The Division of Pulmonary, Critical Care, and Sleep Medicine of the Warren Alpert Medical School at Brown University is strongly committed to the academic mission of the Department of Medicine. We have many ongoing funded research projects in a wide variety of fields from clinical research to bench research both within our own department and through collaboration with the other departments in the Brown research community. Each faculty member, whether full-time basic science, clinical research or clinical practice oriented, is encouraged to pursue independent research efforts. The success of these efforts is measured by the fact that, over the past 2 years, there are over 100 publications in the peer-review literature by division faculty. The strong point in the current research in is the diversity of these efforts. Research in our division encompasses a diverse mix of basic science biology, clinical studies, therapeutic trials, health services, and ethics research. In fact, the division is committed to encouraging a broad array of such research. The funding of research in our division also comes from a wide area of sources, including the NIH, professional societies, dependent foundations, hospital-based, and industry. The Pulmonary/Critical Care Fellows have participated in many of the research projects listed below and have been lead authors on several publications in peer-reviewed journals as a result of their research efforts.
Active Areas of Research Include:
(mechanisms and treatment)
- Knowledge translation
- Acute lung injury
Pulmonary Vascular Disease
(mechanisms and treatment)
- Sleep disordered breathing associated with behavior disorders and treatments
- Systemic vascular co-morbidities of COPD
- Tuberculosis in rural Africa
- End-of-life care in the ICU
- Ethical and Practical aspects of rationing medical care
- Role of Stem Cells in lung injury repair
The Anti-Inflammatory Response in Severe Sepsis
In collaboration with the lab of Dean Jack Elias, Dr. Mitchell Levy, Dr. Alfred Ayala (Division of Surgical Research), Dr. Sean Moynihan, Dr. Deb Bannerjee, Dr. Bing Ma and Dr. Chun Lee and Dr. Steven Opal have a project looking at both in vivo and in vitro elements of the anti-inflammatory response in severe sepsis and correlating the results with clinical outcomes. Tracking septic patients over the first 7 days of admission to the ICU, this project is evaluating levels of PD-1, IL-7 and Chitenase 3 like-1, along with other inflammatory markers, with outcomes and immune suppression.
A Sepsis bio-bank study is also underway with Dr. Levy, Dr. Ventetuolo, Dr. Moynihan and Dr. Elias (Dean of the Medical School) evaluating the timing and identification of several key cytokines during the immunosuppressive phase of sepsis and the development of ARDS.
Knowledge Translation in Sepsis
Mitchell Levy, MD (Division Chief) is conducting work on performance improvement techniques, and has been working with The Surviving Sepsis Campaign to improve the survival of sepsis. The Surviving Sepsis Campaign guidelines were developed and published first in 2004 and then revised and published in 2008, 2012 and 2016. He has conducted several trials, testing the impact of these “sepsis bundles” and a multiple-faceted intervention in facilitating knowledge transfer. In partnership with the Institute for Healthcare Improvement (IHI), two sepsis bundles were developed in 2004, and a multi-faceted performance improvement project (Phase 3) was launched in North American, Europe, Asia and Latin America, the results of which were co-published in Critical Care Medicine and Intensive Care Medicine in January, 2010. The final analysis of 30,000 patients in the sepsis database, demonstrating a clear association with higher compliance with the measures and lower hospitals mortality was also co-published in Critical Care Medicine and Intensive Care Medicine in January, 2015.
Through funding from a Moore Foundation grant, an initiative, “Early identification and management of Sepsis on the medical floors” began in early 2014 and completed in August 2015, demonstrating a significant improvement in compliance with the sepsis measures and an associated decline in mortality from severe sepsis.
Knowledge transfer projects also include the introduction of a Procalcitonin-guided antibiotic de-escalation as a component of antibiotic stewardship, in Rhode Island Hospital.
Health Care Rationing In Critical Care Medicine
Nicholas Ward, MD in 2008 published the first study of the scope and effect of healthcare rationing in critical care medicine in the US. Dr Ward’s work on rationing of critical care in the US is now focusing on Physician staffing shortages in ICUs and he is chairman of the Society of Critical Care Medicine’s Taskforce on ICU staffing that recently published both a study and national guidelines on this issue. As a member of the American Thoracic Society’s Ethics Committee, he is now working on a statement regarding the role of stewardship in allocating critical care resources.
End of Life Care
Mitchell Levy, MD (Division Chief) is continuing his work in end-of-life care. Over the past several years, he has published numerous manuscripts in the field, including one on the visiting hours in the MICU, as well as several opinion pieces, describing the barriers to adequate end-of-life decision-making. Dr. Levy has completed a state-wide initiative on communication bundles in the ICU (with a research fellow as lead author) the results of which have been published in Critical Care Medicine. A new funded project is underway entitled, “Family Care Rituals in the ICU” with Dr. Tim Amass one of the Pulmonary/Critical Care Fellows. This project is evaluating the impact of an intervention aimed at increasing family participation in bedside care of their loved ones admitted to the MICU.
Public Reporting of Quality Measures
Mitchell Levy, MD (Division Chief) is examining large data sets of severely septic patients (New York State sepsis database) to determine the viability of a disease-specific risk-adjusted mortality model in patients with severe sepsis and septic shock. Using recursive partitioning and regression analysis, statistical correlations with these features are being identified. The aim is to generate a predictive model incorporating these factors to identify mortality risk. These efforts are in collaboration with Stan Lemeshow and Gary Phillips, from Ohio State University School of Biostatistics.
Extracorporeal Life Support
Corey Ventetuolo, MD
Christopher Muratore, MD
Rhode Island Hospital and Hasbro Children’s Hospital is an ELSO Center of Excellence. The Adult Extracorporeal Life Support program is directed by Dr. Ventetuolo. A multidisciplinary team which includes critical care faculty, pediatric and cardiothoracic surgery, MICU nursing, and respiratory therapy provide veno-venous and veno-arterial ECMO support for both bridge to recovery and bridge to destination indications for a growing number of adult patients with advanced cardiac and respiratory failure. The ECLS Program also engages in research, participating in registries and clinical trials.
The Extracorporeal Life Support (ECLS) service of Rhode Island Hospital and Hasbro Children’s Hospital was awarded the ELSO Gold Level Award for Excellence in Life Support in 2015. The Adult ECLS program is directed by Corey E. Ventetuolo, MD, MS with partnership from Christopher Muratore, MD in the Division of Pediatric Surgery and collaborative efforts across multiple disciplines including respiratory therapy, critical care nursing, cardiothoracic surgery, vascular and general surgery, and transfusion and coagulation medicine. The research mission of the ECLS service is expanding, with the addition of a local registry, participation in clinical trials, international guideline development, and work in best practice for anticoagulation monitoring modalities during ECMO.
The Pulmonary Hypertension Center
James Klinger, MD
Corey Ventetuolo, MD
The Rhode Island Hospital Pulmonary Hypertension Center (RIPHC) was established in 1991, and has been under the leadership of Dr. James Klinger since 2001. Dr. Corey Ventetuolo was recruited in 2012 for her expertise in right heart function and extracorporeal life support (ECMO). Mary Whittenhall, MSN, APRN, AGACNP is the Center’s nurse practitioner in charge an active support group. The RIPHC was the first Pulmonary Hypertension Center in New England to be accredited as a Center of Comprehensive Care by the Pulmonary Hypertension Association. The Center participates in numerous clinical trials of new and approved therapies for the treatment of pulmonary arterial hypertension (PAH) and is currently enrolling patients in several national registry and bio-banking studies. Clinical trials run through the RIH PHC are supported by the NIH, American Heart Association (AHA), PHA, industry sources and the Brown University Department of Medicine.
Pulmonary Embolism and Deep Vein Thrombosis
Drs. James Klinger and Corey Ventetuolo have been investigating the role of DVT prophylaxis in the ICU and treatment and follow up of acute submassive pulmonary embolism. The RIHPHC also manages an active population of patients with chronic thromboembolic pulmonary hypertension (CTEPH).
Pulmonary Vascular Research
Dr. Klinger’s research is concentrated on the natriuretic peptides, nitric oxide and downstream signaling mechanisms that are regulated by cGMP and cGMP-dependent protein kinase. His interest in these pathways is related to their role in modulating pulmonary hypertensive and right ventricular hypertrophic responses, as well as pulmonary endothelial barrier function. Presently, Drs. Klinger and Harrington are co-PIs on an RO1 that examines the role of natriuretic peptide C in ameliorating acute lung injury.
In collaboration with Dr. Aliotta (see STEM CELL RESEARCH below), Dr. Klinger also investigates the role of mesenchymal stem cells, extracellular vesicles and micoRNA in pathogenesis and treatment of pulmonary hypertension.
Dr. Ventetuolo’s research focuses on genetic and molecular markers in sex hormone pathways and their influence on sex-based phenotypes in pulmonary vascular and right ventricular health and disease. Her work has focused on the influence of estradiol and other hormones on circulating hematopoietic precursors and markers of angiogenesis in pre- and post-menopausal women and men with PAH. Dr. Ventetuolo’s research is funded by the NIH and the AHA. She also serves as a mentor to Dr. Debasree Banerjee who is the recipient of a CHEST Foundation grant that examines alternative splicing of the cardiac sodium channel and its role in RV phenotype and sudden death in PAH.
STEM CELL RESEARCH (Center for Stem Cell Biology, RIH)
Dr. Jason Aliotta is involved in several NIH-funded projects related to the communication between the pulmonary vasculature and stem/progenitor cells of the bone marrow via extracellular vesicles in various animal models of pulmonary hypertension.
Bone marrow-derived endothelial progenitor cells and pulmonary hypertension:
- These projects focus on endothelial progenitor cells isolated from the bone marrow of mice with monocrotaline- or VEGF-inhibitor/hypoxia-induced pulmonary hypertension and how these cells induce pulmonary vascular remodeling when transplanted into healthy mice.
Induction and reversal of pulmonary hypertension with extracellular vesicles:
- These projects focus on the multifaceted role of extracellular vesicles in the regulation of the pulmonary vasculature. They include studies with blood and lung cell-derived extracellular vesicles from mice with pulmonary hypertension and their ability to induce pulmonary hypertension when infused into healthy mice. Other studies focus on extracellular vesicles isolated from mesenchymal stem cells and their ability to reverse right ventricular hypertrophy and pulmonary vascular remodeling in mice with established pulmonary hypertension.
Profiling of extracellular vesicle-based microRNA in patients with pulmonary hypertension:
- In collaboration with Drs. James Klinger and Corey Ventetuolo, circulating extracellular vesicles isolated from blood samples obtained at the time of right heart catheterization of patients with pulmonary hypertension are subjected to microRNA microarray profiling. The goal is to use these data to develop a novel diagnostic and/or prognostic disease biomarker and to obtain a greater understanding of the cellular pathways that are central to the pathogenesis of pulmonary hypertension.
Interstitial Lung Disease Program
Barry Shea, MD
Dr. Shea’s laboratory uses a translational approach to better understand the biological mechanisms which drive the development and progression of lung fibrosis, with a focus on the role of ongoing, repetitive lung injury in idiopathic pulmonary fibrosis (IPF). The Shea lab seeks to integrate information obtained from bench research studies using animal models and cell culture systems with the results of clinical investigations of human disease. Towards this end, Dr. Shea has established a longitudinal clinical database and a biorepository of blood, bronchoalveolar lavage (BAL) fluid, and DNA specimens from patients with IPF and other ILDs, and he collaborates closely with the Elias and Chun labs at The Alpert Medical School of Brown University.
Vascular Research Laboratory
Providence VA Medical Center
The Vascular Research Laboratory is a multidisciplinary group of investigators studying the pulmonary circulation and cardiopulmonary interactions using cells, animal models, clinical studies, and epidemiology studies using database approaches. Faculty include MD’s, PhD’s, pulmonary/critical care and cardiology specialists. Research is multidisciplinary with a focus on diseases resulting in pulmonary edema, pulmonary hypertension, and cardiac complications of pulmonary hypertension.
FACULTY AND PROJECTS:
Siddique Abbasi, MD, is Assistant Professor of Medicine and staff cardiologist at the Providence VAMC. He has been awarded a Pilot Project grant from the CPVB COBRE to use cardiac MRI to study the relationship between pulmonary artery stiffness and right ventricular fibrosis. He collaborates with Choudhary, Jankowich, and Wu.
Won-Kyung Cho, MD, is Assistant Professor of Medicine and staff pulmonologist at the PVAMC. She has been awarded a K-08 from the NHLBI to study IL-13 mediated mechanisms of pulmonary vascular remodeling and a Pilot Project from the CPVB COBRE to study metabolic regulation in immune cells and their role in pulmonary hypertension. She is currently collaborating with Rounds, Lee, and Rand.
Gaurav Choudhary, MD, is Associate Professor of Medicine, Staff Cardiologist and Associate Chief of Staff for Research at the PVAMC. The focus of his research is evaluation of mechanisms underlying vascular dysfunction caused by hypoxia or cigarette smoke exposure utilizing in vivo, ex vivo and in vitro approaches. He studies the role of natriuretic peptides in hypoxia mediated endothelial dysfunction, including the role of C-type natriuretic peptide in vascular remodeling, endothelial ion channels, microvascular endothelial cell proliferation and apoptosis, and endothelial barrier dysfunction. Dr. Choudhary mentors in the area of pulmonary hypertension, endothelial cell dysfunction, lung vascular remodeling, and RV dysfunction. Dr. Choudhary is funded by an RO1 and collaborates with Cho, Harrington, Lu, Rounds, and Wu.
Elizabeth Harrington, PhD, is Professor of Medicine, Associate Dean of Brown BioMed Office of Graduate & Postdoctoral Studies, and Staff Biologist at the Providence VAMC. Dr, Harrington is PI or co-PI on 3 training grants that support undergraduate, medical student, and graduate student research. The focus of her research is characterization of intracellular signaling mechanisms regulating endothelial cell functions and/or responses to environmental cues. Current investigations include elucidation of the molecular mechanism by which PKCd regulates endothelial monolayer permeability and apoptosis and elucidation of signaling pathways which are differentially activated in pulmonary and systemic microvascular endothelial cells in response to oxidative stress. Dr. Harrington has extensive experience collaborating with physician scientists and training students and postdoctoral fellows at all levels. Dr. Harrington mentors in the area of abnormal endothelial cell function. Dr. Harrington is Deputy PI, mentor, and Core Director on the CPVB COBRE, and PI or co-PI on numerous training grants. Harrington, Choudhary, Lu, Klinger, Jamieson, and Rounds have long-standing research collaborations.
Matthew Jankowich, MD, is Assistant Professor of Medicine and Medical Director of the Medical Intensive Care Unit and Invasive Pulmonology at the Providence VAMC. He studies combined pulmonary fibrosis and emphysema and other conditions predisposing to pulmonary hypertension and RV failure. He is a site PI on a VA-funded Clinical Merit Review to study the effects of Tadalafil on pulmonary hypertension associated with COPD. Dr. Jankowich collaborates with Choudhary, Rounds, and Wu.
James Klinger, MD, is Professor of Medicine and Medical Director of the Pulmonary Hypertension Center at Rhode Island Hospital. His basic science interests include the natriuretic peptides-cGMP signaling pathway and its role in modulating pulmonary hypertensive and right ventricular hypertrophic responses and pulmonary endothelial barrier function. Dr. Klinger also examines the role of extracellular vesicles in pathogenesis of pulmonary hypertension. His clinical research is focused on the use of investigational agents to treat adult patients with pulmonary hypertension. He is co-PI with Elizabeth Harrington on an RO1 to study the natriuretic peptides in regulation of endothelial permeability. He has active collaborations with Aliotta, Harrington, Lee, Ventetuolo, and Zhou. He is a mentor on the CPVB COBRE.
Qing Lu, DVM, PhD, is Associate Professor of Medicine and Staff Biologist at the Providence VAMC. The focus of her research is the molecular mechanism(s) underlying pulmonary endothelial dysfunction and injury. She is elucidating the molecular mechanism(s) by which adenosine and cigarette smoke regulate endothelial monolayer permeability, endothelial cell proliferation, and endothelial cell apoptosis. Dr. Lu has mentored several undergraduate students, several PhD and MD postdoctoral fellows, and is currently mentoring a PhD graduate student. Dr. Lu will co-mentor with Drs. Rounds and/or Harrington in the area of acute lung injury. Dr. Lu is a project PI on the CPVB COBRE. She is co-Investigator with Dr. Rounds on a VA Merit Review award and co-Investigator with Drs. Rounds and Rand on a DEANS award. Dr. Lu has established collaborations with Kane, Choudhary, Klinger, Rounds, Harrington, Abid, Lee, and Ayala.
Sharon Rounds, MD, is Professor of Medicine and of Pathology & Laboratory Medicine and staff pulmonologist at the Providence VAMC. She is interested in mechanisms of lung vascular injury in conditions causing pulmonary hypertension and acute lung injury. Her work focuses on mechanisms of lung endothelial cell Injury. Current work in the laboratory focuses on the mechanism of small GTPase carboxylmethylation in regulation of endothelial cell apoptosis, the effects of carboxylmethylation of RhoA GTPase, and the effects of cigarette smoke exposure on endothelial monolayer and pulmonary microvascular permeability. Dr. Rounds mentors in the area of endothelial cell injury and dysfunction, pulmonary edema, and pulmonary hypertension. Dr. Rounds is funded by the VA Merit Review to study cigarette smoke effects on lung function and by a second VA Merit Review to study the effects of Tadalafil on pulmonary hypertension associated with COPD. She is Director of the CPVB COBRE, a $10 million, 5 year grant to develop research on CardioPulmonary Vascular Biology and she is co-PI with Dr. Rand on a DEANS award. She collaborates with Cho, Choudhary, Harrington, and Lu.
Wen-Chih (“Hank”) Wu, MD, MPH, is Associate Professor of Medicine and Chief of Cardiology at the Providence VAMC. He is also an Investigator in the Center of Innovation in Long-Term Services and Supports for Vulnerable Veterans (COIN) at the PVAMC. Dr. Wu studies the relationship between anemia, blood transfusion and death in elderly patients undergoing non-cardiac surgery and delivery of care to patients with CHF. In collaboration with Dr. Choudhary, he also studies factors predisposing to pulmonary hypertension and RV failure. He is funded by the VA and collaborates with Choudhary, Trivedi, and Wilson. He mentors in the areas of epidemiology and outcomes of pulmonary hypertension and CHF.
The Vascular Research Laboratory (VRL) at the Providence VA Medical Center occupies 3000 sq. ft. in the Research Building #35 (8 rooms in 2nd floor and 4 rooms in 1st floor). The VRL includes rooms for general biochemical and molecular biological experiments, including dedicated spaces for RNA work and for generation of cigarette smoke extract, tissue culture, heavy equipment, fluorescence microscopy and life image microscopy, dark room, cold room, and storage room. In addition, there is a fully equipped laboratory for rodent animal studies, including echocardiography, lung mechanics, lung vascular permeability, and exercise studies.
All PI’s (Abbassi, Cho, Choudhary, Harrington, Jankowich, Lu, Rounds, Wu) have at least 500 sq. ft office also located at the Research Building #35 at the Providence VA Medical Center.
One 1000 square foot and one 1500 square foot conference room equipped with projectors and flat screens are available for use by investigators and staff.
Vascular Research Laboratory faculty cumulatively have $2.3 million in direct costs per year of funding to support their research. In addition, the VRL is the site of the CardioPulmonary Vascular Biology Center for Biomedical Research Excellence (CPVB COBRE) with has $1.5 million in direct costs per year.
Vascular Research Laboratory
CardioPulmonary Vascular Biology COBRE
Clinical Research Program at the Providence Veterans Affairs Medical Center
Linda Nici MD (Section Chief) is conducting work on interventions to improve patient-centered outcomes in COPD. Through the Pulmonary Rehabilitation Program as well as the Pulmonary Risk Reduction Initiative, COPD patients at risk for hospital admission or readmission are receiving additional health provider support through education initiatives, promotion of exercise, and identification of risk factors that can be modified to prevent hospitalizations. Current studies include: 1) Rates and predictors of hospital readmission among patients with COPD in the Department of Veterans Affairs using the national VINCI database; 2) The trajectory of physical activity following pulmonary rehabilitation; 3) A brief physician-led education intervention designed to prevent readmission after COPD exacerbation
Matthew Jankowich MD (Co-Director, Providence VAMC Pulmonary Hypertension Clinic) has research interests in pulmonary hypertension and cardiovascular co-morbidities of chronic lung diseases. He has been conducting epidemiologic research with cardiologists Gaurav Choudhary, M.D. and Wen-Chih Wu, M.D. using data from the Jackson Heart Study (JHS), the largest prospective observational study of cardiovascular disease in African-Americans. Brown University is a Vanguard data center for the JHS. Current JHS-approved analyses for which Dr. Jankowich is a lead or co-author include: 1) Neurohormonal markers and pulmonary hypertension in African-Americans in the Jackson Heart Study; 2) The restrictive spirometry phenotype, cardiac structure and function, and heart failure hospitalizations: The Jackson Heart Study; and 3) Iron deficiency in pulmonary hypertension in African-Americans: The Jackson Heart Study. Dr. Jankowich is also site investigator for the Tadalafil for Pulmonary Hypertension Associated with Chronic Lung Disease (TADA-PHiLD) multicenter randomized double-blind placebo-controlled clinical trial (co-PI Dr. Sharon Rounds).
Eric Gartman MD (Director, PFT and CPET laboratories) has research interests in airway disease, diaphragmatic dysfunction and exercise limitation. He is currently the principle investigator for a study evaluating the use of Cardiopulmonary Exercise Testing (CPET) in predicting outcomes after cancer diagnosis and treatment.
In addition to the studies mentioned above, the Providence VAMC implemented lung cancer screening using LDCT starting in December 2013. We are currently evaluating the utility of lung cancer screening in the first two years of implementation in terms of rates of nodule detection, percentage of nodules found to be malignant, and stage at diagnosis compared to the pre-screening population.