The overall objective of this fellowship proposal is to evaluate the role of the adaptive immune system in chronic hypoxia (CH)-induced pulmonary hypertension (PH). Our studies support a role for inflammatory cells, specifically T cells in the development of pulmonary vascular disease. CH (PB=380mmHg 3 weeks) exposure generates structural changes in pulmonary arteries, along with biochemical and functional phenotype alterations in the cells composing the arterial wall. Inflammatory cells have been shown to infiltrate vascular lesions associated with certain forms of PH, however the role for inflammatory cells in the development of PH due to CH is poorly understood. The central hypothesis to be tested is that an increase in interleukin-6 (IL-6) in the lung following CH results in TH17 T cell polarization and TH17-mediated soluble IL-6 receptor (sIL-6R) production which contributes to the development of pulmonary hypertension. The following specific aims will be pursued:
Specific Aim 1 : Determine the contribution of the adaptive immune response to CH-induced PH. Hypothesis: TH17 cells contribute to CH-induced PH.
Specific Aim 2 : Determine the role of TH17 cells in the development of pulmonary vascular dysfunction following CH. Hypothesis: An increase in TH17 mediated release of sIL-6R following CH induces pulmonary artery smooth muscle proliferation, migration and hypertrophy, contributing to PH. Experiments are designed to determine the immune cell/s involved pulmonary vascular dysfunction and hypertension utilizing immune-cell deficient mice along with repletion of specific immune cell populations such as TH17 cells followed by exposure to CH or normoxia. Indices of PH will be measured such as right ventricular (RV) systolic pressure, arterial remodeling, and RV hypertrophy. Also, experiments will address whether TH17 cells secrete sIL-6R following CH, and how the secreted sIL-6R results in vascular dysfunction. This research is innovative because it is expected to elucidate novel mechanisms by which chronic exposure to hypoxia leads to pulmonary dysfunction through inflammation. This study is significant in that identifying the specific cell type involved in this response may lead to new immunotherapeutic interventions in patients with hypoxic diseases of the lung. Furthermore, elucidating the connection between cytokines and vascular smooth muscle function will deepen our understanding of the role for inflammation in various diseases characterized by pro- inflammatory states.
This project will investigate mechanisms of inflammation which underlie the progression of pulmonary hypertension following exposure to chronic (3 weeks) hypoxia. Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), are the third leading cause of death in the United States. Respiratory diseases often cause global lung hypoxia leading to pulmonary hypertension resulting in eventual heart failure. While inflammation has been associated with chronic lung diseases, little work has been done to identify the immune cell involvement in pulmonary hypertension due to hypoxia. Results of the current study may lead to advances in the treatment of chronic respiratory diseases, improving patient care and reducing morbidity and mortality.
