Understanding the Role of Oxidative Stress in Sickle Cell Disease

May 2, 2020

Sickle cell disease (SCD) is a group of related blood disorders, each caused by a single point mutation in a single gene. That one tiny error confers upon people who inherit two copies of the gene a lifetime of episodes of pain and hospitalization and a reduced lifespan.

SCD is the most common genetic disease not only in the United States but also in the world. An estimated 1 in 500 African Americans have the disease, while about 1 in 12 carry the autosomal recessive mutation. Nor is it found only in people of African ancestry — the causative mutation is also common in countries ranging from South and Central America to Mediterranean Europe,

Middle East, and India. Worldwide, about 250 million people carry the gene responsible for SCD and other hemoglobin diseases.

The major cause of pain, suffering, and death in SCD is tissue injury and inflammation caused by repeated vaso-occlusion that results in progressive organ damage. Much remains unknown about exactly how sickled red cells injure the blood vessels and how this leads to the blood-vessel and organ damage observed in patients.

It is known that the causative mutation leaves the body’s hemoglobin prone to sticking together after delivering its oxygen payload from the red blood cells to the tissues. The resulting hemoglobin crystals can break through the cells’ membrane, killing them and spilling the free hemoglobin into the bloodstream.

Deirdre Nolfi-Donegan, MD“Hemoglobin is very damaging when it’s not contained within the protected environment of an intact red cell,” says Deirdre Nolfi-Donegan, MD, assistant professor of pediatrics at the University of Pittsburgh School of Medicine and physician in the Division of Pediatric Hematology/Oncology at UPMC Children’s Hospital of Pittsburgh. “It can release large amounts of reactive oxygen species, which can damage nearby tissues. This is why we and others in the scientific community think that redox — the complementary processes of oxidation and reduction — is a key driver of much of the damage that occurs at both the cellular and organ levels in SCD.”

Cheryl Hillery, MDThe substantial oxidative stress created within red blood cells and, eventually, other organs in SCD has recently emerged as a major area of research interest in the field. “In the last five years, we’ve really moved forward in our understanding of redox signaling as a primary driver of SCD,” says Cheryl A. Hillery, MD, professor of pediatrics at the University of Pittsburgh School of Medicine. Dr. Hillery also is the clinical director of Hematology and director of the Pediatric Sickle Cell Program in the Division of Pediatric Hematology/Oncology at UPMC Children’s.

Despite recent advances in the field, most patients with SCD still die in middle age, says Dr. Hillery. The disease can be cured by bone-marrow transplantation, but this requires a matched donor, and it is rare — even within families — for a matched donor to be available. While recent progress has been made in gene therapy for SCD, says Dr. Hillery, a cure for everyone is not yet at hand. Because of this, research into oxidative stress in the disease remains highly relevant.

Dr. Hillery and Dr. Nolfi-Donegan were recently invited to write a comprehensive review of redox biology in SCD. The paper was published in a Current Opinion in Physiology themed issue on redox regulation in June 2019.

The two researchers have long-standing interests in redox biology. Dr. Hillery, a clinician and bench scientist, began her research career studying molecules involved in platelet adhesion. “Then it was discovered that red cells in SCD are sticky. I put my knowledge into red-cell adhesion, and then I just fell in love with research on SCD,” she says.

Prior to joining UPMC in 2015, Dr. Hillery was on the faculty at the Medical College of Wisconsin, where work in her lab showed that, in a mouse model of SCD, the omega-3 fatty acids found in fish oil — which are potent antioxidants — could improve the flexibility of red blood cells.

Dr. Hillery was recruited to UPMC Children’s to direct the pediatric Sickle Cell Program and build a strong clinical and translational program in benign hematology at the University of Pittsburgh and UPMC Children’s. She has cared for both children and adults with SCD for over 25 years.

Dr. Nolfi-Donegan came to sickle cell research as a fellow at UPMC, after finishing her medical residency at Cohen Children’s Medical Center in New York. “I’m interested in platelets, like Dr. Hillery, and there is a lot of platelet dysregulation and pathology in SCD,” she says. Hypothesizing that a better understanding of basic redox biology in SCD could lead to the development of more effective therapies, Dr. Hillery and Dr. Nolfi-Donegan have been partnering with researchers in the University of Pittsburgh’s Vascular Medicine Institute (VMI) and in particular with Sruti Shiva, PhD, who studies redox reactions in mitochondria.

“We are trying to determine what redox reactions are significant in SCD,” says Dr. Nolfi Donegan. “Should we be focusing on mitochondrial redox reactions? Should we be looking at these reactions in red blood cells? Or between hemoglobin and the endothelium? Is there a specific type of redox reaction that’s the ‘smoking gun’ for many of the problems that patients with SCD develop? These are the kinds of questions we hope to answer.” The three researchers originally came together around their shared interest in a molecule called HMGB1, an inflammatory marker that, depending on its redox status, may activate platelets, says Dr. Nolfi-Donegan.

“My lab was the first to show that HMGB1 is elevated at baseline in SCD, and that it rises further during acute crises in SCD,” says Dr. Hillery. “We’re now looking at how it activates and injures the endothelium, and Dr. Nolfi-Donegan is investigating its effects on platelets.”

In collaboration with Dr. Hillery and Dr. Shiva, Dr. Nolfi-Donegan recently submitted a grant application to explore the role of mitochondrial redox reactions in SCD.

“We want to explore how mitochondrial dysfunction in SCD may drive abnormal platelet activation, which could potentially lead to unwanted clot formation,” says Dr. Nolfi-Donegan.“How do you get from a hemoglobin molecule that has escaped the red cells to platelet activation, and to reactive oxygen species that are possibly driving that platelet activation? There are a lot of dots to connect.”

The UPMC clinical team provides the most advanced care available to both children and adults with SCD, says Dr. Hillery. “We have one of the best adult sickle cell clinical research teams in the world,” she says. The level of expertise available at UPMC to treat adults with sickle cell disease is rare, she says, as until recently most people with the disease died in childhood.

The UPMC sickle cell team also is very involved in clinical research. Several medications recently approved to treat SCD have some antioxidant properties, says Dr. Hillery, though their effect on reducing sickle cell pain crises has been modest. Drugs that more specifically target oxidative stress in the disease are needed, she says.

A clinical trial is now underway at UPMC, which will test a medication that reduces the amount of mitochondrial reactive oxygen species in all cells, including platelets. "Eventually, the aim would be to see if this translates into a reduction in platelet activation, lowers levels of red blood cell destruction (hemolysis), and decreases vascular dysfunction in subjects with SCD," says Dr. Nolfi-Donegan.


Nolfi-Donegan D, Pradhan-Sundd T, Pritchard KA Jr, Hillery CA. Redox Signaling in Sickle Cell Disease. Curr Opin Physiol. 2019 Jun; 9: 26-33.