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Mark T. Gladwin, MD

Vice President for Medical Affairs, UM Baltimore and John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine

Academic Title:

Professor

Primary Appointment:

Medicine

Administrative Title:

Vice President for Medical Affairs; Professor and Dean, University of Maryland School of Medicine

Location:

BRB, 14-029

Phone (Primary):

410-706-7410

Education and Training

Undergraduate and Graduate

  • University of Miami Honors Program, BS and MD, Medical Education, 1991

Postgraduate

  • Oregon Health Sciences University (OHSU), Internship and Residency, Internal Medicine, 1994
  • Oregon Health Sciences University, Chief Resident, Internal Medicine, 1995
  • Warren G. Magnuson Clinical Center, Critical Care Fellow, National Institutes of Health, 1996
  • University of Washington, Pulmonary-Critical Care Fellow, 1998
  • Warren G. Magnuson Clinical Center, Senior Research Fellow, Critical Care Medicine, 2000

Biosketch

Mark T. Gladwin, MD was appointed as the Dean of the University of Maryland School of Medicine (UMSOM) and Vice President for Medical Affairs at the University of Maryland, Baltimore in August 2022. He is a leading heart, vascular, and lung physician-scientist. He maintains an active research group and is currently PI of two R01 awards, a P01 award, and a clinical trials U award.  He has published > 450 manuscripts (google scholar h-index of > 120). His scientific discoveries include the finding that the nitrite salt is a biological signaling molecule that regulates physiological and pathological hypoxic responses, blood pressure and flow, and dynamic mitochondrial electron transport. He also characterized the role of hemoglobin and myoglobin as signaling nitrite reductases that regulate NO production under hypoxia, and his 2003 publication on this work has been cited > 1,800 times and is in Nature Medicine’s Classic Collection. His work on the nitrite anion has led to the development and licensing of intravenous, oral and inhaled nitrite as a human therapeutic, with completion of animal toxicology, GMP formulations and phase Ia and Ib clinical trials, with licensing of the drug.  Phase II trials of inhaled nitrite are now underway for the treatment of pulmonary arterial hypertension, metabolic syndrome, and heart failure with preserved ejection fraction.  In addition to studies of nitrite, he characterized a novel mechanism of disease, hemolysis-associated endothelial dysfunction. This work has described a state of resistance to NO in patients with sickle cell disease, malaria, transfusion of aged blood, and other hemolytic conditions, caused by scavenging of nitric oxide by hemoglobin that is released into plasma during hemolysis.  These studies translated to clinical, and epidemiological description of a human disease syndrome, hemolysis-associated pulmonary hypertension.  Dr. Gladwin has served as PI on several multicenter phase II-III clinical trials in SCD patients, including the DeNOVO trial of NO therapy for acute pain crisis in patients with sickle cell disease, the Walk-PHASST trial of sildenafil for PH secondary to sickle cell disease, the EPIC trial of poloxomer 188 for vaso-occlusive painful crisis, the STERIO-SCD trial of the sGC stimulator riociguat, and the currently running SCD-CARRE, a clinical trial of exchange transfusion therapy. 

Research/Clinical Keywords

sickle cell disease, pulmonary hypertension, nitrite, carbon monoxide

Highlighted Publications

 

Gladwin MT, Shelhamer JH, Schechter AN, Pease-Fye ME, Waclawiw MA, Panza JA, Ognibene FP, Cannon RO III . Role of circulating nitrite and S-nitrosohemoglobin in regulation of regional blood flow in humans. Proceedings of the National Academy of Sciences 2000 Oct 10;97(21):11482-7.

Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle cell-disease.  Nat Med. 2002 Dec 8(12):1383-9.

Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation.  Nat Med. 2003 Dec;9(12):1498-505.

Hunter CJ, Dejam A, Blood AB, Shields H, Kim-Shapiro DB, Machado RF, Tarekegn S, Mulla N, Hooper AO, Schechter AN, Power GG, Gladwin MT. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator.  Nat Med. 2004 Oct;10(10):1122-7.

Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder W, Schechter AN, Rodgers GP, Castro O, Ognibene Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.  N Engl J Med. 2004 Feb 26;350(9):886-95.

Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Schechter AN, Hogg N, Gladwin MT. Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control.  J Clin Invest. 2005 Aug;115(8):2099-107.

Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X, MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ, and Gladwin MT. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer.  J Exp Med. 2007 Sep 3;204(9):2089-102.

Tiso M, Tejero J, Basu S, Azarov I, Wang X, Simplaceanu V, Frizzll S, Jayaraman T, Geary L, Shapiro C, Ho C, Shiva S, Kim-Shapiro DB, Gladwin MT. Human neuroglobin functions as a redox regulated nitrite reductase. J Biol Chem. 2011 May 20;286(20):18277-89. PMCID: PMC3093900

Donadee C, Raat NJ, Kanias T, Tejero J, Lee JS, Kelley EE, Zhao X, Liu C, Reynolds H, Azarov I, Frizzell S, Meyer EM, Donnenberg AD, Qu L, Triulzi D, Kim-Shapiro DB, Gladwin MT. Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation. 2011 Jul 26;124(4):465-76. PMCID: PMC3891836

Azarov I, Wang L, Rose JJ, Xu Q, Huang XN, Belanger A, Wang Y, Guo L, Liu C, Ucer KB, McTiernan CF, O'Donnell CP, Shiva S, Tejero J, Kim-Shapiro DB, Gladwin MT. Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Sci Transl Med. 2016 Dec 7;8(368):368ra173. PMCID: PMC5206801

Additional Publication Citations

Dr. Gladwin's publications can be found on PubMed.

Research Interests

Dr. Gladwin's research activities have led to several major scientific discoveries.

  1. The discovery that the nitrite anion is a circulating storage pool for NO bioactivity (Gladwin, et al. PNAS 2000) that regulates hypoxic vasodilation (Cosby Nature Medicine 2003) and the cellular resilience to low oxygen and ischemia (Duranski JCI 2005).
  2. The discovery of a novel physiological function for hemoglobin as an electronically and allosterically-regulated nitrite reductase (Cosby, et al, Nature Medicine 2003; Huang et al. JCI 2005). These studies reveal that nitrite is a potent vasodilator in humans and is bioactivated by reaction with deoxyhemoglobin (and myoglobin) to generate NO preferentially under hypoxic conditions; they also suggest that hemoglobin has an "enzymatic" property as a nitrite reductase that participates in hypoxic vasodilation. In related translational studies, Dr. Gladwin has demonstrated that inhaled nitrite reverses hypoxic neonatal pulmonary hypertension in sheep (Hunter, et al, Nature Medicine 2004), and that infused nitrite solutions prevent post-subarachnoid hemorrhage-induced vasospasm in primates (Pluta et al, JAMA 2005) and prevent hepatic and cardiac ischemia-reperfusion injury and infarction in mice (Duranski et al. JCI 2005).
  3. The characterization of a novel mechanism of disease, hemolysis-associated endothelial dysfunction (Reiter, et al, Nature Medicine 2002; Morris et al, JAMA 2005; Minneci et al, JCI 2005; Rother et al, JAMA 2005). This work has described a state of resistance to NO in patients with sickle cell disease caused by scavenging of nitric oxide by hemoglobin that is released into plasma during hemolysis.
  4. The mechanistic, clinical, and epidemiological description of a human disease syndrome, hemolysis-associated pulmonary hypertension (Gladwin, et al, NEJM 2004). He has found that pulmonary hypertension occurs in 30% of patients with sickle cell disease, is a major cause of mortality in this population, and is strongly associated with high hemolytic rate, iron overload, and kidney disease.
  5. The biochemistry of hemoglobin superfamily members, including neuroglobin, and relevance to carbon monoxide poisoning. Dr. Gladwin’s work characterized high reactivity of a five-coordinate mutant molecule, H64Q. These molecules bind and react with nitrite, and also bind ligands like oxygen and CO with very high affinities. Heme-based scavenger molecules with very high CO binding affinity such as mutant five-coordinate Ngb (H64Q) are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO. Dr. Gladwin’s group has developed multiple models of CO poisoning, developed and scaled production of recombinant proteins, published a major article on CO poisoning, and has published clinical papers on CO poisoning.

Awards and Affiliations

Honors

  • Achievement Medal, US Public Health Service, NIH, 1999
  • NIH Fellows Award for Research Excellence (FARE 2000), 2000
  • Clinical Center Director's Award for 2002 (category of Science)
  • Chest Foundation 2004 Governors Community Service Award (for leadership as Founding Director of the Cardoza Clinic pulmonary specialty clinic for the care of underserved patients with respiratory diseases in Washington DC)
  • NIH Director's Award for Mentoring in making contributions to understanding the role of nitrite oxide in sickle cell anemia patients, 2006
  • NIH Merit Award in recognition for accomplishments in both basic and clinical sciences in the use of nitrite and NO in clinical applications, 2006
  • Recognition Award for Scientific Accomplishments from the American Thoracic Society, ATS International Conference, Philadelphia, PA, 2013
  • Recognized as Distinguished Professor at the University of Pittsburgh, 2014
  • Chancellor's Distinguished Research Award (Senior Scholar), University of Pittsburgh, 2017
  • Named Distinguished Scientist of the American Heart Association, 2020

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