COPD is associated with high mortality and there is an urgent need to develop new treatments that limit disease progression. Although much is known about how cigarette smoke (CS, the main risk factor for COPD) promotes COPD development, little is known about anti-inflammatory pathways that likely protect some cigarette smokers from developing COPD. Our novel data show that a proteinase with a disintegrin and a metalloproteinase (MP) domain-8 (Adam8) is robustly up-regulated in lung macrophages in wild type (WT) mice exposed to CS. However, CS-exposed Adam8-/- mice have higher lung macrophage counts and worse emphysema associated with decreased lung macrophage apoptosis than CS-exposed WT mice. We hypothesize that Adam8 has anti-inflammatory and protective activities in the CS-exposed murine lung by promoting macrophage apoptosis thereby reducing the half life of destructive macrophages in the lung. Although CS up-regulates anti-inflammatory Adam8 in lung macrophages in mice, ADAM8 levels are reduced in plasma and lung samples from COPD patients when compared to samples from control subjects. We hypothesize that reduced blood and plasma levels of ADAM8 in human COPD patients is linked to disease severity in human COPD via ADAM8 regulating macrophage survival in human lungs. We will test these hypotheses by pursuing the following Specific Aims:
Aim 1 : We will use a loss-of-function strategy (studies of WT vs. Adam8-/- mice in the CS exposure model) to test the hypothesis that Adam8 protects the CS-exposed murine lung from developing emphysema by promoting macrophage cell death. We will identify the mechanisms involved. We will also determine the critical cellular sources of anti-inflammatory Adam8 in the lung by generating and studying Adam8 bone marrow chimeric mice in the murine CS exposure model of emphysema.
Aim 2 : We will use gain-of-function strategies to confirm that Adam8 has anti-inflammatory activities in the CS-exposed murine lung by promoting lung macrophage apoptosis. We will generate transgenic mice that overexpress human Adam8 in an inducible fashion in lung macrophages. We will also use lentiviral vectors to selectively transduce murine lung macrophages with hADAM8 in a durable fashion. We will test whether these strategies prevent CS-induced emphysema and/or limit disease progression.
Aim 3 : We will test our hypothesis that COPD patients have reduced expression of ADAM8. We will measure ADAM8 protein and mRNA levels in blood and lung samples from COPD patients versus control subjects and correlate ADAM8 levels with disease severity, lung macrophage counts, and lung macrophage apoptosis. Significance: Our studies may provide novel insights into the mechanism(s) by which ADAM8 mediates its protective activities in the CS-exposed lung. Our studies may also identify ADAM8 as a novel target for developing therapeutic strategies to limit lung destruction and disease progression in patients with COPD.

Public Health Relevance

COPD is the fourth leading cause of death in the USA, its incidence is increasing worldwide, and we have no treatments that effectively limit disease progression in most COPD patients. Our studies indicate that ADAM8 is an anti-inflammatory protein that protects the cigarette smoke-exposed lung from developing COPD. In the long term, our studies may identify ADAM8 as a novel target for developing improved treatment strategies that limit disease progression in patients with COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL111835-02
Application #
8386987
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Punturieri, Antonello
Project Start
2011-12-01
Project End
2013-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$159,546
Indirect Cost
$64,346
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Lao, Taotao; Jiang, Zhiqiang; Yun, Jeong et al. (2016) Hhip haploinsufficiency sensitizes mice to age-related emphysema. Proc Natl Acad Sci U S A 113:E4681-7
Jiang, Zhiqiang; Lao, Taotao; Qiu, Weiliang et al. (2016) A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin. Am J Respir Crit Care Med 194:185-97
Polverino, Francesca; Laucho-Contreras, Maria; Rojas Quintero, Joselyn et al. (2016) Increased expression of A Proliferation-inducing Ligand (APRIL) in lung leukocytes and alveolar epithelial cells in COPD patients with non small cell lung cancer: a possible link between COPD and lung cancer? Multidiscip Respir Med 11:17
Laucho-Contreras, Maria E; Polverino, Francesca; Tesfaigzi, Yohannes et al. (2016) Club Cell Protein 16 (CC16) Augmentation: A Potential Disease-modifying Approach for Chronic Obstructive Pulmonary Disease (COPD). Expert Opin Ther Targets 20:869-83
Cloonan, Suzanne M; Glass, Kimberly; Laucho-Contreras, Maria E et al. (2016) Mitochondrial iron chelation ameliorates cigarette smoke-induced bronchitis and emphysema in mice. Nat Med 22:163-74
Polverino, Francesca; Doyle-Eisele, Melanie; McDonald, Jacob et al. (2015) A novel nonhuman primate model of cigarette smoke-induced airway disease. Am J Pathol 185:741-55
Polverino, Francesca; Cosio, Borja G; Pons, Jaime et al. (2015) B Cell-Activating Factor. An Orchestrator of Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 192:695-705
Craig, Vanessa J; Zhang, Li; Hagood, James S et al. (2015) Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 53:585-600
Laucho-Contreras, Maria E; Taylor, Katherine L; Mahadeva, Ravi et al. (2015) Automated measurement of pulmonary emphysema and small airway remodeling in cigarette smoke-exposed mice. J Vis Exp :52236
Laucho-Contreras, Maria E; Polverino, Francesca; Gupta, Kushagra et al. (2015) Protective role for club cell secretory protein-16 (CC16) in the development of COPD. Eur Respir J 45:1544-56

Showing the most recent 10 out of 26 publications