Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Carbon monoxide: Poison gas or anti-inflammatory drug?

28.07.2005


Inhaling CO prevents transplant rejection in mice, say U-M scientists. Could become part of future treatment regimen for organ transplant patients

Could become part of future treatment regimen for organ transplant patients. Carbon monoxide, a poisonous gas that kills thousands of Americans every year, could turn out to be a life-saver for patients recovering from organ transplants, strokes or heart attacks, according to new research from the University of Michigan Cardiovascular Center.

In a recent study, U-M scientists found that inhaling small amounts of carbon monoxide for several weeks after transplant surgery prevented the development of a lethal inflammatory reaction in experimental mice receiving transplanted trachea, or windpipes.



If carbon monoxide therapy works as well in human patients as it does in mice, it could prevent an inflammatory response, called obliterative bronchiolitis, which develops in nearly 50 percent of all patients who receive a lung transplant from an unrelated donor. OB is the most common complication following a lung transplant in humans and the most deadly. It occurs when the patient’s immune system rejects the transplanted lung and sends an army of T cells to attack and destroy the foreign tissue.

"No one is sure exactly how it happens, but the small airways in the lung swell and become progressively smaller until the patient cannot breathe," says David J. Pinsky, M.D., the J. Griswold Ruth, M.D. & Margery Hopkins Ruth Professor of Internal Medicine and chief of cardiovascular medicine in the U-M Medical School, who directed the research. "Currently, we have no effective treatments for OB. Unless the patient receives a new lung transplant, the outcome is generally fatal."

Results of the U-M study were published July 18 in the most recent issue of the Journal of Experimental Medicine (JEM).

Pinsky’s research team focuses on the relationship between carbon monoxide and nitric oxide – two poisonous gases produced by different types of cells in the body. U-M research findings suggest that a patient’s chances of living or dying after a lung transplant depend, in large part, on the outcome of an internal power struggle between two enzymes that control cellular production of these gases.

"Hmox, or heme oxygenase enzyme, is responsible for the synthesis of carbon monoxide," Pinsky explains. "It was first identified as a heat shock protein induced under stress conditions to help protect cells from damage. Hmox expression increases in human lung transplant patients with OB.

"Nitric oxide synthase, or iNOS, is the enzyme responsible for the synthesis of nitric oxide," Pinsky adds. "When it’s expressed in endothelial cells in blood vessels, it causes them to dilate and relax. But when it’s expressed in epithelial cells in airways, it generates a flood of leukocytes that trigger an inflammatory response. Expression of iNOS also increases during lung transplant rejection.

"We think that Hmox and carbon monoxide are the body’s way of trying to limit tissue inflammation and injury induced by iNOS and nitric oxide during transplant rejection," Pinsky says. "Our data show that localized CO production provides critical protection against the OB induced by iNOS expression. It’s a balancing mechanism. When Hmox expression goes up, it reduces iNOS expression and suppresses a key signaling pathway involved in the immune response."

To test their hypothesis, U-M scientists studied two types of experimental mice – one group lacked the gene for the Hmox enzyme and were unable to synthesize carbon monoxide. Another group produced unusually high levels of Hmox and CO. When U-M scientists transplanted windpipes from one type of mouse into the other, genetic differences between the two strains of mice triggered transplant rejection, inflammation and significant narrowing of the airway in the transplant recipients.

But U-M scientists discovered they could rescue the mice by having them inhale CO-enriched air (100 ppm) for two weeks after transplantation, or by giving them a drug that induces high levels of Hmox expression.

"We found that naturally occurring levels of the Hmox enzyme were not high enough to prevent airway occlusion in mice after transplant," says Hiroaki Harada, M.D., a U-M research fellow and co-first author of the study. "We had to either use drugs to boost Hmox expression in the mice or boost its end-product with prolonged inhalation of carbon monoxide."

"Carbon monoxide is lethal at certain doses, but the animals tolerated the 100 ppm level for two weeks with no apparent problems," Pinsky says. "In human terms, it’s equivalent to the amount you’d receive sitting in a traffic jam in Mexico City."

The next step was to analyze the amount of Hmox enzyme expressed in white blood cells and in epithelial cells lining the grafted trachea. "We did this to determine the source of CO," Pinsky says. "Was it coming from infiltrating immune cells from the host or from donor epithelial cells lining the graft? In order to prevent airway rejection, our results show that Hmox expression and generation of carbon monoxide must occur in grafted tissue cells."

The researchers also found that while both inhaled and internally produced carbon monoxide had a positive effect on transplant airway inflammation and narrowing, inhaled nitric oxide had no effect and internally produced nitric oxide made the inflammatory reaction worse.

Pinsky’s research team previously published evidence for the therapeutic efficacy of CO inhalation in mice recovering from the type of cardiovascular injuries caused by blood clots to the lungs. Pinsky maintains that the balancing act between CO and NO is an important factor in transplant rejection after heart transplants and in recovery after other types of damage to the cardiovascular system.

Pinsky believes that carbon monoxide may one day be as common in the hospital ICU as inhaled nitric oxide is today, but cautions that a great deal of additional research will be required to resolve important questions of dosing and toxicity.

"The therapeutic window for carbon monoxide is very small," he says. "Small amounts are good, but a little more will kill you. So dosage will always be a serious issue in any future therapies."

Sally Pobojewski | EurekAlert!
Further information:
http://www.umich.edu

More articles from Health and Medicine:

nachricht GLUT5 fluorescent probe fingerprints cancer cells
20.04.2018 | Michigan Technological University

nachricht Scientists re-create brain neurons to study obesity and personalize treatment
20.04.2018 | Cedars-Sinai Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>