Fibrosis is the common final pathway for a number of pulmonary disorders such as sarcoidosis, asbestosis, rheumatoid arthritis, scleroderma and idiopathic pulmonary fibrosis. Although pulmonary fibrosis appears to be the end result of chronic unremitting immune activation, often neither the inciting agents of the inflammatory process nor the precise factors driving the fibrotic response are known. In humans, pulmonary fibrosis is associated with lymphocyte infiltration in the parenchyma and alveolar space. However, the precise role of these cells in the disease process has yet to be established. That is, it is unclear if the lymphocytes participate in accelerating fibrosis, are part of an overwhelmed anti-fibrotic negative feed back loop, or both. In this proposal, using a unique mouse model of selective deletion of CD4+ T cell effector subsets, we will test the hypothesis that T helper cells play a critical role in the modulation of pulmonary fibrosis.
In Aim 1 we will determine the role and mechanism by which Thi, Th2, Th17 and regulatory T cells accelerate or prevent the development of fibrosis.
In Aim 2 we will determine the role of alternatively activated macrophages (AAMs). This relatively new subset of macrophages is induced by the Th2 cytokines IL-4/IL-13 and thus we propose that Th2 T cells promote fibrosis in part through the generation of AAM.
In Aim 3 we will employ agents to modulate the T effector response (the TLR agonist LPS and a live viral vaccine) to test the hypothesis that in vivo skewing of T helper responses can be employed as a novel therapeutic strategy to treat or prevent lung fibrosis.
|Han, Liang; Limjunyawong, Nathachit; Ru, Fei et al. (2018) Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness. Nat Neurosci 21:324-328|
|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|
|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|
|Moldobaeva, Aigul; Jenkins, John; Zhong, Qiong et al. (2017) Lymphangiogenesis in rat asthma model. Angiogenesis 20:73-84|
|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|
|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|
|D'Alessio, F R; Craig, J M; Singer, B D et al. (2016) Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming. Am J Physiol Lung Cell Mol Physiol 310:L733-46|
|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|
|Lagassé, H A Daniel; Anidi, Ifeanyi U; Craig, John M et al. (2016) Recruited monocytes modulate malaria-induced lung injury through CD36-mediated clearance of sequestered infected erythrocytes. J Leukoc Biol 99:659-71|
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