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Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling

¹ Division of Pulmonary Sciences, Department of Medicine, ² Department of Pathology, and ³ Division of Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Laimute Taraseviciene-Stewart, Ph.D., Division of Pulmonary Sciences and Critical Care Medicine, 4200 East Ninth Avenue, C272, Denver, CO 80262. E-mail: laima.taraseviciene{at}uchsc.edu

Rationale: Severe pulmonary arterial hypertension (SPH) is a frequently lethal condition characterized by pulmonary vascular remodeling and right heart strain or failure. SPH is also often associated with autoimmune and collagen vascular disorders.

Objectives: To study the effects of T cells on the development of experimental SPH.

Methods: Athymic nude rats lacking T cells were treated with a single subcutaneous injection of vascular endothelial growth factor (VEGF) receptor blocker SU5416 (20 mg/kg) to induce pulmonary vascular endothelial cell apoptosis. Immunohistochemical analysis and IL-4 levels of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry.

Measurements and Main Results: In contrast to SU5416-treated euthymic rats that develop SPH only in combination with chronic hypoxia, athymic nude rats developed SPH and vascular remodeling (similar to clinical SPH) at normoxic conditions as demonstrated by measurements of pulmonary artery pressure and right ventricle hypertrophy. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells, and macrophages. IL-4, proliferating cell nuclear antigen, and collagen type I levels were markedly increased in SU5416-treated athymic rat lungs. Antibody deposition was noted along the vascular endothelium in rats with SPH. Finally, protection from SPH was conferred by immune challenge with spleen cells from euthymic nude rats.

Conclusions: These studies demonstrate the importance of a complete, intact immune system in protecting against pulmonary angioproliferation in this new model of SPH as well as the importance of intact VEGF receptor signaling for lung endothelial cell homeostasis.

Key Words: pulmonary hypertension • T cells • apoptosis • proliferation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There is no experimental model of immune mechanism–dependent severe pulmonary hypertension. What This Study Adds to the Field T-cell deficiency confers increased pulmonary arterial hypertension and vascular remodeling.

 

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