Leo Otterbein, PhD
Professor of Surgery, Harvard Medical School
Eva Csizmadia, MS
Mahtab Faktari, MD
Ghee Lee, MS
Shazhad Shaefi, MD
Rodrigo Souza, PhD
Inhaled carbon monoxide (CO) is in numerous FDA phase trials, based in large part from the research that has arisen from my laboratory over the past decade. We continue to maintain a focus on the innate immune response and defense mechanisms in models of trauma, infection, ischemia reperfusion injury, and regenerative responses to tissue damage. The foundation of our work lies in the study of protective genes and in particular those that degrade heme and include heme oxygenase-1 (HO-1) and biliverdin reductase (BVR). Both of these genes are intimately involved in the stress response and function in large part by generating CO and bilirubin as endogenous products. We have expanded our research program to include collaborative projects on cancer, neurology and more recently exercise physiology. Each of these complement and advance our understanding of the acute stress response and the roles of HO-1/CO as they relate to immunologic and pathophysiologic responses. Ultimately, we are interested in translational research to provide solutions towards alleviating human suffering.
Role of Heme in Trauma and Infection
This year we reinforced collaborative efforts in models of trauma and the impact on susceptibility to pneumonia. As Co-Director of a 6-project CDMRP Department of Defense focused research award ($10M) awarded in 2017, we are seeking to provide deliverables to benefit the injured warfighter. As PI of one project our approach is to define how heme influences recovery from trauma and susceptibility to bacterial infection. The research involves interactive studies with Carl Hauser, MD (BIDMC, Surgery), Jim Lederer, PhD (BWH, Surgery), Daniel Talmor (BIDMC, Anesthesiology), Simon Robson (BIDMC, Medicine), and Michael Yaffe, MD, PhD (MIT). Our data in sepsis models shows that HO-1 derived CO acts directly on bacteria, coercing them to generate ATP, which activates local immune cells including macrophages and neutrophils and initiates a full immune response to clear bacteria through an inflammasome-mediated mechanism of action. Additionally HO-1/CO promote liver regeneration after a crush injury.
Neuroprotection with HO-1 and the Role of the Circadian Clock
We maintain an active collaboration with Khalid Hanafy, MD, PhD, (BIDMC, Neurology) in the study of hemorrhagic stroke, where we find that glia-expressed HO-1 is critical in resolution of injury and impacts neurotransmission as it relates to memory. Inhaled CO enhances recovery, reduces inflammation and cell death, and improves cognitive function. The mechanism involves the ability of CO to boost phagocytosis of erythrocytes. Recently we reported in Stroke the circadian rhythm of HO-1 in the brain and demonstrate that HO-1/CO promote recovery from hemorrhagic stroke in part by modulation of central clock genes including Period and NPAS2 among others. We are actively collaborating with the labs of Dr. Hanafy (BIDMC, Neurology) and Dr. Eng Lo (MGH, Radiology) in a multi-PI approach in conjunction with pharma to develop CO as a treatment strategy for hemorrhagic stroke.
Given the above salutary effects of CO in the brain, we submitted a proposal to the National Football League (NFL) and were selected as part of a multi-institutional program grant ($18M) to evaluate the effects of CO to alleviate brain injury simulating that which would occur as a result of multiple mild concussions that occur during football games. Together with Dr. Ping Lu (BIDMC, Medicine), and Dr. Patrick Fuller (BIDMC, Neurology) we will test over the next five years the ability of CO to limit injury and promote recovery in preclinical models of concussion. Exciting preliminary data in mice demonstrate the remarkable role of HO-1 in brain homeostasis.
Carbon Monoxide and Kidney Transplant
We are funded with Phase 2 NIH SBIR ($1.5M) to study an exciting and innovative oral CO solution in rat and pig models of kidney transplant in collaboration with Hillhurst Biopharmaceuticals. These studies are ongoing, but complement and expand on those we reported on with inhaled CO, which showed a benefit to reduce delayed graft function and triggered the first human trial. The oral formulation is simple and is being applied to multiple model systems including TBI and trauma. Proof of principal has been demonstrated and the CO formulation is now being prepared for human testing.
HO-1 in Cancer
In collaboration and funded by Agios Pharmaceuticals, we are interested in the role of macrophages in tumor growth testing the hypothesis that the phenotype of the macrophage regulates its ability to direct Tcell function. Using our regulated HO-1 null mice, we find that blockade of HO-1 significantly reduces tumor growth.
Relationship Between the Microbiome, Glycome, and Tissue Damage
It has been known that the intestinal microbiome is important in numerous immune regulatory functions and that HO-1/CO can influence the intestinal flora in models of acute inflammation. Additionally, preliminary data show that injury leads to a change in serum N-glycosylation. This finding is part of a new collaborative project with Richard Cummings (BIDMC, Surgery) and Carl Hauser (BIDMC, Surgery), to integrate glycobiology and microbiome modulation in response to injury comparing human and murine samples.
HO-1 and Exercise Metabolism
A new project in the laboratory, we are interested in how physical exercise influence HO-1 expression and can contribute to offering protection in models described above. Preliminary findings suggest that exercise metabolism is influenced by heme catabolism and the generation of CO.
We continue to be one of the leaders in the area of heme metabolism and the stress response, providing mechanistic insight into the role of HO-1 and its bioactive products carbon monoxide and the bile pigments. Our publications continue to provide important contributions toward therapeutic use of these molecules in the clinic, which guided more than 10 ongoing clinical trials with CO. We consider ourselves a team with excellent technical skills combined with creative and innovative approaches to research design, always with translation to human disease in our sites.
- 10th International Conference on Heme Oxygenases, Seoul, South Korea
- University California San Diego/Scripps Institute of Oceanography
- World Conference on Microcirculation, Vancouver, CA
- American Chemical Society, New Orleans, LA
- Gasotransmitters and Medicine, Atlanta, GA
- Oral Carbon Monoxide, Hillhurst Pharma, Tucson, AZ
- Virtual IACUC Scenario’s, PRIM&R and IACUC Conference, Boston, MA
- Chair of the BIDMC Institutional Animal Care and Use Committee
- BIDMC Site Miner for the Center for Integration of Medicine and Innovative Technology (CIMIT)
- BIDMC representative for the Boston Biomedical Innovations Center (B-BIC), Technology Assessment and Development Group
- Continue in my 15th consecutive year as an NIH study section member for K01, K08, K02, K99, and loan repayment, grant applications
- Served as grant reviewer for the Wellcome Trust, United Kingdom Medical Research Council, Israel Science Foundation, Yale University Pepper awards, New Zealand Research Foundation, and Pasteur Institute among others
Teaching, Training, and Education
I continue to participate in the training of graduate students, post-doctoral fellows, surgical residents, and junior faculty in basic research, grant proposals, and career guidance. I was a preceptor for the Trauma T32 training grant 2017/18 and am currently mentoring a K08 and AHA applications. As the BIDMC CIMIT site miner and as a member of the B-BIC Technology Assessment and Development Group, I mentor and provide specialized expertise in entrepreneurial start-up ventures for innovative technologies. In addition to the science, I also advise on grant submissions, potential commercialization of ideas, interactions with the Technology Ventures Offices, and various accelerator and venture opportunities.
Selected Research Support
DAMP-mediated innate immune failure and pneumonia after trauma; DoD, 2016-2021; Co-Director: Leo Otterbein, PhD
Harvard Trauma Inflammation Training Program; NIH T32 Training Grant, 2013-2019; Preceptor: Leo Otterbein, PhD (Director: Carl Junger, PhD)
HBI-002 to treat delayed graft function after transplant; NIH, 2016-2019; PI: Leo Otterbein, PhD
Immunomodulatory effects of bilirubin are mediated through the aryl hydrocarbon receptor, O2 and purinergic pathways; NIH, 2017-2022; Co-Investigator: Leo Otterbein, PhD (PI: Maria Longhi, MD, PhD)
Heme Oxygenase-1 (HO-1) and tumor growth; Agios Pharmaceuticals, 2017-2019; PI: Leo Otterbein, PhD
HBI-002 to treat traumatic injury; NIH, 2017-2019; Academic Site PI: Leo Otterbein, PhD (PI: Stephen Gomperts, MD, PhD, MGH)
Nemeth Z, Csizmadia E, Vikstrom L, Bisht K, Feiz, A, Otterbein S, Zuckerbraun B, Costa DB, Pandolfi PP, Fillinger J, Döme B, Otterbein LE, Wegiel B. Alterations of tumor microenvironment by carbon monoxide impedes lung cancer growth. Oncotarget 2016;26:23919-32.
Chan MC, Ziegler O, Liu L, Rowe GC, Das S, Otterbein LE, Arany Z. Heme oxygenase and carbon monoxide protect from muscular dystrophy. Skeletal Muscle 2016;28:41.
Itagaki K, Riça I, Zhang J, Gallo D, DePrato M, Otterbein LE, Hauser CJ. Intratracheal instillation neutrophils rescues bacterial overgrowth initiated by trauma damage-associated molecular patterns J. Trauma Acute Care Surg 2017;82: 853-860.
Sandler N, Kaczmarek E, Itagaki K, Zheng Y, Otterbein L, Khabbaz K, Liu D, Senthilnathan V, Gruen RL, Hauser CJ. Mitochondrial DAMPs are released during cardiopulmonary bypass surgery and are associated with postoperative atrial fibrillation. Heart Lung Circ 2018;27(1):122-129.
Longhi MS, Vuerich M, Kalbasi A, Kenison JE, Yeste A, Csizmadia E, Vaughn B, Feldbrugge L, Mitsuhashi S, Wegiel B, Otterbein L, Moss A, Quintana FJ, Robson SC. Bilirubin suppresses Th17 immunity in colitis by upregulating CD39. JCI Insight 2017;2(9).
Lee H, Zhang D, Wu J, Otterbein LE, Jin Y. Lung epithelial cell-derived microvessicles regulate macrophage migration via MicroRNA-17/221-induced integrinb1 recycling. J. Immunol 2017;199:1453-1464.
Schallner N., Lieberum J-L, Gallo D, LeBlanc RH, Fuller PM, Hanafy, KA, Otterbein, LE. Carbon monoxide preserves circadian rhythm to reduce the severity of subarachnoid hemorrhage in mice. Stroke 2017;48: 2565-2573.