Immune and Inflammatory Cell Involvement in the Pathology of Idiopathic Pulmonary Arterial Hypertension

• Published in: American journal of respiratory and critical care medicine Vol. 186; no. 9; pp. 897 - 908
• Main Authors: Savai, Rajkumar, Pullamsetti, Soni S., Kolbe, Julia, Bieniek, Ewa, Voswinckel, Robert, Fink, Ludger, Scheed, Axel, Ritter, Christin, Dahal, Bhola K., Vater, Axel, Klussmann, Sven, Ghofrani, Hossein A., Weissmann, Norbert, Klepetko, Walter, Banat, Gamal A., Seeger, Werner, Grimminger, Friedrich, Schermuly, Ralph T.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.11.2012
• Subjects: Adult; Airway Remodeling; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Chemokines; Cytokines; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - immunology; Hypertension, Pulmonary - pathology; Immunohistochemistry; Inflammation; Intensive care medicine; Lung Transplantation; Lungs; Lymphocytes; Male; Medical sciences; Middle Aged; Pathogenesis; Patients; Pulmonary arteries; Pulmonary hypertension; Rats; Tissue Culture Techniques; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Veins & arteries; Young Adult; Germany; Intensive care; Respiratory disease; Idiopathic; Cardiovascular disease; Inflammation; chemokines; Pulmonary hypertension; Chemokine; Vascular remodeling; Anatomic pathology; pulmonary vascular remodeling; inflammatory cells; Inflammatory cell; pulmonary arterial hypertension; Resuscitation
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201202-0335OC

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. 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. 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. 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. 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.