title: The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease.
abstract: Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, 6431 Fannin, Houston, TX 77030, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Karmouty-Quintana
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhong
authors.forename: Luis
authors.initials: L
authors.lastname: Acero
authors.forename: Tingting
authors.initials: T
authors.lastname: Weng
authors.forename: Ernestina
authors.initials: E
authors.lastname: Melicoff
authors.forename: James D
authors.initials: JD
authors.lastname: West
authors.forename: Anna
authors.initials: A
authors.lastname: Hemnes
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.forename: Richard A
authors.initials: RA
authors.lastname: Johnston
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D017563:Lung Diseases, Interstitial / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000150:complications; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D015850:Interleukin-6; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D011720:Pyrazoles; D043704:Receptor, Adenosine A2B; D001761:Bleomycin; D019830:Adenosine-5'-(N-ethylcarboxamide); C518643:3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione