RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of idiopathic PAH. OBJECTIVES: To systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from explanted lungs of patients with idiopathic PAH versus healthy donor lungs and to demonstrate functional relevance by blocking stromal-derived factor-1 by the Spiegelmer NOX-A12 in monocrotaline-induced pulmonary hypertension in rats. METHODS: Immunohistochemistry was performed on lung tissue sections from patients with idiopathic PAH and healthy donors. All positively stained cells in whole-lung tissue sections, surrounding the vessels, and in the different compartments of the vessels were counted. To study the effects of blocking SDF-1, rats with monocrotaline-induced pulmonary hypertension were treated with NOX-A12 from Day 21 to Day 35 after monocrotaline administration. MEASUREMENTS AND MAIN RESULTS: We found a significant increase of the perivascular number of macrophages (CD68(+)), macrophages/monocytes (CD14(+)), mast cells (toluidine blue(+)), dendritic cells (CD209(+)), T cells (CD3(+)), cytotoxic T cells (CD8(+)), and helper T cells (CD4(+)) in vessels of idiopathic PAH lungs compared with control subjects. FoxP3(+) mononuclear cells were significantly decreased. In the monocrotaline model, the NOX-A12-induced reduction of mast cells, CD68(+) macrophages, and CD3(+) T cells was associated with improvement of hemodynamics and pulmonary vascular remodeling. CONCLUSIONS: Our findings reveal altered perivascular inflammatory cell infiltration in pulmonary vascular lesions of patients with idiopathic pulmonary arterial hypertension. Targeting attraction of inflammatory cells by blocking stromal-derived factor-1 may be a novel approach for treatment of PAH.
RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of idiopathic PAH. OBJECTIVES: To systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from explanted lungs of patients with idiopathic PAH versus healthy donor lungs and to demonstrate functional relevance by blocking stromal-derived factor-1 by the Spiegelmer NOX-A12 in monocrotaline-induced pulmonary hypertension in rats. METHODS: Immunohistochemistry was performed on lung tissue sections from patients with idiopathic PAH and healthy donors. All positively stained cells in whole-lung tissue sections, surrounding the vessels, and in the different compartments of the vessels were counted. To study the effects of blocking SDF-1, rats with monocrotaline-induced pulmonary hypertension were treated with NOX-A12 from Day 21 to Day 35 after monocrotaline administration. MEASUREMENTS AND MAIN RESULTS: We found a significant increase of the perivascular number of macrophages (CD68(+)), macrophages/monocytes (CD14(+)), mast cells (toluidine blue(+)), dendritic cells (CD209(+)), T cells (CD3(+)), cytotoxic T cells (CD8(+)), and helper T cells (CD4(+)) in vessels of idiopathic PAH lungs compared with control subjects. FoxP3(+) mononuclear cells were significantly decreased. In the monocrotaline model, the NOX-A12-induced reduction of mast cells, CD68(+) macrophages, and CD3(+) T cells was associated with improvement of hemodynamics and pulmonary vascular remodeling. CONCLUSIONS: Our findings reveal altered perivascular inflammatory cell infiltration in pulmonary vascular lesions of patients with idiopathic pulmonary arterial hypertension. Targeting attraction of inflammatory cells by blocking stromal-derived factor-1 may be a novel approach for treatment of PAH.
Authors: Daniela Farkas; Aysar A Alhussaini; Donatas Kraskauskas; Vita Kraskauskiene; Carlyne D Cool; Mark R Nicolls; Ramesh Natarajan; Laszlo Farkas Journal: Am J Respir Cell Mol Biol Date: 2014-09 Impact factor: 6.914
Authors: Grégoire Ruffenach; Ellen O'Connor; Mylène Vaillancourt; Jason Hong; Nancy Cao; Shervin Sarji; Shayan Moazeni; Jeremy Papesh; Victor Grijalva; Christine M Cunningham; Le Shu; Arnab Chattopadhyay; Shuchita Tiwari; Olaf Mercier; Frédéric Perros; Soban Umar; Xia Yang; Aldrin V Gomes; Alan M Fogelman; Srinivasa T Reddy; Mansoureh Eghbali Journal: Hypertension Date: 2020-07-27 Impact factor: 10.190
Authors: Jason M Elinoff; Adrien J Mazer; Rongman Cai; Mengyun Lu; Grace Graninger; Bonnie Harper; Gabriela A Ferreyra; Junfeng Sun; Michael A Solomon; Robert L Danner Journal: Am J Physiol Lung Cell Mol Physiol Date: 2019-10-16 Impact factor: 5.464
Authors: Ling Yan; Xinping Chen; Megha Talati; Bethany Womack Nunley; Santhi Gladson; Tom Blackwell; Joy Cogan; Eric Austin; Ferrin Wheeler; James Loyd; James West; Rizwan Hamid Journal: Am J Respir Crit Care Med Date: 2016-04-15 Impact factor: 21.405
Authors: Rasa Tamosiuniene; Olga Manouvakhova; Paul Mesange; Toshie Saito; Jin Qian; Mrinmoy Sanyal; Yu-Chun Lin; Linh P Nguyen; Amir Luria; Allen B Tu; Joshua M Sante; Marlene Rabinovitch; Desmond J Fitzgerald; Brian B Graham; Aida Habtezion; Norbert F Voelkel; Laure Aurelian; Mark R Nicolls Journal: Circ Res Date: 2018-03-15 Impact factor: 17.367