TAG: "cystic fibrosis"

Cystic fibrosis discovery may lead to new strategy to help patients breathe easier


UCSF-led team ID’s why disease thickens mucus in lungs, explores possible new treatments.

By Pete Farley, UC San Francisco

A team led by UC San Francisco professor of medicine John Fahy, M.D., has discovered why mucus in the lungs of people with cystic fibrosis (CF) is thick, sticky and difficult to cough up, leaving these patients more vulnerable to lung infection.

Fahy and his team found that in CF – contrary to previous belief – inflammation causes new molecular bonds to form within mucus, transforming it from a liquid to an elastic sludge.

The scientists also made headway in the lab in exploring a potential new therapeutic approach to dissolve those bonds and return the mucus to a liquid that is easier for the lungs to clear.

CF is a lifelong inherited disease that affects the lungs and digestive system. There is no cure. About 30,000 children and adults in the United States have CF.

Fahy said that the research, a collaborative effort between UCSF, University College Dublin (UCD) in Ireland and the Cleveland Clinic (CC) in Ohio, has implications for other lung conditions characterized by thickened mucus, such as chronic obstructive pulmonary disorder (COPD) and asthma.

The work was reported in today’s (Feb. 25) issue of Science Translational Medicine.

Polymers – naturally-occurring molecules in mucus that form long chains – are the key to the discovery.

Until now, scientists had thought that CF mucus is thicker than healthy mucus because it has a greater concentration of DNA polymers. To test that idea, Fahy and his group exposed mucus samples taken from CF patients to two current CF medications: Pulmozyme, a drug that breaks up DNA polymers, and N-acetylcysteine (NAC), which targets disulfide bonds between mucin polymers. Mucin is a protein that is the major constituent of mucus.

“We thought Pulmozyme would be more effective than NAC in liquefying the mucus, because CF sputum contains lots of DNA,” said Fahy. “But to our surprise, NAC worked much better.”

Using confocal microscopy, the scientists learned why: CF mucus consists of a dense core of mucin with a layer of DNA wrapped around it, like a thin blanket draped over a solid pillow. Thus, while Pulmozyme makes mucus less stiff by eliminating DNA, NAC succeeds in liquefying it by breaking up the mucin.

Fahy and his team then investigated why mucin in CF is so compacted. They found that mucin polymers become linked together crosswise by newly forged disulfide bonds. Fahy likened the polymers to logs floating down a river. “The logs can float down the river as long as they are floating independently,” he said. “But if you bolt them together side to side, they will clog the river.”

The researchers found that inflammation causes the extra disulfide bonds to form, when mucin polymers are exposed to highly reactive oxygen molecules released by inflammatory cells in a process called oxidative stress.

This observation was confirmed by a device invented by lead investigator Leo Shaopeng Yuan, of the UCSF Cardiovascular Research Institute. In separate chambers, mucus from healthy volunteers was exposed to pure oxygen and pure nitrogen. The mucus exposed to oxygen became thick and elastic within seconds. The mucus exposed to nitrogen remained liquid.

“This qualitative change, driven by oxidation, happens with other natural polymers,” said Fahy. “Think of latex, which starts out as liquid tree sap. When it’s vulcanized – a process of chemical cross-linking – it turns into the solid rubber we use in tires.”

Fahy noted that patients who are treated with pure oxygen in hospital intensive care units have long been known to develop sticky mucus. “This could be a function of the oxygen that’s used to treat them,” he said.

Finally, the research team turned its attention to the possibility of creating new treatments for CF that would target disulfide bonds in mucin polymers directly and efficiently.

NAC, which targets mucin polymer bonds, is already an approved medication used to break up mucus. “However,” said Fahy, “there are problems with it. It’s a relatively weak drug, and it smells like rotten eggs.”

Team member Stefan Oscarson, Ph.D., a medicinal chemist from UCD, designed TDG, an experimental compound that targets disulfide bonds. TDG liquefied mucus samples from CF patients much more efficiently than NAC.

Fahy cautioned that TDG cannot yet be given to human beings. He noted that while the team has applied for funding to develop their promising new therapeutic approach, “there are at least five years of testing ahead before we can say we have a new medication.”

Fahy predicted that the new finding will explain the reason for thick mucus in other lung diseases known to be associated with oxidative stress, including COPD and asthma. “We’re very confident that we’ve uncovered a ubiquitous mechanism here,” he said.

Co-authors of the study are Martin Hollinger, Ph.D., of UCD; Marrah E. Lachowicz-Scroggins, Ph.D., Sheena C. Kerr, Ph.D., Eleanor M. Duncan, M.D., and Brian M. Daniel, R.R.T., of UCSF; Sudakshina Ghosh Ph.D., Serpel C. Erzurum, M.D., Belinda Willard, Ph.D., and Stanley L. Hazen, M.D., Ph.D., of the Cleveland Clinic; Xiaozhu Huang, M.D., of UCSF; and Stephen D. Carrington, Ph.D., of UCD.

The study was supported by funds from the National Institutes of Health and Genentech.

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Lung transplant recipient defies all odds


New approach to oxygenation helps patient live long enough for surgery.

Meara Schmidt, 28, almost died a few weeks ago. Lying in her hospital bed at UCLA, the seriously ill cystic fibrosis patient felt herself slipping away and her life flashing by. But then the image of her husband appeared, and she knew she was not ready to go.

With a strong will to live and a generous “gift of life” from an organ donor who provided her with two lungs, Schmidt has now been given a second chance.

Cystic fibrosis is a genetic disease characterized by the build-up in the lungs of thick, sticky mucus that traps infection-causing bacteria. There is no cure, but lung transplantation can help alleviate many of the symptoms.

Schmidt grew up with the condition but always enjoyed activities like hiking, cooking and singing. However, her illness started getting worse about two years ago. Walking became an exercise in logistics as she was constantly forced to calculate if she had enough breath to get from point A to point B.

In March of this year, she developed respiratory failure and was admitted to Ronald Reagan UCLA Medical Center with the goal of getting a double lung transplant. While candidates considered “high risk” are often declined by most transplant programs, UCLA is well-recognized for accepting individuals like Schmidt who have drug-resistant lung infections and other patients who suffer from collagen-vascular diseases such as scleroderma, individuals experiencing chronic rejection who need re-transplantation, older patients, lymphoma patients, and those with heart problems.

However, a series of dramatic medical ups and downs had Schmidt “on” the transplant list, then “off” the list. At one point, her right lung stopped functioning, her left lung only partially worked and a machine that provided oxygen had to be dialed up to 100 percent.

Twice, when her tracheostomy and mechanical ventilation was insufficient to provide enough oxygen, she was put on a last-ditch life-support system called extra-corporeal membrane oxygenation, or ECMO, which took over her breathing function through a cannula surgically placed in her neck.

But she would not give up.

In fact, while on ECMO and attached to a tower of medicine lines and pumps, she was able to get up and walk. Traditionally, patients on ECMO are sedated and immobile, but a new innovative ambulatory ECMO approach has been shown to help certain patients gain strength and muscle mass in preparation for surgery. With this new “bridge” approach, Schmidt was not sedated but alert and able to walk, which helped keep her well enough for transplant surgery. She was also working hard to gain weight and fight off various disease-related infections.

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Organ transplant surgeons perform UCLA’s 1st double lung-liver transplant


19-year-old patient receives rare combination surgery.

Jennifer Golden received the first double lung-liver transplant performed at UCLA.

Jennifer Golden, a 19-year-old college student from Las Vegas, got her Christmas gift early this year — a pair of life-saving lungs and a liver at Ronald Reagan UCLA Medical Center on Dec. 4.

The rare combination surgery, thanks to the gift of one donor, also marked a milestone for the hospital’s organ transplant program: It was the first operation of its kind ever performed at UCLA.

The young woman has a genetic condition called cystic fibrosis, which causes thick, sticky mucus in her lungs that traps infection-causing bacteria. As a result, Jennifer experienced shortness of breath, excess mucus, coughing, an inability to gain weight and diabetes.

Her disease was managed by a routine of “tune-ups” to clear the mucus in her lungs with antibiotics, intravenous medications, physical therapy and other procedures. However, over the years, her lungs developed infections that became increasingly difficult to treat. To make matters more complicated, Jennifer’s liver function was also affected by the disease. By her senior year, she was so sick she could no longer attend high school.

At age 17, with her lungs and liver simultaneously deteriorating, she was told her only chance at life was organ donation.

“I felt every emotion — scared, nervous, but also happy that this could save my life,” Jennifer recalled.

A double lung-liver transplant surgery is rare. According to the most current data available from the United Network for Organ Sharing which manages the country’s organ donation system, only 44 lung-liver transplants have been performed in the United States. It is also unusual for a cystic fibrosis patient to need both lungs and a liver. More commonly, because of the way the disease progresses, the patient needs only one organ or the other.

“Because of her small size and the necessity for both the lungs and liver to be usable, she knew — as did we — that her wait might be long,” said Dr. Sue McDiarmid, professor of pediatrics and surgery, director of the pediatric liver transplant program and Jennifer’s doctor for 10 years.

Meantime, Jennifer’s entire lung and liver transplant team — including surgeons, physicians and anesthesiologists — spent a lot of time planning for her complex surgery. For example, the surgeons decided that the best approach would be for the lung transplant to be performed first.

“We also consulted with reconstructive surgeons to map out where we would make our incisions so that Jennifer’s abdominal muscles, bone and skin would not be impacted,” added Dr. Doug Farmer, professor of surgery and surgical director of the pediatric liver transplant program. “Our goal was to perform the surgery efficiently and with minimal blood loss.”

Two years later, on Saturday, Dec. 3, Jennifer got the call that a donor had been found. She and her mom quickly flew to UCLA while her dad followed behind in the family car.

Jennifer was wheeled into surgery around 4:45 a.m. on Dec. 4. The team’s intense planning paid off, and the 13-hour operation went smoothly.

When Jennifer came out of her surgery, her ability to breath was immediately improved. With the diseased lungs removed, her illness is now gone although her cystic fibrosis is not technically cured since it is part of her genes.

“We are quite optimistic that Jennifer will do well,” said Dr. Abbas Ardehali, professor of cardiothoracic surgery and surgical director of the heart and lung transplant program at UCLA. “This is our mission here at UCLA to expand the horizon of transplant patients we can serve.”

The former high school tennis team captain can now look to the future, and her plans include being with her fiancé, continuing her college studies and hitting the tennis courts again.

She also has a vital message to deliver.

“I hope that if a family out there is ever suffering with the death of loved one, they will consider the priceless gift of organ donation,” Jennifer said. “Someone did that for me, and it saved my life. My family and I cannot thank them enough.”

“Without organ donors and their families, stories like Jennifer’s would have only tragic endings. Jennifer now breathes with ease — she is pink — her new liver is working very well, and all this because of this one donor whose life lives on in another,” said McDiarmid.

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Researchers discover new airway stem cell


UCLA findings could shed light on pulmonary diseases like asthma, cystic fibrosis.

Bridgitte Gomperts, UCLA professor of pediatrics and hematology–oncology

Brigitte Gomperts, UCLA

Researchers at UCLA have identified a new stem cell that participates in the repair of the lungs’ large airways, which play a vital role in protecting the body from infectious agents and toxins in the environment.

The airways protect the body by generating and clearing mucus, which is largely produced by the airways’ specialized mucus glands. While the mechanisms of normal and excessive mucus production are not well understood, this newly discovered lung stem cell for the mucus glands will likely yield insights into this critical process.

The study, by scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, represents the first time anyone has found the cell of origin for the many types of cells that make up the mucus glands and which can also repair the surface epithelium. The finding, the study states, is of “major importance to the field of lung regeneration.”

“We’re very excited that we found this population of cells because it will allow us to study mechanisms of diseases of the upper airway,” said Dr. Brigitte Gomperts, a UCLA assistant professor of pediatrics and hematology–oncology and the study’s senior author. “For example, there currently are no treatments for excess mucus production, which we see in cystic fibrosis, asthma and chronic obstructive pulmonary disease. But if we can understand the mechanisms of how these stem cells repair the mucus glands, then we may be able to find a way to put the brakes on the system and prevent mucus over-production.”

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