The roles of metalloproteinase-8 (MMP-8) have not been determined in acute lung injury (ALI). PMN, the predominant inflammatory cell in the lung during the acute-exudative phase of ALI contain MMP-8 within their granules, and release it as a soluble proteinase when they degranulate. Soluble MMP-8 is thought to mediate the activities of the enzyme. However, our data show that activated PMN express a novel form of MMP-8 on their cell surface, in vitro and during ALl in mice. Membrane-bound MMP-8 has similar catalytic activity as soluble MMP-8, but unlike soluble MMP-8, membrane-bound MMP-8 is resistant to inhibition by tissue inhibitors of MMPs (TIMPs). This indicates that it could be an important bioactive form of the proteinase in vivo. Novel data indicate that, surprisingly, TIMP-1 an inhibitor of MMP-8 is also expressed on the surface of PMN where it functions as the receptor for active MMP-8 on the PMN surface. To assess the roles of MMP-8 in ALI, we have generated mice deficient in MMP-8 by gene targeting (MMP-8 -/- mice) and studied them in murine models having features of the acute-exudative and fibro-proliferative phases of ALI. MMP-8-/- mice have increased influx of PMN into the lungs in the acute-exudative phase of ALl compared to wild type mice. However, MMP-8-/- mice are protected from progression to fibro-proliferation in the sub-acute phase. This indicates that MMP-8 has an unexpected anti-inflammatory role in the acute-exudative phase of ALI, and a counterintuitive, pro-fibrotic role in the sub-acute phase of ALl. Our central hypothesis is that PMN-derived MMP-8 plays distinct roles in different phases of ALI As a corollary to this, we will also examine the hypothesis that membrane-bound MMP-8 on PMN is a bioactive form of the proteinase which may contribute in important ways to its activities in vivo. To test our hypotheses, we propose three Specific Aims:
Specific Aim 1 : Test the hypothesis that on the PMN surface, MMP-8 and TIMP-1 form complexes mediated by the interaction of the COOH-terminals of both molecules, and the NH2-terminal inhibitory domain of TIMP-1 anchors the complex to the PMN surface.
Specific Aim 2 : Test the hypothesis that MMP-8 down-regulates acute lung inflammation during ALl by inactivating PMN chemokines.
Specific Aim 3 : Test the hypothesis that MMP-8 promotes progression to fibro-proliferation in ALl by: A) downregulating the lung inflammatory response to injury; and or B) proteolytically regulating the biologic activities of pro-, and/or anti-fibrotic mediators. We anticipate that these studies will provide novel information about the biologic activities of MMP-8 in ALl, and the mechanisms by which MMP-8 retains its activity in vivo. The ALl will be the first lung disease in which MMP-8's activities will be studied. We anticipate that in the future, our studies will facilitate the development of new treatment strategies that may reduce mortality and morbidity in ALl syndromes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063137-07
Application #
6995189
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
1999-07-01
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
7
Fiscal Year
2006
Total Cost
$394,262
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
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
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
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

Showing the most recent 10 out of 30 publications