T helper 2 Inflammation &Severe Muscularization of Arteries in the Lungs Project Summary / Abstract Pulmonary arterial remodeling, characterized by severe muscularization, is commonly seen in infections with helminth parasites that spend part of their life cycle in the pulmonary artery (e.g. Dirofilaria immitis). These parasites induce a T helper 2 (Th2) response. This same type of lesion is also seen in the bronchial artery in asthma, another Th2-response associated disease, particularly in individuals with asthma of long duration, or in asthmatic cigarette smokers. These associations indicate that severe muscularization of the pulmonary or bronchial arteries might be a consequence of a Th2 driven inflammation. Classically, severe pulmonary arterial muscularization has been described in pulmonary arterial hypertension (PAH). An immune-pathology has been suspected in PAH associated with autoimmune diseases such as systemic scleroderma, viral, or parasitic diseases. In preliminary experiments, we have shown that the Th2 response to soluble antigen alone is sufficient to induce severe pulmonary arterial muscularization and increased right ventricular systolic pressures following acute hypoxia. This was induced in immunized C57BL/6 mice that were given intermittent airway challenges over a prolonged period of time with either of two different antigens. CD4+ T cells and Interleukin (IL)-4 were necessary for the development of pulmonary arterial muscularization and transient depletion of an important Th2 cytokine, IL-13, decreased the severity of the lesion. IL-13 alone was not sufficient indicating that a complex Th2 - initiated process induced severe arterial muscularization. Which components of the Th2 response directly cause the arterial muscularization and how the Th2 response components interact are important questions yet to be answered. To address these questions, three specific aims are proposed to identify the roles of T cells and dendritic cells (DCs) and soluble immune mediators (IL-17, IL-33) for the effector phase during which arterial muscularization occurs. Experiments are proposed to deplete or to adoptively transfer T cells, dendritic cells, and soluble immune mediators during the time periods that arterial injury and remodeling occur in the lungs. Using techniques that are securely established in my laboratory, the hypothesis to be tested is that T cells and DCs control the production of IL-17 and IL-33 thereby directly determining the degree of pulmonary arterial muscularization and right ventricular function. The long range goal of this work takes advantage of the mouse model developed in my laboratory to identify targets for the diagnosis, prognosis and management for inflammation associated PAH, such as PAH seen in scleroderma patients. This is unique and significant because a large body of clinical data has suspected the involvement of the immune response, but has not yet dissected the causal relationship between the immune response and severe muscularization of arteries in the lungs.

Public Health Relevance

T helper 2 inflammation &severe muscularization of arteries in the lungs Project Narrative Pulmonary arterial muscularization is a frequent histological lesion seen in pulmonary arterial hypertension (PAH). Severe arterial muscularization is also typical for diseases associated with T helper 2 (Th2) immune responses: helminth parasite infections, auto-immune diseases affecting pulmonary arteries and asthma affecting bronchial arteries. Building on our previous work developing Th2-immune-response induced mouse models of severe pulmonary arterial muscularization, this proposal seeks to identify T cell response controlled cells and mediators that are new targets for the management of pulmonary hypertension associated with severe inflammatory diseases caused for example by auto-immunity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095764-04
Application #
8505019
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Caler, Elisabet V
Project Start
2010-07-01
Project End
2014-11-30
Budget Start
2013-07-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$376,992
Indirect Cost
$141,372
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Durmus, Nedim; Park, Sung-Hyun; Reibman, Joan et al. (2016) Aberrant immune response with consequent vascular and connective tissue remodeling - causal to scleroderma and associated syndromes such as Raynaud phenomenon and other fibrosing syndromes? Curr Opin Rheumatol 28:571-6
Park, Sung-Hyun; Chen, Wen-Chi; Durmus, Nedim et al. (2015) The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles from Air Pollution. PLoS One 10:e0129910
Grunig, Gabriele; Durmus, Nedim (2015) Spotlight on Inflammation in Pulmonary Hypertension. Am J Respir Crit Care Med 192:913-5
Grunig, Gabriele; Baghdassarian, Aram; Park, Sung-Hyun et al. (2015) Challenges and Current Efforts in the Development of Biomarkers for Chronic Inflammatory and Remodeling Conditions of the Lungs. Biomark Insights 10:59-72
Blum, Jason L; Rosenblum, Lauren K; Grunig, Gabriele et al. (2014) Short-term inhalation of cadmium oxide nanoparticles alters pulmonary dynamics associated with lung injury, inflammation, and repair in a mouse model. Inhal Toxicol 26:48-58
Grunig, Gabriele; Marsh, Leigh M; Esmaeil, Nafiseh et al. (2014) Perspective: ambient air pollution: inflammatory response and effects on the lung's vasculature. Pulm Circ 4:25-35
Esmaeil, Nafiseh; Gharagozloo, Marjan; Rezaei, Abbas et al. (2014) Dust events, pulmonary diseases and immune system. Am J Clin Exp Immunol 3:20-9
Bleck, Bertram; Grunig, Gabriele; Chiu, Amanda et al. (2013) MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust particles and ambient particulate matter in human bronchial epithelial cells. J Immunol 190:3757-63
Chen, Wen-Chi; Park, Sung-Hyun; Hoffman, Carol et al. (2013) Right ventricular systolic pressure measurements in combination with harvest of lung and immune tissue samples in mice. J Vis Exp :e50023
Park, Sung-Hyun; Chen, Wen-Chi; Hoffman, Carol et al. (2013) Modification of hemodynamic and immune responses to exposure with a weak antigen by the expression of a hypomorphic BMPR2 gene. PLoS One 8:e55180

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