Pulmonary arterial hypertension (PAH) is a multifactorial disease that remains without cure and is characterized by vascular injury, vasoconstriction, and vessel wall remodeling with resultant right ventricular (RV) hypertrophy and eventual failure. A growing body of recent literature has implicated lung inflammation as a critical determinant underlying the development of PAH. Macrophages (M?s), in particular, are prominent components of inflammatory infiltrates observed in the lungs of patients with PAH as well as in animal models of disease. Macrophages respond to environmental signals with remarkable plasticity and undergo different forms of polarized activation that can be broadly categorized as classically-activated (M1) and alternatively- activated (M2). The complexity and diversity of M? activation is rapidly expanding and remains to be fully analyzed. Currently, in addition to M1-M2, there is an anti-inflammatory (regulatory) phenotype that is widely recognized to modulate inflammation and disease. We have demonstrated that alternative activation of M?s is critical for the development of pulmonary hypertension in a hypoxic mouse model (defined as HPH) and that overexpression of the cytoprotective enzyme, heme oxygenase-1 (HO-1), induced a switch in lung M? polarity toward an anti-inflammatory phenotype. Importantly, modulation of early hypoxic inflammation was sufficient to confer protection from HPH under chronic hypoxia. In this proposal, we will test the hypothesis that activated M s promote the vascular injury and vessel wall remodeling underlying the pathogenesis of PAH and will investigate mechanisms of M? activation in HPH, with the goal to identify molecular pathway(s) for therapeutic targeting. We propose the following specific aims:
Aim 1 : Define the role of M polarization in the pathogenesis of HPH.
Aim 2 : Define mechanisms by which HO-1 modulates M phenotype and function.
Aim 3 : Define epigenetic mechanisms that regulate M? phenotype in HPH and identify therapeutic targets.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a lethal disease often seen in association with other chronic lung or autoimmune diseases that affect a large segment of the population. Our group has shown that lung macrophages become activated and likely play a key role in the development of PAH. The main goal of this proposal is to fully characterize macrophage activation and define the epigenetic regulators that modify macrophage phenotype, aiming to test specific small molecule inhibitors to reverse PAH in experimental models of human disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055454-19
Application #
9419317
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xiao, Lei
Project Start
1996-09-06
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
19
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston Children's Hospital
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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