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. !
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.
|Carver, Phillip I; Anguiano, Vincent; D'Armiento, Jeanine M et al. (2015) Mmp1a and Mmp1b are not functional orthologs to human MMP1 in cigarette smoke induced lung disease. Exp Toxicol Pathol 67:153-9|
|Brehm, Anthony; Geraghty, Patrick; Campos, Michael et al. (2014) Cathepsin G degradation of phospholipid transfer protein (PLTP) augments pulmonary inflammation. FASEB J 28:2318-31|
|Wallace, Alison M; Loy, Leanna B; Abboud, Raja T et al. (2014) Expression of matrix metalloproteinase-1 in alveolar macrophages, type II pneumocytes, and airways in smokers: relationship to lung function and emphysema. Lung 192:467-72|
|Geraghty, Patrick; Hardigan, Andrew A; Wallace, Alison M et al. (2013) The glutathione peroxidase 1-protein tyrosine phosphatase 1B-protein phosphatase 2A axis. A key determinant of airway inflammation and alveolar destruction. Am J Respir Cell Mol Biol 49:721-30|
|Goldklang, Monica P; Perez-Zoghbi, Jose F; Trischler, Jordis et al. (2013) Treatment of experimental asthma using a single small molecule with anti-inflammatory and BK channel-activating properties. FASEB J 27:4975-86|
|Nkyimbeng, Takwi; Ruppert, Clemens; Shiomi, Takayuki et al. (2013) Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis. PLoS One 8:e73279|
|Goldklang, Monica P; Marks, Sarah M; D'Armiento, Jeanine M (2013) Second hand smoke and COPD: lessons from animal studies. Front Physiol 4:30|
|Morishita, Asahiro; Zaidi, M Raza; Mitoro, Akira et al. (2013) HMGA2 is a driver of tumor metastasis. Cancer Res 73:4289-99|
|Goldklang, Monica; Golovatch, Polina; Zelonina, Tina et al. (2012) Activation of the TLR4 signaling pathway and abnormal cholesterol efflux lead to emphysema in ApoE-deficient mice. Am J Physiol Lung Cell Mol Physiol 302:L1200-8|
|George, Joseph; Sun, Jie; D'Armiento, Jeanine (2012) Transgenic expression of human matrix metalloproteinase-1 attenuates pulmonary arterial hypertension in mice. Clin Sci (Lond) 122:83-92|
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