Autoimmunity has long been associated with pulmonary hypertension (PH) but has not been systematically examined as a root cause for this frequently fatal condition. Connective tissue disease and viral infections are systemic disorders that are strongly linked with PH and are characterized by or have a propensity to autoimmunity. Using an experimental model of vascular endothelial growth factor receptor (VEGFR) blockade-induced PH, it is evident that autoimmune injury may actually initiate this disease. It has been previously demonstrated that VEGFR blockade leads to pulmonary vascular endothelial cell apoptosis and that if animals are exposed to hypoxemia, PH will ensue. However, this experimental model, as with most experimental models, can not recreate the clinical evolution of PH which occurs in patients living in normoxic environments. Preliminary findings demonstrate that severe PH will develop following VEGFR blockade in Denver altitude conditions if administered to experimental animals that lack T cells (i.e. the athymic nude rat) but not if lymphocytes are restored to these animals. These seminal observations have formed the basis for this revised R01 proposal. The overarching hypothesis for this project is that there is an autoimmune basis for the development of PH. This autoimmunity may be the result of a lack of appropriate regulatory T cell activity.
Specific Aim I will determine whether CD4 or CDS cell populations are responsible for preventing PH in athymic rats treated with VEGFR blockade and test the general hypothesis that T cell subsets are sufficient to prevent VEGFR blockade-induced PH in athymic rats. An additional component of this Aim will be to demonstrate that protection from PH correlates with prevention of anti-endothelial antibody formation.
Specific Aim II will be to determine whether spleen cell protection of VEGFR blockade-induced PH in athymic rats is time-dependent to test the hypothesis that PH may be prevented during a putative initiation phase but becomes irreversible during a progressive phase.
Specific Aim III will be to determine whether PH can be induced in euthymic rats with CD4 depletion and will test the hypothesis that acquired immunodeficiency in wild type rats is sufficient to render these animals susceptible to VEGFR blockade-induced PH. If it can be determined that PH has its roots in autoimmune events, rational therapeutic design can better consider early disease pathogenesis in this frequently lethal condition. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL082662-02
Application #
7256392
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Gail, Dorothy
Project Start
2006-07-01
Project End
2010-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$360,581
Indirect Cost
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Jiang, Xinguo; Tian, Wen; Tu, Allen B et al. (2018) Endothelial HIF-2? is Required for the Maintenance of Airway Microvasculature. Circulation :
Tamosiuniene, Rasa; Manouvakhova, Olga; Mesange, Paul et al. (2018) Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension. Circ Res 122:1689-1702
Saito, Toshie; Miyagawa, Kazuya; Chen, Shih-Yu et al. (2017) Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension. Circulation 136:1920-1935
Voelkel, Norbert F; Tamosiuniene, Rasa; Nicolls, Mark R (2016) Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 14:939-51
Qian, Jin; Tian, Wen; Jiang, Xinguo et al. (2015) Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension. Hypertension 66:1227-1239
Nicolls, Mark R; Laubach, Victor E (2014) Traumatic brain injury: lungs in a RAGE. Sci Transl Med 6:252fs34
Rabinovitch, Marlene; Guignabert, Christophe; Humbert, Marc et al. (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115:165-75
Tian, Wen; Jiang, Xinguo; Sung, Yon K et al. (2014) Leukotrienes in pulmonary arterial hypertension. Immunol Res 58:387-93
Farkas, Daniela; Alhussaini, Aysar A; Kraskauskas, Donatas et al. (2014) Nuclear factor ?B inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats. Am J Respir Cell Mol Biol 51:413-25
Chung, Lorinda; Farber, Harrison W; Benza, Raymond et al. (2014) Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest 146:1494-1504

Showing the most recent 10 out of 38 publications