Category: Featured Stories and Interviews

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Making a Lung Replacement

Making a Lung Replacement by the NIH

Hot on the heels of progress toward a liver transplant substitute, researchers have made transplantable lung grafts for rats. The accomplishment could pave the way for the development of an engineered human lung.

Blood vessels are preserved in the decellularized lung matrix. Image courtesy of Petersen et al., Science.

Lungs have a limited ability to regenerate. The primary therapy for severely damaged lungs is currently lung transplantation—surgery to remove the lung and replace it with a healthy lung from a deceased donor. However, lung transplants are limited by the small number of donor organs available—not much more than 1,000 per year.

To be successful, an artificial lung would need to retain the complex branching geometry of the lung’s airways. It would also require a large network of small blood vessels to transport oxygen and nutrients throughout the structure. Decellularization—the process of removing cells from a structure but leaving a scaffold with the architecture of the original tissue—has shown some success in other organs, including heart and liver. A team of researchers led by Dr. Laura Niklason of Yale University set out to build on this recent progress and develop a similar approach for lungs. Their work was supported by NIH’s National Heart, Lung and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS).

The researchers harvested lungs from adult rats. Treating the lungs with a mild detergent solution for 2 to 3 hours removed the cells but left the lung architecture intact, as reported in the early online edition of Science on June 24, 2010. A careful analysis showed that a matrix of proteins remained behind to hold the lung’s shape.

To see if they could repopulate the matrix with cells and engineer a functional lung, the researchers injected endothelial cells into the blood vessels and epithelial cells into airways. They kept the matrix for up to 8 days in a novel bioreactor that was designed to mimic the pressure changes and ventilation a lung would experience. The researchers found that the cells reseeded the surfaces of the matrix in their appropriate locations. This finding suggests that the decellularized matrix maintains cues for the cells to attach and thrive.

The researchers tested the engineered lungs in rats for short time intervals (45-120 min) and found that the lungs inflated with air, with only some modest bleeding into airways. Most importantly, the lungs successfully exchanged oxygen and carbon dioxide like natural lungs.

To see whether their method might apply to human tissues, the researchers got human lung segments from a tissue bank. They were able to decellularize the tissues while preserving their architecture. They then reseeded the matrices with epithelial and endothelial cells and found that they adhered at their appropriate locations. This result supports the idea that the approach holds promise for human lung tissue.

“We succeeded in engineering an implantable lung in our rat model that could efficiently exchange oxygen and carbon dioxide, and could oxygenate hemoglobin in the blood. This is an early step in the regeneration of entire lungs for larger animals and, eventually, for humans,” says Niklason. She notes that years of research with adult stem cells will likely be needed to develop ways to repopulate lung matrices and produce fully functional lungs for people.

—by Harrison Wein, Ph.D.
Related Links:

* Lung Transplant:
http://www.nhlbi.nih.gov/health/dci/Diseases/lungtxp/lungtxp_whatis.html

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Protein linked to severe asthma – The Press Association

Study Points to Key Genetic Driver of Severe Allergic Asthma

CINCINNATI, Aug. 29 /PRNewswire-USNewswire/ — Scientists have identified a genetic basis for determining the severity of allergic asthma in experimental models of the disease.

The study may help in the search for future therapeutic strategies to fight a growing medical problem that currently lacks effective treatments, researchers from Cincinnati Children’s Hospital Medical Center report in the Aug. 29 Nature Immunology.

The prevalence of asthma has been increasing in recent years, according to Marsha Wills-Karp, Ph.D., director of the division of Immunobiology at Cincinnati Children’s and the study’s senior investigator. The disease can be triggered in susceptible people by a variety of environmental contaminants – such as cigarette smoke, allergens and airborne pollution.

Dr. Wills-Karp’s research team has found a molecular tipping point that upsets a delicate balance between underlying mild disease and more severe asthma. They identify the pro-inflammatory protein, interleukin-17 (IL-17A), as the chief culprit behind severe asthma-like symptoms in mice.

“This study suggests that at some point it may be possible to treat or prevent severe forms of asthma by inhibiting pathways that drive the production of IL-17A,” Dr. Wills-Karp said.

The disease process appears to begin when airway exposure to environmental allergens causes dysfunctional regulation of a gene called complement factor 3 (C3), which works through a part of the immune system called the complement activation cascade. This leads to overzealous production of IL-17A by airway cells and sets off what the scientists describe as an “amplification loop,” when IL-17A in turn induces more C3 production at the airway surface.

The amplification loop perpetuates increasing inflammatory responses involving irregular T helper cells, other interleukin proteins (IL-13 and IL-23), as well as airway hyper-responsiveness and airflow obstruction.

Previous studies have shown the presence of IL-17A proteins in human asthma but no apparent role. Earlier research involving mouse models of the disease has suggested possible roles for IL-17A in asthma, and this study expands on those findings.

The current study involved mice bred genetically to closely resemble people susceptible to severe asthma. Mouse airways were exposed to house dust mite allergen extract to gauge the severity of disease and analyze biochemical responses in airway tissues.

One group of mice was deficient in the immune system gene C5, which normally prevents harmful airway immune responses to inhaled environmental allergens. These mice generated high numbers of T helper cells (known specifically in this instance as Th17 cells) that produced significant IL-17A and caused airway hyper-responsiveness. When researchers blocked IL-17A production in this group, the mice had less airway hyper-responsiveness.

A second group of mice was deficient in the C3aR gene (a receptor for C3), which regulates the dysfunctional response to airway allergens that lead to asthma. These mice had fewer IL-17A producing Th17 cells and less airway hyper-responsiveness. When researchers increased the amount of IL-17A in the airways of this group, the mice experienced greater airway hyper-responsiveness.

As Dr. Wills-Karp and her colleagues continue their research, they will study the relationship between C3 and IL-17A in severe asthmatics, and explore the effectiveness of targeting either the C3 or IL-17A pathways for the treatment of severe asthma. A drug that blocks the function of C3 is currently under development and testing outside of Cincinnati Children’s for treatment of the eye disease macular degeneration.

Funding support for the study came from the National Institutes of Health and the Parker B. Francis Fellowship Program.

Also collaborating on the study were co-first authors Stephane Lajoie, Ph.D., and Ian Lewkowich, Ph.D., research fellows in Dr. Wills-Karp’s laboratory.

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Harold Dow Believed to Have Suffered Asthma Attack

Harold Dow, Veteran CBS News Correspondent, Dies
Five-Time Emmy Award Winner Worked on “48 Hours” Since 1988 Premiere, Interviewed Patricia Hearst, O.J. Simpson

Longtime CBS News Correspondent Harold Dow died suddenly Saturday morning.

Dow has been a correspondent for “48 Hours” since 1990 after serving as a contributor to the broadcast since its premiere Jan. 19, 1988. Dow was also a contributor to the critically acclaimed 1986 documentary “48 Hours on Crack Street,” which led to creation of the single-topic weekly news magazine.

“CBS News is deeply saddened by this sudden loss,” said Sean McManus, president of CBS News and Sports. “The CBS News family has lost one of its oldest and most talented members, whose absence will be felt by many and whose on-air presence and reporting skills touched nearly all of our broadcasts. We extend our deepest condolences to his wife Kathy and their children Joelle, Danica and David.”

Harold

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Ozone and cigarette smoke worse for asthma than smoke alone – Los Angeles Times

Ozone and cigarette smoke worse for asthma than smoke alone

The LA Times is reporting that Ozone generators are often used in hotel rooms, cars and private homes to get rid of the smell of cigarette smoke, but new evidence suggests that this cure may be worse than the disease. Researchers at the Univeristy of California’s Lawrence Berkeley National Laboratory have found that ozone combines with nicotine and other components of cigarette smoke to produce chemicals that are a greater asthma hazard than the original smoke. In particular, the chemicals combine to form ultrafine aerosols that can carry dangerous chemicals deep into the lungs, where they trigger the development of asthma.

Environmental chemist Mohamad Sleiman and his colleagues used the Advanced Light Source at the laboratory to monitor the interaction of ozone with nicotine and other components of cigarette smoke. They reported in the journal Atmospheric Environment that, to their surprise, the chemicals reacted to form the ultrafine aerosols — smaller than those generated by smoking itself, and thus able to penetrate more deeply into the lungs. They also generated toxic compounds with a strong potential to stimualte asthma.

“The results predict that exposure to these ultrafine particles containing many oxidized species with high ‘Asthma Hazard Indices’ may increase the risks of asthma,” Sleiman said in a statement. “Formation of ultrafine particles appears to be a key dynamic step in the transformation of secondhand smoke to thirdhand smoke.”

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The Berkeley group had reported earlier this year that smoking can deposit nicotine and other products on furniture and other surfaces, where it can be released over long periods of time. This so-called thirdhand smoke constitutes a previously unsuspected source of exposure to carcinogenic and asthma-inducing chemicals. Attempting to removethe residue with ozone — which was thought to react with the chemicals and destroy them — can apparently create even more hazardous compounds, the researchers found.

The study was funded by the Tobacco-Related Disease Research Program of the University of California Office of the President.