Division of Pulmonary, Allergy
and Critical Care Medicine
Research Laboratories
Jeannine D'Armiento,
M.D., Ph.D.
Assistant
Professor of Medicine, Division of Pulmonary, Allergy and Critical Care
Medicine
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Laboratory Address 630 Phone 212-305-3745 Fax
212-305-7072 |
The research in our laboratory
centers on several projects directed at understanding the role of matrix metalloproteinases in tissue destruction during disease
processes. Our laboratory has made use of transgenic mice in which to express
these enzymes at pathophysiological levels in
specific tissues so as to recreate the natural proteolytic
imbalance. Through the generation of these transgenic animals we have been able
to develop several mouse models of emphysema, atherosclerosis and heart failure
and also gain insight into the role these enzymes may be playing in the
pathogenesis of these diseases.
Several years ago we
demonstrated that transgenic mice which express human MMP-1 (matrix
metalloproteinase 1, interstitial collagenase) in the
lung develop emphysema. We have recently demonstrated that human patients with
emphysema express MMP-1 within their lung parenchyma and normal patients do
not. In this study it was found that the type II pneumocyte
of the lung of patients with emphysema expressed MMP-1. Therefore, we are
proceeding with in vitro studies to determine the mechanism by which MMP-1 is
induced in the type II pneumocyte. In our preliminary
work we have found that cigarette smoke extract can induce MMP-1 expression in
lung epithelial cells and this occurs through activation of the MAP Kinase signaling pathway. Through in vitro promoter studies
we have identified the region of the MMP-1 promoter that responds to cigarette
smoke.
These studies demonstrate that
cigarette smoke induced changes on the epithelial cell of the lung from
patients with emphysema may be critical in disease pathogenesis. Our future studies will attempt to identify
the molecular pathway leading to up regulation of MMP-1 and other genes in the
emphysema lung and possibly provide us with alternative drug targets for this
disease.
1.
D’Armiento,
J., Dalal, S., Okada, Y., Berg, R. A., and Chada, K.
(1992). Collagenase
Expression in the Lungs of Transgenic Mice Causes Pulmonary Emphysema. Cell, 71:955-961.
2.
D'Armiento,
J., DiColandrea, T., Dalal,
S., Okada, Y. and Chada, K. (1995).
Transgenic Overexpression of Collagenase in Mouse Skin Increases the Susceptibility to Tumorigenesis. Mol. Cell. Biol., 15:5732-5739.
3.
D'Armiento,
J., Dalal, S., and Chada, K. (1997). Tissue Expression of Haptoglobin.
Gene 195:19-27
4.
Jiang,
X., D’Armiento, J., Mallampalli, R. K., Mar, J., Yan, S-F., and Lin, M. (1998). Expression of plasma phospholipid
transfer protein mRNA in normal and emphysematous lungs and regulation by hypoxia.
J. Biol. Chem, 273:15714-15718.
5.
Lemaitre,
V., O’Byrne, T.K., Dalal, S.S., Tall, A.R. and
D’Armiento, J. (1999) Macrophage-Specific Expression of Human Collagenase (MMP-1) in Transgenic Mice. Annals
6.
Kim,
H., Dalal., S.S., Young, E., Legado,M.,
Weisfeldt, M.L., and D’Armiento, J. (2000) Disruption of the cardiac matrix leads to
altered myocardial function in transgenic mice expressing collagenase
(MMP-1) in the heart. J. Clin. Invest. 106:857-866.
7.
Imai,
K., Dalal, S., Chen, E.S.,
8.
Lemaître, V., O’Byrne, T.K., Okada, Y., Borczuk,
A. C., Tall, A.R. and D’Armiento, J (2001) Apo E knock-out mice expressing
human interstitial collagenase (MMP-1) in macrophages
have less advanced atherosclerosis. J. Clin. Invest.
107:1227-1234.
9.
Foronjy, B. and D’Armiento, J. (2001) The
role of collagenase in emphysema. Respiratory Review. 2:348-352.
10. Schluger, N. W. and D’Armiento, J.
(2002) The Pathogenesis and Pathophysiology
of Emphysema. In:Lung Volume Reduction Surgery Ed. M Argenziano and M. Ginsburg Humana Press, Totowa, N.J;
pp.3-15.
11. D’Armiento, J. (2002) Matrix
Metalloproteinase Disruption of the Extracellular
Matrix and Cardiac Dysfunction. Trends in Cardiovascular Medicine 12:97-101.
12. Marx, S., Kurokawa,
J., Reiken, S., Motoike,
H., D’Armiento, J., Marks, A.R., Kass, R.S. (2002) Requirement of a Macromolecular
Signaling Complex for b Adrenergic Receptor Modulation of the KCNQ1-KCNE1
Potassium Channel Science 295:466-9.
13. Reiken, S., Gaburjakova,
M., Guatimosim, S., Gomez, A.M., D'Armiento, J., Burkhoff, D., Wang, J., Vassort,
G., Lederer, W. J., and Marks, A.. (2003) PKA phosphorylation of the cardiac calcium release channel in
normal and failing hearts: role of phosphatases and
response to isoproterenol. J. Biol. Chem. 278:444-53..
14. Shiomi, T., Okada, Y., Foronjy,
B., Schiltz,
J., Jaenish, R., and D'Armiento, J. (2003).
Emphysematous changes are caused by degradation of type III collagen in
transgenic mice overexpressing tissue collagenase. Exp.
Lung Res. 29:1-15.
15. Lemaître, V., Soloway,
P.D., and D’Amiento,, J. (2003) Increased medial
Degradation with Pseudo-aneurysm Formation in ApoE
Knockout Mice deficient in Tissue Inhibitor of Metalloproteinases-1.
Circulation.107:333-338.
16. Foronjy, R. F., Okada, Y., Cole, R., and
D’Armiento, J. (2003) Progressive Adult-Onset Emphysema in Transgenic Mice
Expressing Human MMP-1 in the Lung. Am. J. Physiol.
Lung Cell Mol. Physiol. 284:L727-37.
17. Wehrens, X. H. T., Lehnart,
S. E., Huang, F., Vest, J.A., Reiken, S.R., Mohler, P.J., Sun, J., Guatimosim,
S., Long-Sheng, S., Rosemblit,
N., D’Armiento, J.M., Napolitano C., Memmi, M.,
Priori, S., Lederer, W.J., and Marks, A. M. (2003) FKBP12.6 deficiency and
defective calcium release channel (ryanodine
receptor) function linked to exercise-induced sudden cardiac death Cell.
113:829-40.
18. Kim, H., Xu,
G.L., Borozuk, A.C., Busch, S., Filmus,
J., Capurro, M., Brody, J.S., Lange, J., D’Armiento,
J. M., Rothman, P.B., and
19. D’Armiento, J. (2003) Decreased elastin in vessel walls puts the pressure on. J. Clin. Invest.
112:1308-10.
20. Mercer, B., Kolesnikova,
N., Sonett, J. and D’Armiento, J. (2004) Erk-1/2 MAP Kinase is upregulated in
Pulmonary Emphysema and Mediates MMP-1 Induction by Cigarette Smoke. J. Biol.
Chem. 279:17690-17696.
21. Imai K, Mercer BA,
Schulman LL, Sonett J, D'Armiento J. Correlation of lung surface area to apoptosis
and proliferation in human emphysema. 2005 Eur Respir J 25(2) 1-9.
22. Lemaître, V. and D’Armiento, (2004) Are
Matrix Metalloproteinases Detrimental or Beneficial
to Atherosclerosis? In Press
23. Foronjy, R., Mercer, B., Maxfield, M.,
Okada, Y., Powell, C., and D’Armiento, J. (2005) Structural Emphysema Does Not
Correlate with Lung Compliance:Lessons
from the Mouse Smoking Model (In Press, Exp. Lung Research).
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