Our understanding of emphysema, the airspace destruction and enlargement in COPD, greatly outweighs our knowledge regarding the airway component, particularly acute exacerbations of COPD. Two seminal observations in the 1960s led to the elastase:antielastase hypothesis which remains the central theme in the pathogenesis of emphysema. First, was the experimental finding that instillation of elastases led to emphysema in animal models, and second was the clinical finding that patients with deficiency in alpha-1- antitrypsin (A1 AT) were at increased risk for emphysema. As was done for emphysema 40 years ago, in this proposal we will apply 21st century versions of animal models and human genetics in an attempt to launch our understanding of acute exacerbations which greatly lags behind our understanding of emphysema. Our overall hypothesis is that the risk and outcome of acute exacerbations in COPD are determined by the environmental etiology combined with genetic susceptibility. Thus, in this proposal, we will generate murine models of acute exacerbations in COPD combining cigarette smoking with viral and bacterial infection, and we will apply gene targeted mice to dissect pathogenetic pathways of acute exacerbations with an emphasis on inflammatory cells and proteinase effects on fighting infection, airway remodeling and subsequent emphysema. We will also test our hypothesis that polymorphisms in candidate genes for COPD susceptibility and innate and adaptive immunity genes will influence the frequency and severity of COPD exacerbations. We will develop a population of patients with moderate to severe COPD (FEV1 < 50% predicted) and will classify the patients as either non-frequent (0) or frequent (2 or more per year) """"""""exacerbators"""""""" based upon their clinical course during the three years before the study. Single nucleotide polymorphisms (SNPs) in twenty candidate genes will be studied for genetic association with COPD exacerbations in 400 frequent exacerbators and 400 non-frequent exacerbators. Candidate genes for COPD susceptibility will be selected from COPD linkage studies and previous case-control genetic association studies; candidate genes for innate and adaptive immunity will be selected based on the animal model studies in Aim 1.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL082541-01
Application #
7008368
Study Section
Special Emphasis Panel (ZHL1-CSR-A (S1))
Program Officer
Croxton, Thomas
Project Start
2005-09-15
Project End
2010-07-31
Budget Start
2005-09-15
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$441,284
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Lin, Lan; Betsuyaku, Tomoko; Heimbach, Lisa et al. (2012) Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid. Matrix Biol 31:38-44
Chen, Kong; Pociask, Derek A; McAleer, Jeremy P et al. (2011) IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke. PLoS One 6:e20333
Foreman, Marilyn G; Kong, Xiangyang; DeMeo, Dawn L et al. (2011) Polymorphisms in surfactant protein-D are associated with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 44:316-22
Wan, Emily S; DeMeo, Dawn L; Hersh, Craig P et al. (2011) Clinical predictors of frequent exacerbations in subjects with severe chronic obstructive pulmonary disease (COPD). Respir Med 105:588-94
Minematsu, Naoto; Blumental-Perry, Anna; Shapiro, Steven D (2011) Cigarette smoke inhibits engulfment of apoptotic cells by macrophages through inhibition of actin rearrangement. Am J Respir Cell Mol Biol 44:474-82
Yoshida, Toshinori; Mett, Igor; Bhunia, Anil K et al. (2010) Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 16:767-73
Khatwa, Umakanth A; Kleibrink, Bjoern E; Shapiro, Steven D et al. (2010) MMP-8 promotes polymorphonuclear cell migration through collagen barriers in obliterative bronchiolitis. J Leukoc Biol 87:69-77
Houghton, A McGarry; Hartzell, William O; Robbins, Clinton S et al. (2009) Macrophage elastase kills bacteria within murine macrophages. Nature 460:637-41
Mouded, Majd; Egea, Eduardo E; Brown, Matthew J et al. (2009) Epithelial cell apoptosis causes acute lung injury masquerading as emphysema. Am J Respir Cell Mol Biol 41:407-14
Foreman, M G; DeMeo, D L; Hersh, C P et al. (2008) Polymorphic variation in surfactant protein B is associated with COPD exacerbations. Eur Respir J 32:938-44

Showing the most recent 10 out of 14 publications