Cigarette smoke is the major cause of COPD and lung cancer and studies have demonstrated that cigarette smoke can directly induce matrix metalloproteinase (MMP) expression in the lung parenchyma. Thus, it is essential that COPD research focuses on improving our understanding of the specific cellular and biochemical injury induced by smoke within the lung. It has been demonstrated that MMPs when expressed in the lung of transgenic mice, lead to the development of emphysema therefore documenting the critical role for MMPs in lung destruction. Also, our laboratory has identified increased expression of MMP1, a human collagenase, in the epithelial cell of patients with COPD and defined the molecular regulation of the smoke induced expression of MMP1. Also, we identified several novel polymorphisms within this cigarette smoke responsive element of the MMP1 promoter. It remains to be determined whether blockade of MMPs will protect the lung from destruction and disease initiated by cigarette smoke. Furthermore, the role of this newly defined cigarette smoke responsive element in MMP1 in disease susceptibility is not know. Therefore, we propose to perform the following studies. First, we will test the hypothesis we will determine through genetic and pharmacological methodology whether inhibition of the collagenolytic enzymes protects from the development of emphysema. We have within the laboratory the animal models and compounds available to complete this study. In the second aim we will identify whether blockade of the cigarette smoke induction pathway protects from lung inflammation and emphysema utilizing the mouse and rabbit model of smoke exposure. Preliminary studies have already identified candidate small molecules targeting this pathway. Finally, in collaboration with Dr. Edwin Silverman and Michael Cho we will translate our findings utilizing samples from the COPD gene Study. Here we will determine whether SNPs within MMP1, MMP13 or genes within the smoke induced pathway confer susceptibility to emphysema. Upon completion of this proposal our goal is to determine whether the collagenolytic enzymes are a therapeutic target in emphysema and whether this pathway is useful as a disease susceptibility marker.

Public Health Relevance

Cigarette smoke stimulates the TLR4 pathway and induces MMP expression through activation of the MAP kinase pathway. Chronic expression of MMPs leads to the development of COPD, a major cause of morbidity and mortality. Our group will extend prior studies to determine if blockade of MMPs and the cigarette smoke induced pathways can protect from the development of emphysema. Finally, by taking advantage of the COPDGene population, we propose to examine whether SNPs within the cigarette smoke responsive element of MMP-1 increase susceptibility to emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086936-07
Application #
8881261
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (04))
Program Officer
Postow, Lisa
Project Start
2007-02-19
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
7
Fiscal Year
2015
Total Cost
$537,809
Indirect Cost
$161,037
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Sonett, Jarrod; Goldklang, Monica; Sklepkiewicz, Piotr et al. (2018) A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure. FASEB J :fj201701381
Sakornsakolpat, Phuwanat; Morrow, Jarrett D; Castaldi, Peter J et al. (2018) Integrative genomics identifies new genes associated with severe COPD and emphysema. Respir Res 19:46
Unachukwu, Uchenna; Trischler, Jordis; Goldklang, Monica et al. (2017) Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs. FASEB J 31:2340-2351
Goldklang, Monica P; Tekabe, Yared; Zelonina, Tina et al. (2016) Single-Photon Emission Computed Tomography/Computed Tomography Imaging in a Rabbit Model of Emphysema Reveals Ongoing Apoptosis In Vivo. Am J Respir Cell Mol Biol 55:848-857
Geraghty, Patrick; Baumlin, Nathalie; Salathe, Matthias A et al. (2016) Glutathione Peroxidase-1 Suppresses the Unfolded Protein Response upon Cigarette Smoke Exposure. Mediators Inflamm 2016:9461289
D'Armiento, Jeanine; Shiomi, Takayuki; Marks, Sarah et al. (2016) Mesenchymal Tumorigenesis Driven by TSC2 Haploinsufficiency Requires HMGA2 and Is Independent of mTOR Pathway Activation. Cancer Res 76:844-54
Trischler, Jordis; Shiomi, Takayuki; Turner, Damian L et al. (2016) Immune Modulation of the T Cell Response in Asthma through Wnt10b. Am J Respir Cell Mol Biol 54:584-93
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
Xiao, Rui; Goldklang, Monica P; D'Armiento, Jeanine M (2016) Parenchymal Airspace Profiling: Sensitive Quantification and Characterization of Lung Structure Evaluating Parenchymal Destruction. Am J Respir Cell Mol Biol 55:708-715
Pollack, Daniel; Xiao, Yuxuan; Shrivasatava, Vibha et al. (2015) CDK14 expression is down-regulated by cigarette smoke in vivo and in vitro. Toxicol Lett 234:120-30

Showing the most recent 10 out of 46 publications