Columbia University

College of Physicians & Surgeons

Division of Pulmonary, Allergy & Critical Care

Faculty

Jeannine D'Armiento, M.D., Ph.D.

Assistant Professor of Medicine

Mailing Address:

Biography:

Honors:

Henry Rutgers Honors, 1985

Clinical and Research Interests:

The research in our laboratory centers on several projects directed at understanding the role of matrix metalloproteinases in tissue destruction during certain 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 that occurs during a disease process. 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 Il-1 and cigarette smoke extract can induce MMP-1 expression in lung epithelial cells. These studies will allow us to identify the molecular pathway leading to upregulation of MMP-1 in the emphysema lung and possibly provide us with alternative drug targets.

Changes in the balance of matrix synthesis and degradation are also believed to be important in the process of ventricular remodeling and in the pathophysiology of chronic heart failure. Transgenic mice have been generated harboring a collagenase transgene that dictates cardiac myocyte specific expression (cardiac-collagenase transgenic mice). Histological analyses reveal that the transgenic mouse hearts develop myofibrillar disarray and increased numbers of mitochondria consistent with hypertrophy. In addition, hemodynamic measurements demonstrated increased left ventricular systolic function in the hearts of these mice at 6 months of age that significantly deteriorates over time when compared to normal mice. The collagenase transgenic mouse model directly demonstrates a role for MMP-1, in the development of cardiac dysfunction and further implicate this enzyme in the process of cardiac remodeling providing an important new model in which to study these processes.

Matrix metalloproteinases also play an important role in atherosclerotic plaque formation and evolution. To examine the role of this family of proteases and inhibitors in atherosclerosis a series of genetic experiments were performed in collaboration with Dr. Alan Tall. Transgenic mice which express human collagenase in their macrophages were crossed with the atherosclerosis susceptible ApoE K0 mice. A study population of ApoE K0 mice was generated that carried the MMP-1 transgene and compared to ApoE K0 littermates without the MMP-1 transgene. After 16 weeks on the Western diet, lesions in the ApoE K0/MMP-1 mice were found to be less extensive and immature when compared to their littermate controls. Intimal collagen staining was much less evident in the MMP-1 transgenic mice. The observed difference in lesion size was demonstrated through a quantitative atherosclerosis assay which showed decreased average subintimal lipid deposition in the proximal aortas of MMP-1 transgenic/ApoEK0 mice (459,134 ± 150,351 µm2, n=10) as compared to the ApoEK0 controls (673,470 ± 139,868 µm2, n=10; P < 0.005). This MMP-1 transgenic mouse study demonstrates that the in vivo expression of MMP-1 in the macrophages of ApoEKO mice may be protective in lesion formation.

As described above increased expression of MMPs has been detected in injured arteries and atherosclerotic plaques. The protein TIMP-1 inhibits all MMPs and has high affinity for MMP-1, MMP-2, MMP-3 and MMP-9. Therefore mice deficient in the TIMP-1 gene were crossed into the ApoE KO background. After 10 weeks of a high fat diet, the mean lesion sizes of the two groups of animals were not significantly different and lesions had a similar content of fibrillar collagen. However, the Timp-1 KO/Apo E KO mice developed severe aortic aneurysms. The Timp-1 KO/Apo E KO mice averaged 1.9 +/- 1.2 aneurysm per animal, compared to 0.5 +/- 0.7 for the Apo E KO controls (p<0.005). In situ zymography demonstrated that gelatinolytic activity at the site of medial rupture associated with macrophages and could be inhibited by the addition of MMP inhibitors. This study provides direct evidence that MMP activity is critical in the aneurysm degeneration of the vessel wall associated with atherosclerosis, and that a lack of inhibition of MMPs by Timp-1 increases the formation of aneurysms.

The above-described transgenic models have not only provided us with significant insight into the role of these enzymes in disease but have also generated unique animal models in which to study the pathophysiology of lung and heart disease.

Publications:

1. Berg, R.A., Capodici, C., and D’Armiento, J. (1989). Collagenase Activation. In Therapeutic Approaches to Inflammatory Diseases, Lewis, A., Doherty, N. and Ackerman, N. Elsevier Science Publishing Co.

2. Buttice, G., Kaytes, P., D’Armiento, J., Bogeli, G., and Kurkinen, M. (1990). Evolution of Collagen IV Genes From a 54-Base Pair Exon: A Role for Introns in Gene Evolution. J. Mol. Evol., 30:479-488.

3. 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.

4. D'Armiento, J. and Chada, K. (1995). Frontiers in Transgenics. Trends in Pharmacology 19:26-28.

5. 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.

6. Cherath, L., Tkachenko, A., D'Armiento, J., Welsh, J., McClelland, M., and Chada, K. (1996). RNA Fingerprinting by Arbitrarily-Primed PCR. In: Laboratory Guide to RNA: Isolation, Analysis and Synthesis. Ed. Paul Kreig. Wiley-Liss Inc., N.Y.; pp..251-271.

7. D'Armiento, J., Dalal, S., and Chada, K. (1997). Tissue Expression of Haptoglobin. Gene 195:19-27

8. 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.

9. DiColandrea, T., Wang, L., Wille, J., D’Armiento, J. and Chada, K. (1998) Epidermal expression of callgenase delays wound-healing in transgenic mice. J. Invest. Dermatol. 111:1029-103.

10. 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 New York Acad. Sci. 878:736-739.

11. DiColandrea, T., D’Armiento, J., Kesari, K.V., and Chada, K. (2000) Collagenase Induction Promotes Mouse Tumorigenesis via Two Independent Pathways. Molecular Carcinogenesis 29:8-16.

12. 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.

13. Dalal, S., Chen, E.S., Downey, R., Shulman, L., Ginsburg, M., and D’Armiento, J. (2001) Presence of Human Collagenase (MMP-1) in the lung of Patients with Emphysema. Am. J. Resp, Crit. Care Med. 163:786-791.

14. Lemaitre, 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.

15. Foronjy, B. and D’Armiento, J. (2001) The role of collagenase in emphysema. Respiratory Review. 2:348-352.

16. 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.

17. Arbiser, J.L., Brat, D., Hunter, S., D’Armiento, J., Henske, E.P., Arbiser, Z.K., Bai, X., Goldberg, G., Cohen, C., and Weiss, S.W. (2002) Tuberous Sclerosis-Associated Lesions of the Kidney, Brain, and Skin are Angiogenic Neoplasms J. Am. Acad. Dermatol. 46:376-80.

18. D’Armiento, J. (2002) Matrix Metalloproteinase Disruption of the Extracellular Matrix and Cardiac Dysfunction. Trends in Cardiovascular Medicine 12:97-101.

19. 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.

20. 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..

21. 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.

22. Lemaitre, 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.

23. 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. In Press Am. J. Physiology