ADAM15 is a member of the ADAM family (proteinases with a disintegrin and a metalloproteinase domain). It is expressed by inflammatory cells, but little is known about its roles in the lung. Our studies of ADAM15-/- mice in a murine model of acute lung injury show that ADAM15 promotes PMN accumulation in the lung, and promotes alveolar capillary barrier injury. ADAM15 delays PMN apoptosis in the lung, and reduces macrophage uptake of apoptotic targets in vitro. ADAM15 is stored in PMN, and rapidly translocates to the PMN surface when cells are activated. ADAM15 degrades a lung extracellular matrix protein. We will investigate the mechanisms by which ADAM15 increases the lung PMN burden during ALI, and the cell biology and enzyme biochemistry of ADAM15 in PMN. We propose to pursue the following Specific Aims:
Specific Aim 1. Investigate the mechanism by which ADAM15 promotes PMN survival in the lung:
Aim 1 A: We will test our hypothesis that ADAM15 increases the lung PMN burden by delaying PMN apoptosis by shedding of TNF receptor family members that regulate apoptosis.
Aim 1 B: We will test our hypothesis that ADAM15 also increases the lung PMN burden by inhibiting uptake of apoptotic PMN by lung macrophages.
Specific Aim 2. Investigate the cell biology of ADAM15 in PMN.
Aim 2 A. We will test our hypothesis that ADAM15 is stored as a preformed proteinase within PMN cytoplasmic storage sites, and rapidly translocates to the cell surface when PMN are activated to degranulate. We will identify the storage sites for ADAM15 in PMN.
Aim 2 B. We will test our hypothesis that ADAM15 is subsequently internalized from the surface of activated PMN by a clathrin-dependent mechanism.
Specific Aim 3. We will test our hypothesis that ADAM15 expressed on the surface of PMN is a TIMPresistant proteinase that cleaves matrix and non-matrix proteins to promote lung inflammation and injury. We hope that our studies will provide novel insights into the mechanisms by which ADAM 15 promotes neutrophilic lung inflammation and lung injury during ALI, and that in the long term, this will facilitate the design of new treatment strategies for ALI in man. ? ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL086814-01
Application #
7185955
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2007-01-12
Project End
2010-12-31
Budget Start
2007-01-12
Budget End
2007-12-31
Support Year
1
Fiscal Year
2007
Total Cost
$403,750
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Polverino, Francesca; Rojas-Quintero, Joselyn; Wang, Xiaoyun et al. (2018) A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 198:1254-1267
Wang, Xiaoyun; Polverino, Francesca; Rojas-Quintero, Joselyn et al. (2018) A Disintegrin and A Metalloproteinase-9 (ADAM9): A Novel Proteinase Culprit with Multifarious Contributions to COPD. Am J Respir Crit Care Med :
Polverino, Francesca; Laucho-Contreras, Maria E; Petersen, Hans et al. (2017) A Pilot Study Linking Endothelial Injury in Lungs and Kidneys in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 195:1464-1476
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
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; 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
Roychaudhuri, Robin; Hergrueter, Anja H; Polverino, Francesca et al. (2014) ADAM9 is a novel product of polymorphonuclear neutrophils: regulation of expression and contributions to extracellular matrix protein degradation during acute lung injury. J Immunol 193:2469-82
Craig, Vanessa J; Polverino, Francesca; Laucho-Contreras, Maria E et al. (2014) Mononuclear phagocytes and airway epithelial cells: novel sources of matrix metalloproteinase-8 (MMP-8) in patients with idiopathic pulmonary fibrosis. PLoS One 9:e97485

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