Anesthesia Center for Critical Care Research

Overview

Research in the Anesthesia Center for Critical Care Research (ACCCR) at Massachusetts General Hospital focuses on elucidating the fundamental mechanisms that underly intensive care medicine’s central problems including sepsis, acute respiratory failure, blood transfusion, pulmonary hypertension and cardiac dysfunction. Our goal is to develop novel treatment strategies that improve outcomes for patients who are critically ill.

The center takes a multidisciplinary approach to research. Clinicians and basic scientists collaborate on various research studies that use small and large animal models.

Current projects include:

• Characterization of the role of bone morphogenetic protein signaling in cardiovascular diseases and iron metabolism
• Development of novel therapeutic approaches to treat patients who have been resuscitated from cardiac arrest
• Elucidation of the mechanisms regulating hypoxic pulmonary vasoconstriction
• Identification of novel small molecules that modulate hemoglobin functions
• Studies of the mechanisms responsible for the adverse effects associated with transfusing blood stored for prolonged periods
• Studies of the mechanisms by which common genetic variants identified in genome-wide association studies contribute to the pathogenesis of systemic hypertension

Laboratories & Research Projects

Bloch Lab

The long-term objective of the Bloch Lab, led by Donald Bloch, MD, is to investigate the role of intracellular iron in the pathogenesis of anemia, inflammation and atherosclerosis. We are studying the regulation of ferroportin, the cell’s only mechanism for exporting iron. These studies involve examining the roles of hepcidin and ubiquitin in the proteolytic degradation of the iron channel. We anticipate that the results of these studies will give rise to novel treatments for patients with anemia associated with malignancy and chronic inflammation. In addition, we anticipate that by studying the pathways that regulate intracellular iron, we will identify novel approaches to the treatment of atherosclerosis. 

A second objective of the Bloch Lab is to identify the putative infectious agent or agents that initiate autoimmune disease. This goal is especially difficult to attain because the first events that trigger an autoimmune disease may occur years, if not decades, before the occurrence of clinical symptoms. Recent studies show that autoantibodies may be detected many years prior to clinical manifestations of disease. Autoantibodies and the antigens that they recognize may provide the only clues to the events that occurred early in the course of the disease. Dr. Bloch has taken advantage of autoantibodies and recent advances in proteomics to characterize novel structures in the cell nucleus and cytoplasm, including the PML nuclear body and the cytoplasmic mRNA processing body. These structures have critical roles in innate cellular defense against both DNA and RNA viruses. Using the autoantigens in these structures, Dr. Bloch’s group will identify interacting viral proteins that are involved in autoimmune disease pathogenesis.

Ichinose Lab

The overarching research goal of the Ichinose Lab, led by Fumito Ichinose, MD, PhD, is to elucidate the molecular mechanisms responsible for the cardio-cerebral dysfunction and injury often found in patients suffering critical illness including sepsis, cardiac arrest and CPR, and neurodegenerative disorders. Objectives of our current research programs include characterization of the biological effects of NO and hydrogen sulfide (H₂S) in cellular function and to develop novel therapeutic strategies.

1. We are investigating the role of hydrogen sulfide catabolism in ischemic or hypoxic brain injury and neurodegeneration. We use multiple animal models including hibernating 13-lined ground squirrels, murine primary cortical neurons and novel genetically modified mice models. To characterize the effects of sulfide catabolism, we developed a series of new sulfide scavengers using a database of sulfide-specific chemical probes. We also use in vivo gene transfer techniques directly into murine brains using custom-made adeno-associate virus vectors. These studies are expected to illuminate the role of sulfide catabolism not only in hypoxia tolerance and neurodegenerative diseases but also in mammalian physiology in extreme environment.
2. Originally, H₂S was discovered and studied as an environmental hazard. H₂S intoxication is the second most common cause of gas-related death after carbon monoxide. Related to the first project, in this project, we seek to develop countermeasures against H₂S poisoning using the newly developed library of sulfide scavengers. We will develop and examine sulfonyl azide and selenium oxide-based sulfide scavengers using established in vitro screening assays. Promising lead compounds will be tested in novel murine models of H₂S intoxication and H2S-induced cardiopulmonary arrest developed in our laboratory. This project was recently funded by NIH CounterAct program.
3. H₂S is considered a gas that existed in ancient earth when life was born. Many micro-organisms retain the ability to use sulfide as an important energy source. We are investigating the role of sulfide metabolism in micro-organisms including fungus and bacteria. Targeting sulfide metabolism may enable us to develop anti-microorganismal agents, which are based on novel mechanisms. Furthermore, because abundance of sulfide-producing bacteria is known to correlate with a number of bowel diseases including inflammatory bowel disease, manipulating sulfide metabolism may also prove to be therapeutic against diseases of host.
4. We are examining the role of NO/cGMP-dependent mechanisms in blood-related disorders including hypercoaguability after cardiac arrest and storage lesion of blood. In particular, we are studying the effects of NO/sGC-dependent signaling in a newly developed murine model of hemorrhagic shock-induced cardiac arrest resuscitated with stored blood. Insight gained from these studies may lay foundations to develop novel therapeutic approach to transfusion-related critical illness.
5. Although post cardiac arrest patients are routinely sedated with anesthetics (e.g., propofol), effects of post-arrest sedation on post-arrest outcomes are unknown. We are investigating the role of post-cardiac arrest sedation on brain injury and neurological recovery using a mouse model of cardiac arrest and CPR. Effects of post-arrest sedation with propofol and dexmedetomidine on neurological outcomes are examined using telemetric EEG, cerebral blood flow measurements with laser Doppler flowprobe, histological analysis and neurological functional analysis using a well-established mouse model of cardiac arrest and CPR.

Berra Clinical Research Group

Our research group, led by Lorenzo Berra, MD, focuses on translating highly innovative laboratory research to large animal research and first in-human research to improve diagnosis, monitoring and treatment of critically ill patients. Our most recent efforts are focused to:

• Assess NO gas therapy to prevent organ (kidney, lung, heart and brain) injury mediated by ischemia and by cell-free heme as it occurs following cardiac arrest, cardiac surgery, blood transfusions or hemoglobin-based oxygen carrier
• Evaluate feasibility, safety and efficacy of prolonged (and home) delivery of continuous, low dose of NO gas therapy to patients with chronic pulmonary hypertension
• Test safety and efficacy of in-hospital short and repeated sessions of high dose treatments with NO gas breathing in severe lung infection
• Improve cardio-pulmonary mechanical support in patients with cardio-pulmonary failure by integration of novel bedside cardio-pulmonary monitoring (e.g., electrical impedance tomography, lung-heart ultrasound) with physiological data (e.g., regional ventilation, V/Q perfusion, pleural pressure)

Malhotra Lab

Atherosclerosis and its downstream clinical consequences including myocardial infarction (MI), stroke and peripheral vascular disease affect more than 40 million people in the U.S. and is the number one cause of morbidity and mortality worldwide. Atherosclerotic plaques build up on the walls of blood vessels and consist of lipids and calcium deposits. Although treatments exist that target risk factors for cardiovascular disease (such as dyslipidemia or anti-hypertensives), there is currently no treatment to directly prevent or reverse vascular calcification.

The Malhotra Lab, led by Rajeev Malhotra, MD, MS, studies the molecular mechanisms by which atherosclerosis and calcification develop in the vessel wall in the hopes of uncovering novel targets for the development of new disease treatments.

Dr. Malhotra’s research program focuses on the role of histone deacetylases (HDACs), autophagy, matrix Gla protein and bone morphogenetic proteins (BMPs) in the pathogenesis of vascular calcification and atherosclerosis. His laboratory has identified polymorphisms in the HDAC9 locus that confer increased risk of vascular calcification, MI and stroke in humans and have demonstrated that HDAC9 promotes vascular calcification using both in vitro and in vivo models. Furthermore, his laboratory has demonstrated that pharmacologic inhibition of BMP signaling reduces the burden of vascular calcification, likely through inhibition of endothelial-to-mesenchymal transition. More recently, Dr. Malhotra’s laboratory has identified an essential role for matrix Gla protein in regulating arterial stiffness. Using a combination of human genetic and biomarker approaches, vascular smooth muscle cell and endothelial cell assays, and in vivo models, Dr. Malhotra’s laboratory aims to identify novel genetic and molecular mechanisms of cardiovascular disease.

Selected Publications

View publications of:

• Warren M. Zapol, MD
• Aranya Bagchi, MBBS
• Lorenzo Berra, MD
• Donald Bloch, MD
• Fumito Ichinose, MD, PhD
• Rajeev Malhotra, MD

Group Members

The center takes a multidisciplinary approach to research.

In Memory

Warren M. Zapol, MD

Dr. Zapol, ACCCR director, Mass General emeritus anesthetist-in-chief and the Reginald Jenney Distinguished Professor of Anaesthesia at Harvard Medical School, passed away on December 14, 2021. Learn more about his legacy.

Principal Investigators

• Lorenzo Berra, MD
• Donald Bloch, MD
• Fumito Ichinose, MD, PhD
• Rajeev Malhotra, MD, MS

Faculty

• Aranya Bagchi, MBBS
• Ryan Carroll, MD
• Eizo Marutani, MD
• Akito Nakagawa, PhD
• Roberta Santiago, MD, PhD, RRT
• Binglan Yu, PhD

Administration

• Margaret Flynn

Post-doctoral Fellows

• Talisa Buehl, MD
• Stefano Cenci, MD
• Raffaele Di Fenza, MD
• Mariko Ezaka, MD
• Shunsaku Goto, MD
• Takamitsu Ikeda, MD
• Wanlin Jiang, MBBS, PhD
• Eiki Kanemaru, MD
• Yusuke Miyazaki, MD
• Kuldeep Singh, PhD
• Abraham Sonny, MD
• Wenjie Tian, MBBS, PhD
• Dario Winterton, MD

Residents

• Lauren Gibson, MD
• Sylvia Ranjeva, MD

Medical Students

• Beverly Ejiofor

Research Assistants

• Sophie Boerboom
• Martin Capriles
• Kyle Medeiros
• Katrina Ostrom
• Natalie Rebollo
• Claire Sinow

Biomedical Engineer

• Hatus Wanderley