Cell Mol. Biol, vol.49, pp.1038-1047, 2013.

H. Karmouty-quintana, Y. Xia, and M. R. Blackburn, , 2013.

, Adenosine signaling during acute and chronic disease states, J. Mol. Med, vol.91, pp.173-181

H. Karmouty-quintana, H. Zhong, L. Acero, T. Weng, E. Melicoff et al., The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease, FASEB J, vol.26, pp.2546-2557, 2012.

R. E. Klabunde, Dipyridamole inhibition of adenosine metabolism in human blood, Eur. J. Pharmacol, vol.93, pp.21-26, 1983.

J. R. Klinger, Group III pulmonary hypertension: pulmonary hypertension associated with lung disease: epidemiology, pathophysiology, and treatments, Cardiol. Clin, vol.34, pp.413-433, 2016.

K. J. Lee, L. Czech, G. B. Waypa, and K. N. Farrow, Isolation of pulmonary artery smooth muscle cells from neonatal mice, J. Vis. Exp. e50889, 2013.

P. F. Lennon, C. T. Taylor, G. L. Stahl, and S. P. Colgan, Neutrophilderived 5'-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A2B receptor activation, J. Exp. Med, vol.188, pp.1433-1443, 1998.

C. Liu, R. E. Kellems, and Y. Xia, Inflammation, autoimmunity, and hypertension: the essential role of tissue transglutaminase, Am. J. Hypertens, vol.30, pp.756-764, 2017.

C. Liu, R. Luo, S. E. Elliott, W. Wang, N. F. Parchim et al., Elevated transglutaminase activity triggers angiotensin receptor activating autoantibody production and pathophysiology of Preeclampsia, J Am Heart Assoc, vol.4, p.2323, 2015.

C. Liu, W. Wang, N. Parchim, R. A. Irani, S. C. Blackwell et al., Tissue transglutaminase contributes to the pathogenesis of preeclampsia and stabilizes placental angiotensin receptor type 1 by ubiquitination-preventing isopeptide modification, Hypertension, vol.63, pp.353-361, 2014.

N. W. Morrell, X. Yang, P. D. Upton, K. B. Jourdan, N. Morgan et al., Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins, Circulation, vol.104, pp.790-795, 2001.

K. Oh, H. B. Park, O. J. Byoun, D. M. Shin, E. M. Jeong et al., Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice, J. Exp. Med, vol.208, pp.1707-1719, 2011.

K. C. Olsen, A. P. Epa, A. A. Kulkarni, R. M. Kottmann, C. E. Mccarthy et al., Inhibition of transglutaminase 2, a novel target for pulmonary fibrosis, by two small electrophilic molecules, Am. J. Respir. Cell Mol. Biol, vol.50, pp.737-747, 2014.

K. C. Olsen, R. E. Sapinoro, R. M. Kottmann, A. A. Kulkarni, S. E. Iismaa et al., Transglutaminase 2 and its role in pulmonary fibrosis, Am. J. Respir. Crit. Care Med, vol.184, pp.699-707, 2011.

M. Pedroza, D. J. Schneider, H. Karmouty-quintana, J. Coote, S. Shaw et al., Interleukin-6 contributes to inflammation and remodeling in a model of adenosine mediated lung injury, PLoS ONE, vol.6, p.22667, 2011.

K. C. Penumatsa, D. Toksoz, R. R. Warburton, A. J. Hilmer, T. Liu et al., Role of hypoxia-induced transglutaminase 2 in pulmonary artery smooth muscle cell proliferation, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.307, pp.576-585, 2014.

K. C. Penumatsa, D. Toksoz, R. R. Warburton, M. Kharnaf, I. R. Preston et al., Transglutaminase 2 in pulmonary and cardiac tissue remodeling in experimental pulmonary hypertension, Am. J. Physiol. Lung Cell. Mol. Physiol, vol.313, pp.752-762, 2017.

G. Pitsiou, D. Papakosta, and D. Bouros, Pulmonary hypertension in idiopathic pulmonary fibrosis: a review, Respiration, vol.82, pp.294-304, 2011.

H. D. Poor, R. Girgis, and S. M. Studer, World Health Organization Group III pulmonary hypertension, Prog. Cardiovasc. Dis, vol.55, pp.119-127, 2012.

N. Ricard, L. Tu, M. Le-hiress, A. Huertas, C. Phan et al., Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension, Circulation, vol.129, pp.1586-1597, 2014.
URL : https://hal.archives-ouvertes.fr/inserm-02578269

R. M. Ruggiero, S. Bartolome, and F. Torres, Pulmonary hypertension in parenchymal lung disease, Heart Fail. Clin, vol.8, pp.461-474, 2012.

A. Y. Saadjian, F. Paganelli, M. L. Gaubert, S. Levy, and R. P. Guieu, Adenosine plasma concentration in pulmonary hypertension, Cardiovasc. Res, vol.43, pp.228-236, 1999.

S. Schroll, M. Arzt, D. Sebah, M. Nüchterlein, F. Blumberg et al., Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan, Respir. Physiol. Neurobiol, vol.170, pp.32-36, 2010.

S. Schroll, T. J. Lange, M. Arzt, D. Sebah, A. Nowrotek et al., Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin-treated rats, Acta Physiol, vol.208, pp.191-201, 2013.

A. Song, Y. Zhang, L. Han, G. G. Yegutkin, H. Liu et al., Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent, Nat. Commun, vol.8, p.14108, 2017.

C. X. Sun, H. Zhong, A. Mohsenin, E. Morschl, J. L. Chunn et al., Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury, J. Clin. Invest, vol.116, pp.2173-2182, 2006.

K. Sun, H. Liu, A. Song, J. M. Manalo, A. Hansen et al., Erythrocyte purinergic signaling components underlie hypoxia adaptation, J. Appl. Physiol, vol.123, pp.951-956, 2017.

K. Synnestvedt, G. T. Furuta, K. M. Comerford, N. Louis, J. Karhausen et al., Ecto-5'-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia, J. Clin. Invest, vol.110, pp.993-1002, 2002.

S. Toldo, H. Zhong, E. Mezzaroma, B. W. Van-tassell, H. Kannan et al., GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse, J. Pharmacol. Exp. Ther, vol.343, pp.587-595, 2012.

A. Van-linden and H. K. Eltzschig, Role of pulmonary adenosine during hypoxia: extracellular generation, signaling and metabolism by surface adenosine deaminase/CD26. Expert Opin, Biol. Ther, vol.7, pp.1437-1447, 2007.

Z. Van-rheen, C. Fattman, S. Domarski, S. Majka, D. Klemm et al., Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling, Am. J. Respir. Cell Mol. Biol, vol.44, pp.500-508, 2011.

C. E. Ventetuolo and J. R. Klinger, WHO Group 1 pulmonary arterial hypertension: current and investigative therapies, Prog. Cardiovasc. Dis, vol.55, pp.89-103, 2012.

J. B. Volmer, L. F. Thompson, and M. R. Blackburn, Ecto-5 ? -nucleotidase (CD73)-mediated adenosine production is tissue protective in a model of bleomycin-induced lung injury, J. Immunol, vol.176, pp.4449-4458, 2006.

M. Wakamiya, M. R. Blackburn, R. Jurecic, M. J. Mcarthur, R. S. Geske et al., Disruption of the adenosine-deaminase gene causes hepatocellular impairment and perinatal lethality in mice, Proc. Natl. Acad. Sci. U.S.A, vol.92, pp.3673-3677, 1995.

F. Wirsdörfer, S. De-leve, F. Cappuccini, T. Eldh, A. V. Meyer et al., Extracellular adenosine production by ecto-5 ? -nucleotidase (CD73) enhances radiation-induced lung fibrosis, Cancer Res, vol.76, pp.3045-3056, 2016.

Y. Zhou, J. N. Murthy, D. Zeng, L. Belardinelli, and M. R. Blackburn, Alterations in adenosine metabolism and signaling in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, PLoS ONE, vol.5, p.9224, 2010.

Y. Zhou, D. J. Schneider, and M. R. Blackburn, , 2009.

, Adenosine signaling and the regulation of chronic lung disease, Pharmacol. Ther, vol.123, pp.105-116

M. A. Zimmerman, A. Grenz, E. Tak, M. Kaplan, D. Ridyard et al., Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver, Proc. Natl. Acad. Sci. U.S.A, vol.110, pp.12012-12017, 2013.

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