Injury to extracellular matrix components by matrix metalloproteinases (MMPs) derived from leukocytes is a pivotal pathogenetic event in disabling chronic diseases such as pulmonary emphysema, cystic fibrosis, acute respiratory distress syndrome, and rheumatoid arthritis. The prevailing concept of MMP-mediated tissue injury is that MMPs are freely secreted into the extracellular space as proenzymes. However, there is little information available about the mechanisms by which proMMPs are activated in vivo, or how they circumvent the effects of high- affinity inhibitors within the extracellular space. Our preliminary data indicate that MMP-7 (matrilysin), MMP-8 (neutrophil collagenase), and MMP-9 (92 kDa gelatinase; 92 kDa type IV collagenase; gelatinase B) are expressed on the cell surface of human leukocytes, and that their expression is upregulated by pro-inflammatory mediators. We propose to test the hypothesis that when MMPs are confined to the cell surface of leukocytes, they are focused and protected from naturally- occurring inhibitors. In doing so, we will pursue the following Specific Aims: 1. Determine which MMPs (MMP-7, -8, -9 and MMP- 12[macrophage metalloelastase]) are expressed on the cell surface of neutrophils and monocytes, quantify their expression in response to cellular activation, and investigate the possibility that coordinate expression of MMPs and adhesion molecules on activated cell membranes facilitates MMP-mediated extracellular proteolysis. 2. Examine the consequences of binding of MMPs to the cell surface of inflammatory cells with respect to proenzyme activation, catalytic activity and susceptibility to inhibition. 3. Investigate the mechanisms of binding of MMPs to leukocyte cell membranes. We anticipate that the proposed studies will provide novel insights into the mechanisms by which MMPs mediate tissue injury, and that this knowledge will facilitate rational development of effective therapeutic strategies for many chronic and disabling diseases in which MMP-mediated tissue injury is a critical event.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL063137-04
Application #
6589945
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
2002-01-15
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$224,000
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
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
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
Petersen, Hans; Sood, Akshay; Meek, Paula M et al. (2014) Rapid lung function decline in smokers is a risk factor for COPD and is attenuated by angiotensin-converting enzyme inhibitor use. Chest 145:695-703

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