Published ahead of print on April 5, 2007, doi:10.1164/rccm.200608-1189OC
Am. J. Respir. Crit. Care Med., Volume 175, Number 12, June 2007, 1280-1289
A more recent version of this article appeared on June 15, 2007
Submitted on August 21, 2006
Accepted on April 5, 2007
Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling
Laimute Taraseviciene-Stewart1*, Mark R Nicolls1, Donatas Kraskauskas1, Robertas Scerbavicius1, Nana Burns1, Carlyne Cool2, Kathy Wood2, Jane E Parr2, Susan A Boackle3, and Norbert F Voelkel1
1 Division of Pulmonary Sciences, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA,
2 Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA,
3 Division of Rheumatology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. 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 receptor blocker SU5416 (20 mg/kg) in order to induce pulmonary vascular endothelial cell apoptosis. Measurements of pulmonary artery pressure, right ventricle hypertrophy, IL-4 levels and immunohistochemical analysis of the lung tissue were performed. Cell death and proliferation were assessed by Western blot and immunohistochemistry.
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. Pulmonary arterioles became occluded with proliferating endothelial cells and were surrounded by mast cells, B cells and macrophages. IL-4, PCNA 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
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