The innate immune system plays critical roles in maintaining a healthy lung and in shaping the responses to challenge. As for most biological processes, the extent, pattern, duration, and consequence of inflammation are controlled by a balance between positive and negative factors. Our preliminary data indicates that stromelysin-2 (MMP10), a member of the matrix metalloproteinase gene family, functions to govern the influx and activation state of infiltrated macrophages and has diverse roles in cigarette smoke-induced lung damage. On one hand, it moderates the extent of inflammation, particularly, the influx and activation state of infiltrated macrophages. On the other, MMP10 promotes alveolar destruction. We propose that these phenotypes are due to differences in macrophage activation. Specifically, we hypothesize that MMP10 moderates macrophage activation towards an M1 phenotype (classically activated; proinflammatory), thereby promoting the differentiation of more M2 (alternatively activated or anti-inflammatory) macrophages. M2 macrophages, which are known to over-represented in the lungs of smokers, are considered to be reparative and to mediate matrix remodeling. However, with sustained inflammation, a reparative phenotype would lead excessive remodeling and tissue destruction. Hence, we further hypothesize that by promoting the differentiation of M2 macrophages, MMP10 contributes-directly or indirectly-to development of emphysema. To study the role of MMP10 in alveolar destruction more detail, we propose to 1) determine the role of MMP10 in shaping macrophage differentiation.;2) determine the relative roles of epithelial- and macrophage-derived MMP10;and 3) assess the role of MMP10 in governing the macrophage response to bacterial infection.

Public Health Relevance

These studies will characterize a novel, fundamental mechanism controlling macrophage activation and tissue destruction in COPD. Knowledge from this work may provide an effective strategy to limit inflammation-associated damage not only in lung, but in all tissues.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL089455-04
Application #
8584308
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (02))
Program Officer
Punturieri, Antonello
Project Start
2011-01-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$409,150
Indirect Cost
$164,150
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Wight, Thomas N; Frevert, Charles W; Debley, Jason S et al. (2017) Interplay of extracellular matrix and leukocytes in lung inflammation. Cell Immunol 312:1-14
Secor, Patrick R; Michaels, Lia A; Smigiel, Kate S et al. (2017) Filamentous Bacteriophage Produced by Pseudomonas aeruginosa Alters the Inflammatory Response and Promotes Noninvasive Infection In Vivo. Infect Immun 85:
McMahan, Ryan S; Birkland, Timothy P; Smigiel, Kate S et al. (2016) Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation. J Immunol 197:899-909
Brauer, Rena; Ge, Lingyin; Schlesinger, Saundra Y et al. (2016) Syndecan-1 Attenuates Lung Injury during Influenza Infection by Potentiating c-Met Signaling to Suppress Epithelial Apoptosis. Am J Respir Crit Care Med 194:333-44
Vandivort, Tyler C; An, Dowon; Parks, William C (2016) An Improved Method for Rapid Intubation of the Trachea in Mice. J Vis Exp :53771
Lee, Vivian; McMahan, Ryan S; Hu, Xiaoge et al. (2015) Amphiphilic polymer-coated CdSe/ZnS quantum dots induce pro-inflammatory cytokine expression in mouse lung epithelial cells and macrophages. Nanotoxicology 9:336-43
Secor, Patrick R; Sweere, Johanna M; Michaels, Lia A et al. (2015) Filamentous Bacteriophage Promote Biofilm Assembly and Function. Cell Host Microbe 18:549-59
Apte, Suneel S; Parks, William C (2015) Metalloproteinases: A parade of functions in matrix biology and an outlook for the future. Matrix Biol 44-46:1-6
Rohani, Maryam G; McMahan, Ryan S; Razumova, Maria V et al. (2015) MMP-10 Regulates Collagenolytic Activity of Alternatively Activated Resident Macrophages. J Invest Dermatol 135:2377-2384
Giannandrea, Matthew; Parks, William C (2014) Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 7:193-203

Showing the most recent 10 out of 19 publications