Incessant damage of epithelial layer and lack of ordered epithelial regeneration are known to be the hallmarks of lung remodeling. The endoplasmic reticulum (ER) stress plays a critical role in epithelial apoptosis, and the subsequent pathology of lung remodeling. Patients with asthma exhibit increased airway structural remodeling marked by collagen deposition and smooth muscle cell hypertrophy, which correlates with decreased lung function, morbidity, mortality and increased health care costs. However, the mechanisms regulating the key steps leading to airway fibrotic remodeling in asthma are unknown. Our novel preliminary results demonstrate that allergen house dust mite (HDM), causes severe ER stress, activation of ER stress transducer-transcription factor, ATF6, disulfide isomerase ERp57 and disulfide bridges in proapoptotic Bak, leading to apoptosis of airway epithelial cells and production of growth factors from the injured airway epithelium, which is associated with airway fibrotic remodeling in mice. Importantly, we also observed that deletion of ATF6a and ERp57 or treatment with a chemical chaperone; tauroursodeoxycholic acid (TUDCA) attenuated allergen induced airway fibrosis in mice. The central hypothesis to be addressed herein is that allergen exposure induces ER stress mediated apoptosis and injury to airway epithelial cells and subsequent production of fibrotic mediators leading to airway structural remodeling via the ATF6-ERp57-Bak signaling axis.
In Specific Aim #1 we will determine the functional roles of ER stress transducer ATF6 in regulating allergen- induced expression of disulfide isomerase, ERp57, and subsequent induction of epithelial cell death and development of airway structural remodeling.
The specific Aim #2 seeks to explore the functional requirement of allergen-induced protein disulfide isomerase ERp57 in disulfide mediated oligomerization of proapototic Bak to cause epithelial injury and subsequent development of airway remodeling.
In Specific Aim #3 we will assess the efficacy of a chemical chaperone, TUDCA in alleviating ER stress and decreasing subsequent epithelial cell death, ultimately resulting in resolution of allergen-induced airway remodeling. We will use complementary human primary epithelial cell culture and mouse transgenic approaches, coupled with detailed biochemical analysis of these processes in mouse lung tissues. Completion of proposed experiments is likely to impart a significant knowledge on allergen-induced epithelial ER stress, and its transducers which may be targeted in the future using small molecule inhibitors to attenuate airway fibrosis. Furthermore, our project will evaluate the efficacy of a naturally occurring bile acid (TUDCA) in attenuating airway fibrosis. Given the dearth of treatment options in chronic asthma and fibrosis, TUDCA may prove to be an alternative therapeutic for treatment of airway remodeling.

Public Health Relevance

The over-arching objective of this project is to identify the role of a specific organelle of the cell, the endoplasmic reticulum (ER) in activating the death of airway epithelial cells, impact on development of scar in the lung and subsequent decrease in lung function. In this proposal specifically we will examine the critical impact of stress caused b airborne-allergen house dust mite in the ER and activation of cell death in airway epithelial cells of the lung. The importance of this process will be determined by removing or deleting the proteins or enzymes that relay stress and ultimately cause damage to the airway epithelial cells. We also will take advantage of a drug tauroursodeoxycholic acid (TUDCA) which is already in various clinical trials for diseases such as amyotrophic lateral sclerosis (ALS) and cystic fibrosi associated liver disease to evaluate if this drug can be used in preventing the allergen induced lung scarring. This project will demonstrate that therapeutics to prevent scars should be directed to decrease ER stress in airway epithelial cells, and may therefore provide new opportunities to stop the process of scarring in the future.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL122383-04
Application #
9402639
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Noel, Patricia
Project Start
2015-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Siddesha, Jalahalli M; Nakada, Emily M; Mihavics, Bethany R et al. (2016) Effect of a chemical chaperone, tauroursodeoxycholic acid, on HDM-induced allergic airway disease. Am J Physiol Lung Cell Mol Physiol 310:L1243-59
Hoffman, Sidra M; Chapman, David G; Lahue, Karolyn G et al. (2016) Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness. J Allergy Clin Immunol 137:822-32.e7
McMillan, David H; van der Velden, Jos L J; Lahue, Karolyn G et al. (2016) Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase ?. JCI Insight 1: