Jeanine M. D'Armiento, MD, PhD
Jeanine D’Armiento, M.D, Ph.D. has been caring for patients with LAM for over ten years. She received her M.D. and Ph.D. from UMDNJ-Robert Wood Johnson, and completed Internal Medicine residency and Pulmonary fellowship at Columbia University Medical Center.
Her research focus in LAM centers on the role of HMGA2 in disease pathogenesis. She has been performing pulmonary research for more than 15 years, with interests in LAM, emphysema, and lung injury and repair.
We are dedicated to the comprehensive evaluation of patients with lymphangioleiomyomatosis and other lung diseases in parallel with a commitment to basic research and application of principles to the therapeutic aspects of lung disease.</p>
We are a multi-disciplinary center focusing on the care of patients with LAM and other rare lung diseases. In addition to the care of patients with LAM, we conduct both clinical and basic science research focusing on this disease.</p>
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.
The cystic lung disease seen in LAM is quite similar to the cysts seen in emphysema, and as such, I have a longstanding interest in this disease. Additionally, we have taken a lead role in investigating the possible role for HMGA2, an architectural transcription factor critical in the formation of mesenchymal tumors, in LAM pathogenesis. We were able to demonstrate the activation of the HMGA2 pathway in 100% of human and mouse tumor samples and revealed by genetic models an absolute requirement for HMGA2 activation in this disease. These studies have identified a novel molecular pathway that can generate therapeutic targets for use in treating LAM.
Smoke Induced Lung Injury
Our early work demonstrated that MMP-1 expression in the lung leads to tissue destruction. We have a large interest in redefining the mechanistic understanding of emphysema with the goal of providing the basis for novel therapeutic approaches. It has been hypothesized that the proteases leading to lung tissue destruction in emphysema come from the inflammatory cells infiltrating the tissue after smoke exposure. Our studies have identified the mechanisms by which cigarette smoke upregulates protease expression within airway epithelial cells, ultimately leading to tissue destruction. Our most recent MMP-1 related work has been in the identification of the toll-like receptor (TLR) 4 signaling cascade as an upstream regulator of MMP-1 expression. Blockade of this pathway inhibits cigarette smoke induction of MMP-1 in vitro.
In addition, our laboratory is now exploring pathways activated during epithelial injury in emphysema. We have established a role for the Wnt signaling pathway in emphysema and lung injurty. The Wnt inhibitor sFRP-1 is a regulator of lung progenitor cells and is critical in both normal lung development and lung injury. Extensive examination of this pathway in emphysema and lung injury in general determined that sFRP-1, an inhibitor of the WNT pathway, is critical for normal alveolar septation but during lung injury functions as a regulator of lung progenitor cells. These studies emphasize a novel role in tissue repair processes for molecules critical in lung development.
Cigarette Smoke Related Vascular Disease
Through the utilization of animal models of atherosclerosis, we have established a critical role for abnormal expression of MMPs, and their inhibitors, TIMPs, in disease pathogenesis. We have identified specific cigarette smoke components that cause MMP induction. Utilizing our smoke exposure models we have defined several important proteases involved in smoke induced injury in vascular disease and have recently identified a possible common pathway between atherosclerosis and emphysema.
Tissue Destruction in Alternative Lung Diseases
Over the last few years our laboratory has expanded studies examining the role of protease to other lung diseases including tuberculosis, acute lung injury, and lung metastasis. Our work in tuberculosis has demonstrated that MMP-1 is produced in the lungs of Tb infected individuals and Tb infection directly induces MMP-1. When MMP-1 expressing mice are infected with Tb these mice develop cysts and greater lung destruction. Other ongoing projects in the laboratory include an investigation of biomass exposure in two cohorts of women from India, as well as asthma related projects examining airway smooth muscle remodeling.