. Control of systemic angiogenesis in the lung remains pooriy understood despite the fact that neovascularization is an integral and pathologic feature of several lung diseases including chronic pulmonary thromboembolism. Ligafing a pulmonary artery in experimental animals models the disease sequelae. We have shown that the innate immune system is critical for the growth of new vessels in mice after left pulmonary artery ligafion (LPAL) where resident macrophages release pro-angiogenic CXC chemokines. Yet, the process whereby neovascularizafion is stopped or slowed is unknown. Preliminary data demonstrate a role for the adaptive immune system in controlling the slow progression or cessation of neovascularizafion. We hypothesize that 1): CD4+ T-cells are recruited to the neovasculature and promote angiostasis. It is known that IL-10 is secreted by CD4+ T-cells, can limit infiammafion, and in our preliminary work, IL-10 deficient mice showed increased angiogenesis 21 days after LPAL compared to wild type LPAL mice. We further hypothesize that 2): angiostasis results from IL-10 release from CD4+ T-cells. Others have shown in vitro that IL-10 can significantly inhibit monocyte differenfiafion through downregulafion of granulocyte macrophage sfimulating factor and inhibit chemokine release from acfivated macrophages. Because we have shown that macrophage derived CXC chemokines appear to be critical for neovascularizafion and that the magnitude of angiogenesis 14 days after LPAL is closely correlated with the number of lung macrophages, we hypothesize that 3): IL-10 directly limits chemokine growth factor release from macrophages as the primary mechanism of angiostasis. Determining the molecular and cellular mechanisms involved in angiostasis is critical for the development of therapeutic strategies to limit chronic inflammation, prevent hemoptysis, and decrease pathologic systemic lung perfusion. Using our well-characterized mouse model of lung neovascularizafion during chronic pulmonary ischemia (>21 days after LPAL), we will determine the subtype of CD4+ T-cell that predominates in this chronic injury model and the mechanisms by which these cells limit lung angiogenesis. We will use flow cytometry, adoptive transfer, transgenic mice, and in vitro coculture, to define the role of CD4+ T-cell subtypes, their associated cytokines, and the mechanisms of angiostasis in the lung during chronic pulmonary ischemia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL010342-44
Application #
8376018
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-02-29
Budget End
2013-02-28
Support Year
44
Fiscal Year
2012
Total Cost
$468,216
Indirect Cost
$185,244
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Oh, Min-Hee; Collins, Samuel L; Sun, Im-Hong et al. (2017) mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages. Cell Rep 20:2439-2454
Craig, John M; Scott, Alan L; Mitzner, Wayne (2017) Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models. Cell Tissue Res 367:591-605
Moldobaeva, Aigul; Jenkins, John; Zhong, Qiong et al. (2017) Lymphangiogenesis in rat asthma model. Angiogenesis 20:73-84
Hallowell, R W; Collins, S L; Craig, J M et al. (2017) mTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis. Nat Commun 8:14208
Lin, Amanda H Y; Shang, Yan; Mitzner, Wayne et al. (2016) Aberrant DNA Methylation of Phosphodiesterase [corrected] 4D Alters Airway Smooth Muscle Cell Phenotypes. Am J Respir Cell Mol Biol 54:241-9
Zhong, Qiong; Jenkins, John; Moldobaeva, Aigul et al. (2016) Effector T Cells and Ischemia-Induced Systemic Angiogenesis in the Lung. Am J Respir Cell Mol Biol 54:394-401
Vigeland, Christine L; Collins, Samuel L; Chan-Li, Yee et al. (2016) Deletion of mTORC1 Activity in CD4+ T Cells Is Associated with Lung Fibrosis and Increased ?? T Cells. PLoS One 11:e0163288
Eldridge, Lindsey; Moldobaeva, Aigul; Zhong, Qiong et al. (2016) Bronchial Artery Angiogenesis Drives Lung Tumor Growth. Cancer Res 76:5962-5969
Collins, Samuel L; Chan-Li, Yee; Oh, MinHee et al. (2016) Vaccinia vaccine-based immunotherapy arrests and reverses established pulmonary fibrosis. JCI Insight 1:e83116
Limjunyawong, Nathachit; Fallica, Jonathan; Ramakrishnan, Amritha et al. (2015) Phenotyping mouse pulmonary function in vivo with the lung diffusing capacity. J Vis Exp :e52216

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