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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL010342-45
Application #
8444458
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
45
Fiscal Year
2013
Total Cost
$396,241
Indirect Cost
$158,580
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
D'Alessio, Franco R; Zhong, Qiong; Jenkins, John et al. (2015) Lung Angiogenesis Requires CD4(+) Forkhead Homeobox Protein-3(+) Regulatory T Cells. Am J Respir Cell Mol Biol 52:603-10
Moldobaeva, Aigul; Rentsendorj, Otgonchimeg; Jenkins, John et al. (2014) Nitric oxide synthase promotes distension-induced tracheal venular leukocyte adherence. PLoS One 9:e106092
Hamblin, Mark J; Eberlein, Michael; Black, Katharine et al. (2014) Lovastatin Inhibits Low Molecular Weight Hyaluronan Induced Chemokine Expression via LFA-1 and Decreases Bleomycin-Induced Pulmonary Fibrosis. Int J Biomed Sci 10:146-57
Mock, J R; Garibaldi, B T; Aggarwal, N R et al. (2014) Foxp3+ regulatory T cells promote lung epithelial proliferation. Mucosal Immunol 7:1440-51
Zhao, Hongyun; Chan-Li, Yee; Collins, Samuel L et al. (2014) Pulmonary delivery of docosahexaenoic acid mitigates bleomycin-induced pulmonary fibrosis. BMC Pulm Med 14:64
Schmieder, Anne H; Wang, Kezheng; Zhang, Huiying et al. (2014) Characterization of early neovascular response to acute lung ischemia using simultaneous (19)F/ (1)H MR molecular imaging. Angiogenesis 17:51-60
Fallica, Jonathan; Boyer, Laurent; Kim, Bo et al. (2014) Macrophage migration inhibitory factor is a novel determinant of cigarette smoke-induced lung damage. Am J Respir Cell Mol Biol 51:94-103
Parkinson, Rose M; Collins, Samuel L; Horton, Maureen R et al. (2014) Egr3 induces a Th17 response by promoting the development of ?? T cells. PLoS One 9:e87265
Brown, Mary Beth; Hunt, William R; Noe, Julie E et al. (2014) Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke. Pulm Circ 4:260-8
Sokolowska, Milena; Chen, Li-Yuan; Eberlein, Michael et al. (2014) Low molecular weight hyaluronan activates cytosolic phospholipase A2? and eicosanoid production in monocytes and macrophages. J Biol Chem 289:4470-88

Showing the most recent 10 out of 34 publications