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 New malaria analysis method reveals disease severity in minutes
14.08.2017 | University of British Columbia

nachricht New type of blood cells work as indicators of autoimmunity
14.08.2017 | Instituto de Medicina Molecular

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: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>