Mark Gladwin, M.D.
Mark Gladwin received his M.D. from the University of Miami Honors Program in Medical Education in 1991. After completing his internship and chief residency at the Oregon Health Sciences University in Portland, Ore., he joined the NIH in 1995 as a critical care fellow in the Clinical Center. After completion of a clinical fellowship in pulmonary medicine at the University of Washington in Seattle, he returned for a research fellowship at the Critical Care Medicine Department, CC, under the mentorship of James Shelhamer, Frederick Ognibene, Alan Schechter, and Richard Cannon. He later served as the Chief of the Pulmonary and Vascular Medicine Branch within the NHLBI, NIH. In August of 2008, Dr. Gladwin became Chief of the Pulmonary, Allergy and Critical Care Medicine Division at the University of Pittsburgh School of Medicine and the Director of the newly formed Vascular Medicine Institute.
Dr. Gladwin’s clinical research and expertise focuses on pulmonary hypertension and pulmonary complications of sickle cell disease. He is currently the PI on the multi-center clinical trials Walk-PHASST (Pulmonary Hypertension and Sickle Sildenafil Therapy Trial) and DeNOVO (Delivery of NO for Vaso-Occlusive pain crisis in sickle cell disease). He has served as a principal or associate investigator on more than 25 human subjects protocols and holds seven FDA INDs for the use of investigational therapeutic medications, including nitrite, carbon monoxide, L-NMMA, and sildenafil.
Since 1998, Dr. Gladwin's research activities have led to four scientific discoveries. The discoveries described below have resulted in more than 150 published peer-reviewed manuscripts, 25 approved human subject protocols, and more than 1,000 patient protocol enrollments at the NIH Clinical Center, during Dr. Gladwin’s Tenure as an NIH Branch Chief. These investigations form the backbone of Dr. Gladwin’s current work at the University of Pittsburgh’s Vascular Medicine Institute and the Division of Pulmonary, Allergy and Critical Care Medicine.
(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).
The figure below illustrates the role of nitrite in various organs in the body: In the stomach it is acidified and reduced to form NO, regulation stomach blood flow, mucous production and mucosal host defense; in the blood it forms from ceruloplasmin and regulates hypoxic vasodilation, via reactions with hemoglobin; in the tissues it is a potent cytoprotective molecule in the setting of severe ischemia. After conversion to NO by myoglobin, mitochondria, and xanthine oxidoreductase, it protects mitochondria from injury.
(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).
The figure below illustrates how nitrite is converted to NO and NO-modified proteins and lipids as oxygen and pH drop. This promotes signaling and is now being harnessed to treat many diseases.
(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. The cartoon below (click on the play button on the image to play) shows how hemolysis in sickle cell disease, releases hemoglobin from the red blood cells into plasma (red molecules) which react with endothelial NO in a scavenging reaction. The hemoglobin is oxidized to methemoglobin (brown molecules) and simultaneously destroy the NO, producing vasoconstriction and vessel narrowing. Inhaled NO can be given therapeutically to restore NO levels, inhibit the plasma hemoglobin by oxidation, and vasodilate the circulation.
(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 (odds ratio 10:1), and is strongly associated with high hemolytic rate, iron overload, and kidney disease. The echocardiographic image below shows a video loop from a patient with severe pulmonary hypertension and sickle cell anemia. The image reveals tricuspid valve regurgitation and dilated right ventricle and right atrium (upper left chamber and lower left chamber respectively).
Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter C, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter A, Cannon RO, and Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nature Medicine 2003; 9:1498-1505.
Duranski MR, Greer JJM, Dejam A, Sathya J, Hogg N, Langston W, Patel RP, Yet S-F, Wang X, Kevil CG, Gladwin MT, and Lefer DJ. Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. Journal of Clinical Investigation 2005; 115(5):1232-1240.
Gladwin MT, Sachdev V, Jison M, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder W, Schechter AN, Rodgers GP, Castro O, and Ognibene FP. Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease. New England Journal of Medicine 2004; 350:886-895.
Gladwin MT, Ognibene FP, Pannell LK, Nichols JS, Pease-Fye ME, Shelhamer JH, and Schechter AN. Relative role of heme nitrosylation and β-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation. Proceedings of the National Academy of Sciences 2000; 97: 9943-9948.
Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Schechter AN, Hogg N, and Gladwin MT. Enzymatic function of hemoglobin as a nitrite reductase that produces nitric oxide under allosteric control. Journal of Clinical Investigation 2005; 115:2099-2107.
Hunter CJ, Dejam A, Blood AB, Shields H, Kim-Shapiro DB, Machado RF, Tarekegn S, Mulla N, Hooper AO, Schechter AN, Power GG, and Gladwin MT. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nature Medicine 2004; 10:1122-1127.
Minneci PC, Deans KJ, Huang Z, Yuen P, Star RA, Banks SM, Schechter AN, Natanson C, Gladwin MT and Solomon SB. Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. Journal of Clinical Investigation 2005; 115:3409-3417.
Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen ST, Vichinsky EP, Morris SM Jr. and Gladwin MT. Dysregulated arginine metabolism, hemolysis –associated pulmonary hypertension and mortality in sickle cell disease. Journal of the American Medical Association 2005; 294:81-90.
Pluta RM, Dejam A, Grimes G, Gladwin MT and Oldfield EH. Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. Journal of the American Medical Association 2005; 293:1477-1484.
Reiter CD, Wang X, Tanos-Santos J, Hogg N, Cannon RO,Schechter AN, and Gladwin MT. Cell free hemoglobin limits NO bioavailability in sickle cell disease. Nature Medicine 2002; 8:1383-1389.
Rother RP, Bell L, Hillmen P, and Gladwin MT. The clinical sequelae of intravascular hemolysis and estracellular plasma hemoglobin. Journal of the American Medical Association 2005; 293:1653-1662.
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News and press releases
Dr. Gladwin's research on the stored blood is featured in the Wall Street Journal.
Dr. Gladwin talks about Nitrite and bloodflow on NPR's All things Considered. The New York Times also covered this story.
Pulmonary hypertension in sickle cell disease - New York Times, 2004
Pain of sickle cell disease linked to excess hemoglobin - New York Times, 2002
Dr. Gladwin's book is available on Amazon