Cardiothoracic surgeon Dr. John Dunning and team performed the transplantation of  donor lung kept “breathing” in human-like conditions

For all the advances in organ transplantation, most organs are still transferred from donor to recipient in a cooler packed with ice. The clock begins ticking as soon as the donor organ is recovered – and in the case of a heart or lung, for instance, a transplant is usually no longer viable after four to six hours.

Now, the USF Health Heart and Lung Transplant Program at Tampa General Hospital (TGH) has become the first in the state to use or formally study the sophisticated organ transplant system designed to keep donor lungs and hearts healthier longer and increase the number of transplants.  TGH is also assessing the Organ Care System (OCS ), manufactured by medical device company TransMedics Inc., for use in extending the life of donor livers.

//www.youtube.com/watch?v=oKmStWSZifk

Video footage courtesy of TransMedics, Inc.

The first lung transplant in Florida using this system was performed Oct. 22, 2019 by a team led by John Dunning, MD, professor of cardiothoracic surgery at the USF Health Morsani College of Medicine and surgical director for Health and Lung Transplantation at TGH. (The FDA has already approved the OCS technology for lung transplant, but its use for hearts and livers is still investigational.)

TGH is among the top 10 busiest transplant centers in the nation, having now performed more than 10,000 transplant operations.

The new OCS technology – often referred to as “lung in a box” or “heart in a box” — allows the donor organ to keep functioning almost as if it were still inside the human body while it is transported to the hospital in a portable sterile machine equipped with probes and tubing. During a process called normal temperature perfusion, the organ is oxygenated and nourished with continuously circulating blood. The flow of blood prompts the heart to continue beating, the lungs breathe with a puff of ventilator air, and the liver produces bile. A touch-screen tablet lets surgeons assess the fitness of organs right up to the time they arrive in the operating room for transplant.

“We can maintain the organs for longer periods, which means we can retrieve them from a wider geographic area,” Dr. Dunning said. “And the condition of the organs at the time of transplant is better,” compared to the conventional method.

Dr. John Dunning, USF Health professor of cardiothoracic surgery at Tampa General Hospital, led the first Florida lung transplant using the OCS technology.

The conventional way involves covering the organ with preservation solution in a plastic bag and putting it on ice in a cooler, but this cold storage can limit tissue survival time, especially over long distances.  The OCS uses a different approach, transporting the organs at a warmer, near-normal body temperature.

The process has been shown to reduce the risk of rejection in lung transplants, and organs in some cases become healthier after being placed in the high-tech OCS machines.  For example, a potential donor who is on a ventilator in a hospital might develop fluid in their lungs as a side effect.  But this can clear up when the lung is placed in the OCS.  This improvement means more organs not considered healthy enough for donation in the past are likely to become medically suitable for transplantation to treat end-stage heart, lung or liver disease.

“We can actually monitor their function on the machine and see their function improving prior to transplantation,” Dr. Dunning said.

Each year, the number of patients on the waiting list continues to be much larger than both the slower growing number of donors and transplants. The U.S. Health Services & Resources Administration estimates 20 people die each day waiting for a transplant. Health professionals hope that new preservation technology like the OCS can safely reduce the dire shortage of lungs, hearts and other organs for transplantation, in part by making organs previously excluded due to age, oxygenation complications and other donor selection criteria acceptable.

Traditionally donor lungs come from deceased patients declared brain dead. But the OCS also allows lung transplants from patients after cardiac (circulatory) death, which could potentially expand the donor pool by 20 to 30 percent.

Dr. Dunning is Florida principal investigator for a multicenter post-approval study known as the OCS Lung TOP registry, which will track both the survival and outcomes of patients who receive transplants of OCS-preserved organs and the quality of the organs themselves. He is also among a handful of lead investigators from academic medical centers nationwide participating in a pivotal clinical trial to evaluate the safety and effectiveness of the OCS for heart transplantation after circulatory death.

USF Health researcher Mack Wu, MD, studies what happens when the microvascular endothelial barrier controlling blood-tissue exchange is compromised during ischemia-reperfusion injury, a condition that can lead to irreversible tissue damage. He also investigates the molecular control of gut permeability, also known as “leaky gut,” in tissue injuries caused by trauma and severe burns.

His group’s work has broad implications for a variety of conditions including stroke, heart attack, thrombosis, sepsis, trauma or other inflammatory diseases associated with microvascular injury.

Mack Wu, MD, is a professor of surgery and molecular medicine at USF Health Morsani College of Medicine and a research physiologist at James A. Haley Veterans’ Hospital. On the monitor next to him are images of microvessels in the small intestine injected with fluorescent dye.

The closely connected endothelial cells lining the interior of blood vessel walls play a critical role in limiting the how much fluid, proteins and small molecules cross the wall of the tiny blood vessels, or microvessels. However when this protective endothelial barrier is damaged, excessive amounts of blood fluid, proteins and molecules leak outside the microvessels into nearby body tissue – a process known as microvascular hyperpermeability. If this breech of endothelial barrier is associated with a body-wide inflammatory response, it can trigger a chain of events leading to edema (swelling), shock from severe blood and fluid loss (hypovolemic shock), and ultimately multiple organ failure.

Pinpointing potential solutions for ischemia-reperfusion injury

Previous research by Dr. Wu’s laboratory and other groups discovered that ischemia-reperfusion injury can cause endothelial barrier damage leading to vascular hyperpermeability, or abnormally leaky blood vessels.

Ischemia-reperfusion injury is typically associated with conditions like organ transplantation, stroke, heart attack, or cardiopulmonary bypass where blood supply to a vital organ is temporarily cut off (ischemia), resulting in oxygen deprivation. For instance, a period of ischemia occurs while a donor organ is transported to a recipient in the operating room, or when a clot interrupts blood circulation to the brain. When blood supply is re-established with new blood returned to the previously oxygen-deprived area (reperfusion), tissue injury can worsen because the reperfusion itself causes inflammation and oxidative damage rather than restoring normal function. It its severest form, ischemia-reperfusion injury can result in multiple organ failure, or even death.

“I believe endothelial barrier injury is one of the key elements of ischemia-reperfusion injury, so my group is trying to find out which molecule is ultimately responsible for the endothelial barrier damage,” said Dr. Wu, a professor of surgery and molecular medicine at USF Health Morsani College of Medicine and a research physiologist at James A. Haley Veterans’ Hospital.

Dr. Wu with some members of his laboratory team. From left, Rebecca Eitnier, research assistant; Shimin Zhang, Department of Molecular Medicine graduate student; Ricci Haines, research associate; and Fang Wang, research assistant.

With the support of a $1.49-million, four-year R01 grant from the National Heart, Lung and Blood Institute, Dr. Wu’s team is zeroing in on a molecule known as focal adhesion kinase, or FAK, an enzyme that may play a role in weakening the microvascular endothelial barrier during ischemia-reperfusion injury.   Using cell models and a newly developed mouse model in which the endothelial-specific gene for FAK is knocked out, the USF researchers are testing whether selectively inhibiting FAK activity can rescue the endothelial barrier from such injury.

The work is critical because no FDA-approved treatment exists to prevent tissue damage following reperfusion. Identifying a new mechanism for the injury would provide potential targets for drug development, Dr. Wu said. So for instance, he said, after an initial stroke a new intravenously administered drug selectively targeting endothelial cells in the brain’s microvessels might stop further harmful swelling of the brain caused by stroke.

Defining molecular control of “leaky gut” in severe burn trauma

A second grant from the U.S. Department of Veterans Affairs funds Dr. Wu’s studies to define the underlying molecular mechanisms of leaky guts induced by traumatic injury associated with thermal (fire, scald or chemical) burns.  Massive burn trauma is a significant cause of injury and death in American soldiers. With a $960,000 VA Merit Award, Dr. Wu focuses on how intestinal epithelial barrier damage happens during severe burns, with the aim of developing targeted therapies to prevent posttraumatic complications.  In particular, he is working to determine the pathways by which the protein palmitoylation in gut epithelial cells are stimulated by burn injury.

.

Epithelial cells line the interior of the small intestines, and after severe burn injury, this protective epithelial barrier commonly breaks down, causing bacteria and toxins to flow from the intestine into the circulating blood.  The result of this abnormal epithelial permeability, or “leaky gut,” can be deadly if sepsis ensues – a bacterial infection in the bloodstream sets up a body-wide inflammatory response leading to multiple organ failure.

While the role gut barrier failure plays in posttraumatic complications is well recognized, its cellular and molecular mechanisms remain poorly understood.  Currently, pushing IV fluids to help prevent hypovolemic shock and administering antibiotics and anti-inflammatories are the only therapies, mostly supportive, Dr. Wu said.

“More effective early therapeutic interventions to prevent leaky gut and systemic inflammatory response will be key to preventing sepsis,” he added, whether in soldiers with trauma or VA patients with inflammatory bowel diseases.

From industry to academia

Dr. Wu joined USF Health and the Haley VA Hospital in 2011.  He came from Sacramento, Calif, where he was an associate professor of surgery at the University of California at Davis School of Medicine and a research physiologist at Sacramento VA Medical Center.   Previously, Dr. Wu was a faculty member in the Department of Medical Physiology at Texas A&M University Health Science Center. He screened pharmaceutical compounds as a toxicologist in a biotechnology laboratory before joining Texas A&M, moving from industry to academia in 1995.

.

Dr. Wu received his MD degree from Second Military Hospital in Shanghai, China, and conducted an internship at Shanghai Second Hospital.

One of his earliest and most highly cited studies, published in the American Journal of Physiology (1996), was first to report nitric oxide’s role in contributing to cardiovascular injury. The study showed an increase in nitric oxide induces vascular endothelial growth factor (VEGF) to promote leakage in tiny coronary veins.

Another more recent study in Shock (2012) provided direct evidence that thermal burn injury causes intestinal barrier disruption and inflammation characterized by intestinal mucosal permeability (leakage) and an infiltration of immune system cells known as neutrophils.

Something you may not know about Dr. Wu:

He loves deep-sea fishing. Dr. Wu has fished for sharks off the Golf coast of Texas, rockfish off the Pacific coast of California, and grouper off the west coast of Florida.

Dr. Wu is a member of the USF Health Heart Institute. His team’s work has broad implications for a variety of conditions including stroke, heart attack, thrombosis, sepsis, trauma or other inflammatory diseases associated with microvascular injury.

Photos by Eric Younghans, USF Health Communications and Marketing

Taking a cue from USF’s own innovative pharmacy program of introducing students to as many specialties as possible before they enter the workforce, two USF pharmacy students have formed an interest group aimed at exposing rising pharmacists to the field of transplant medicine and the huge role pharmacists have in helping transplant patients manage their care.

Misty Ochotny adn Athar Naif.

The Solid Organ Transplant Interest Group was started by Athar Naif and Misty Ochotny, two students from the USF College of Pharmacy’s charter class. The goal of the group is to raise awareness of the specialty, as well as raise awareness for organ donation, said Naif. Athar and Misty are both entering into their fourth year of pharmacy school and plan to specialize in organ transplantation.

“Transplant pharmacists play a critical role on interdisciplinary teams caring for transplant patients. In addition to assuming the role of the medication expert, transplant pharmacists are becoming more involved with patient care,” Naif said.

“These pharmacists are with the patient before receiving transplant, during the acute care phase and post-transplant. You really establish a special bond with the patient and that patient-pharmacist relationship is one of the many reasons why I became interested in transplant pharmacy.”

“The Solid Organ Transplant Interest Group broadens student pharmacist’s knowledge about the field of transplant and this special patient population,” Ochotny said. “Our group works through patient cases, conducts journal clubs and holds topic discussions on topics such as organ allocation.”

The group also aims to raise awareness of organ donation, Ochotny said.

“Over 120,000 men, women and children are currently awaiting organ transplants to save their lives,” Ochotny said. “You can register as an organ, eye and tissue donor, because you have the power to donate such a special gift: life.”

“Interest groups continue to validate that pharmacy plays an integral part in patient care,” said Kevin B. Sneed, PharmD, professor and dean of the USF College of Pharmacy. “Clearly, the next generation of pharmacists who have lived the interprofessional education at a very high level in our program and have taken active roles in groups like this will do well in tomorrow’s healthcare teams.”

Wondering just how special organ donations can be? Just ask Ala Ahmad, MD, a fellow in the USF Health Morsani College of Medicine Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine.

Dr. Ahmad was in medical school when he was diagnosed with renal failure and needed a kidney transplant. The lifesaving gift was a possibility for Dr. Ahmad because of the national registry and meant he could fulfill his dream of becoming a physician.

“I was given a second chance at life and I’m thankful every day for that,” Dr. Ahmad said. “And the pharmacists helped me a lot along the way. Even today, I have a strong relationship with my pharmacist and, because I’ll need medication forever, I will for the rest of my life.”

For more information about the group or how to become an organ donor, please contact Misty Ochotny at mmuscare@health.usf.edu or visit donatelife.net