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 (now the Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute).
Dr. Gladwin’s clinical research and expertise focuses on pulmonary hypertension and pulmonary complications of sickle cell disease. He served as 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).
Gladwin MT, Shelhamer JH, Schechter AN, Pease-Fye ME, Waclawiw MA, Panza JA, Ognibene FP, Cannon III RO. Role of circulating nitrite and S-nitrosohemoglobin in regulation of regional blood flow in humans. Proc Natl Acad Sci 2000; 97:11482-11487. PMID: 11027349. PMC17226
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.
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, Gladwin MT. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 2003; 9:1498-1505. PMID: 14595407
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; 10:1122-1127. PMID: 15361865
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.
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. PMC1177999
Shiva S, Wang X, Ringwood LA, Xu X, Yuditskaya S, Annavajjhala V, Miyajima H, Hoog N, Harris ZL, Gladwin MT. Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO hemostasis. Nat Chem Biol 2006; 2(9):486-483. PMID: 16906150
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.
Shiva S, Huang Z, Grubina R, Sun J, Ringwood LA, MacArthur PH, Xu X, Murphy E, Darley-Usmar VM, Gladwin MT. Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res. 2007 Mar 16;100(5):654-61
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, Gladwin MT. Nitrite augments tolerance to ischemia/ reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 2007; 204:2089-2102. PMC2118713
Lundberg JO, Weitzberg E, and Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nature Reviews Drug Discovery 2008; 7:156-167.
Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med. 2008 Nov 20;359(21):2254-65.
Lee JS, Gladwin MT. Bad blood: the risks of red cell storage. Nat Med. 2010 Apr;16(4): 381-2.
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11;376(9757):2018-31.
Sachdev V, Kato GJ, Gibbs JS, Barst RJ, Machado RF, Nouraie M, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli EM, Gigris RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Castro OL, Taylor JG 6th, Hannoush H, Goldsmith JC, Gladwin MT, Gordeuk VR, Walk-PHASST Investigators. Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom. Circulation. 2011 Sep 27; 124 (13): 1452-60. PMCID: PMC3183314
Gladwin MT, Tejero J. Nitrite-NO bailout for a NOS complex too big to fail. Nat Med. 2011 Dec 6;17(12):1556-7.
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. (2011). Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation. 124(4):465-76. PMID: 21747051. PMC Journal – In Process. NIHMSID: NIHMS307708.
Gladwin MT. Adenosine receptor crossroads in sickle cell disease. Nat Med. 2011 Jan;17(1):38-40.
Machado RF, Barst RJ, Yovetich NA, Hassell KL, Kato GJ, Gordeuk VR, Gibbs JS, Little JA, Schraufnagel DE, Krishnamurti L, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Onyekwere O, Castro OL, Sachdev V, Waclawiw MA, Woolson R, Goldsmith JC, Gladwin MT; on behalf of the walk-PHaSST Investigators and Patients. Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity. Blood. 2011 Jul 28;118(4):855-864. PMC3148167
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 Feb 4. [Epub ahead of print] PMC3093900
Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA. 2012 Mar 28;307(12):1254-6. PMC3511048
Gladwin MT, Kanias T, Kim-Shapiro DB. Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. J Clin Invest. 2012 Mar 26:1-4. doi: 10.1172/JCI62972. PMID: 22446184. PMC3314481
Gladwin MT, Kim-Shapiro DB. Vascular biology: Nitric oxide caught in traffic. Nature. 2012 Nov 15;491(7424):344-5.
Yazji I, Sodhi CP, Lee EK, Good M, Egan CE, Afrazi A, Neal MD, Jia H, Lin J, Ma C, Branca MF, Prindle T, Richardson WM, Ozolek J, Billiar TR, Binion DG, Gladwin MT, Hackam DJ. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9451-6. PMCID: PMC3677476
Wood KC, Cortese-Krott MM, Kovacic JC, Noguchi A, Liu VB, Wang X, Raghavachari N, Boehm M, Kato GJ, Kelm M, Gladwin MT. Circulating Blood Endothelial Nitric Oxide Synthase Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1861-1871. PMCID in process.
Click on icons for related publications.
News and press releases
Dr. Gladwin, Ryan Clark, Pitt, and UPMC launch "Cure League" sickle cell initiative
Dr. Gladwin is the first University of Pittsburgh faculty member to be elected to the Council of the American Society for Clinical Investigation
A touching lung transplant patient story in The Washington Post
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