Technologies

Summary

Smoking cigarettes is the primary cause of chronic obstructive pulmonary disease (COPD), also known as emphysema, a disease hallmarked by the degradation of lung tissue. Matrix metalloproteinases (MMPs) are a class of proteins that are involved in normal tissue degradation and turnover, but over-production of MMP-1 stimulated by cigarette smoke has recently been implicated in the progression of COPD in smokers. This technology is two separate and structurally distinct classes of drugs that inhibit cigarette smoke-induced MMP-1 production. These therapeutics have the potential to slow or prevent the development of COPD in smokers.

SSRIs and statins both inhibit MMP-1 at nanomolar concentrations

This technology uses two already well-studied types of drugs – selective serotonin reuptake inhibitors (SSRIs) and statins – as inhibitors of MMP-1. Molecules in each class were identified through a high-throughput screen of 727 structurally diverse molecules in a mammalian-cell-line-based transfection assay. Both the SSRIs and the statins blocked transcriptional activity of MMP-1 induce by cigarette smoke in less than 10 nM concentrations. MMP-1 has also been implicated in tumor invasion, arthritis, skin repair and atherosclerotic plaque rupture, suggesting that these small molecules may have broad clinical value.

In further laboratory studies, the SSRI duloxetine was successfully shown to block MMP-1 expression both in cell culture and in a rabbit cigarette smoke model.

Publications

• Woode D, Shiomi T, D’Armiento JM “Collagenolytic Matrix Metalloproteinases in Chronic Obstructive Lung Disease and Cancer.” Cancers (Basel). 2015 Mar; 7(1): 329–341.




• Carver PI, Anguiano V, D’Armiento JM, Shiomi T. “Mmp 1a and Mmp 1b Are Not Functional Orthologs to Human MMP1 in Cigarette Smoke Induced Lung Disease.” Exp Toxicol Pathol. 2015 Feb; 67(2): 153–159.




• Wallace AM, Loy LB, Abboud RT, D’Armiento JM, Coxson HO, Muller NL, Kalloger S, Li X, WM, English JC, Finley RJ, Paré PD. “Expression of Matrix Metalloproteinase-1 in Alveolar Macrophages, Type II Pneumocytes, and Airways in Smokers: Relationship to Lung Function and Emphysema.” Lung. 2014; 192(4): 467–472.




• Goldklang MP, Marks SM, D’Armiento JM. “Second hand smoke and COPD: lessons from animal studies.” Front Physiol. 2013; 4: 30.




• Wallace AM, Mercer BA, He J, Foronjy RF, Accili D, Sandford AJ, Paré PD, D’Armiento JM. “Functional characterization of the matrix metalloproteinase-1 cigarette smoke-responsive region and association with the lung health study.” Respir Res. 2012; 13(1): 79.




• Lemaître V, Dabo AJ, D’Armiento JM. “Cigarette Smoke Components Induce Matrix Metalloproteinase-1 in Aortic Endothelial Cells through Inhibition of mTOR Signaling.” Toxicol Sci. 2011 Oct; 123(2): 542–549.




• Mercer BA, Wallace AM, Brinckerhoff CE, D’Armiento JM. “Identification of a Cigarette Smoke–Responsive Region in the Distal MMP-1 Promoter.” Am J Respir Cell Mol Biol. 2009 Jan; 40(1): 4–12.