During the previous funding period we elucidated the molecular mechanisms of Bik/Nbk-induced apoptosis in hyperplastic airway epithelial cells (AECs) and identified Bik-derived peptides that activate Bak and reduce mucous cell hyperplasia (MCH) in mice. While we were evaluating the effects of Bik deficiency on MCH, we noticed that among females, but not males, bik-/- compared with bik+/+ mice show enhanced inflammation in response to LPS and cigarette smoke exposure. Further, we noticed that instillation of Bik-derived peptides or transgenic expression of Bik in AECs in an inducible fashion suppressed allergen-induced inflammation. Even more striking was that IL-6 levels were increased in lung tissues of bik-/- compared with bik+/+ mice at baseline in the absence of inflammatory stimuli, and that bik-/- mice develop emphysema at 80 weeks of age. The role of Bik in regulating inflammation was confirmed by our observation that primary murine airway epithelial cells (MAECs) from female bik-/- compared with bik+/+ show increased levels of nuclear factor kappaB (NF-?B). In humans, we identified a single nucleotide polymorphism (SNP) within the BIK promoter region that is associated with decline in lung function in four independent cohorts for subjects older than 60 years of age. The A?G change causes reduced BIK gene expression and females with reduced Bik levels show increased circulating IL-6 levels. Because Bik blocks baseline inflammation in nave bik-/- mice we propose that this is the actual function of Bik rather than it's cell death inducing activity; and if left unchecked can lead to lung destruction during aging. Therefore, this renewal application is focused on elucidating the central role of Bik in blocking inflammation by reducing nuclear p65 levels.
Aim 1 will determine the importance of localization of Bik and Bcl-2 at the ER for reducing inflammation at baseline in the absence of inflammatory stimuli. Mutations of functional sites within Bik and Bcl-2 proteins will show the sites of interaction between Bik, Bcl-2 and p65. Further, the possible role of increased Bcl-2 expression in female cells causing the sex-dependent differences in inflammation will be explored.
Aim 2 will test the causal role of Bik deficiency on increased inflammation by restoring Bik levels using adenoviral expression of Bik or treating with the Bik-derived peptide to reduce secreted IL-6 levels in differentiated bik-/- MAECs and primary human airway epithelial cells homozygous for the G allele. Further, the causal role of Bik in the development of emphysema in aging female mice will be evaluated using transgenic inducible expression of Bik in the lungs of bik-/- mice to block baseline inflammation. These studies will lay the foundation for a precision medicine-based treatment of COPD and asthmatic bronchitis.

Public Health Relevance

We identified susceptible individuals with increased blood inflammation due to reduced expression of a protein called Bik. Our studies are designed to understand the molecular mechanisms how this protein, known for its cell death function, inhibits baseline inflammation that results in emphysema in mice and rapid decline in lung function in humans with increasing age. This project will test Bik-derived peptides that block inflammation and therefore, could provide treatments that will improve lung function in older age.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Punturieri, Antonello
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Brigham and Women's Hospital
United States
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Vazquez Guillamet, Rodrigo; Petersen, Hans; Meek, Paula et al. (2018) Grading Severity of Productive Cough Based on Symptoms and Airflow Obstruction. COPD 15:206-213
Chand, Hitendra S; Harris, Jennifer F; Tesfaigzi, Yohannes (2018) IL-13 in LPS-Induced Inflammation Causes Bcl-2 Expression to Sustain Hyperplastic Mucous cells. Sci Rep 8:436
Zhang, C; Jones, J T; Chand, H S et al. (2018) Noxa/HSP27 complex delays degradation of ubiquitylated IkB? in airway epithelial cells to reduce pulmonary inflammation. Mucosal Immunol 11:741-751
Petersen, Hans; Vazquez Guillamet, Rodrigo; Meek, Paula et al. (2018) Early Endotyping: A Chance for Intervention in Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol 59:13-17
Chand, Hitendra S; Mebratu, Yohannes A; Kuehl, Philip J et al. (2017) Blocking Bcl-2 resolves IL-13-mediated mucous cell hyperplasia in a Bik-dependent manner. J Allergy Clin Immunol 140:1456-1459.e9
Jang, Jun-Ho; Chand, Hitendra S; Bruse, Shannon et al. (2017) Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity. COPD 14:228-237
Jones, Jane Tully; Tassew, Dereje D; Herrera, Lois K et al. (2017) Extent of allergic inflammation depends on intermittent versus continuous sensitization to house dust mite. Inhal Toxicol 29:106-112
Sood, Akshay; Petersen, Hans; Qualls, Clifford et al. (2016) Spirometric variability in smokers: transitions in COPD diagnosis in a five-year longitudinal study. Respir Res 17:147
Diaz, Alejandro A; Petersen, Hans; Meek, Paula et al. (2016) Differences in Health-Related Quality of Life Between New Mexican Hispanic and Non-Hispanic White Smokers. Chest 150:869-876
Chand, Hitendra S; Mebratu, Yohannes A; Montera, Marena et al. (2016) T cells suppress memory-dependent rapid mucous cell metaplasia in mouse airways. Respir Res 17:132

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