Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene protects lung from damage due to pneumonia, sepsis, trauma, transplants

09.02.2011
Lung injury is a common cause of death among patients with pneumonia, sepsis or trauma and in those who have had lung transplants. The damage often occurs suddenly and can cause life-threatening breathing problems and rapid lung failure.

There are no effective treatments. Patients usually are put on ventilators to give their lungs a chance to heal, but there is little else doctors can do but wait and hope for the best.

Now, researchers at Washington University School of Medicine in St. Louis report they have identified a gene that limits damage to the lung during acute stress from illness, trauma or transplant. Defects in the bcl3 gene likely leave some patients more vulnerable to lung injury, they say.

The scientists also have demonstrated that this critical gene, which is active in bone marrow cells, can prevent lung injury in mice. The research is published in the Journal of Clinical Investigation.

The new discovery lays the groundwork for developing therapies to reduce complications of pneumonia, trauma and lung transplants, which affect many thousands of people annually in the United States.

"Acute lung injury is a very serious problem," says senior author Andrew Gelman, PhD, assistant professor of surgery and of pathology and immunology. "Patients' lungs fill with fluid, they can't breathe, and sadly there are no drugs available to reverse the condition."

The real culprits underlying acute lung injury are infection-fighting white blood cells called neutrophils. When the body makes too many neutrophils, however, they begin to attack healthy tissue, causing even more damage and sometimes even death.

"In mice, we found that the bcl3 gene essentially controls how many neutrophils the body produces under acute stress in the lung," Gelman says.

The same gene exists in people. Mutations in bcl3 have long been associated with the development of leukemia and lymphoma. Only recently has it been found to play a role in inflammation.

The research team stumbled onto bcl3 as part of an effort to determine why a newly transplanted lung often becomes injured in the hours after surgery. The damage occurs as the blood begins to flow through the organ again and increases the risk of rejection. In earlier studies, they had found that soon after a lung transplant, the new lung signals to the bone marrow to produce massive amounts of neutrophils.

"We wanted to understand how the lung is talking to the bone marrow and what is driving this extraordinary increase in neutrophils," Gelman says. "The lung tends to be unique in this manner; we don't see this with other organ transplants, such as the heart."

In a series of experiments in mice undergoing lung transplants, the researchers found that in response to acute stress in the lung, a cytokine called granulocyte colony stimulating factor (G-CSF) accumulates in the blood, which in turn stimulates the production of neutrophils in the bone marrow.

But there's a counterbalance built into the system. When G-CSF builds up in the blood, the bcl3 gene is activated in the bone marrow to begin shutting down neutrophil production.

When the scientists transplanted healthy mouse lungs into mice that lacked bcl3 in their bone marrow, things went haywire. Without the gene, neutrophil production went unchecked, and the mice developed acute lung injury.

The investigators measured four times as many neutrophils in the blood of mice that lacked bcl3 compared with normal mice. The bcl3 gene, they showed, acts like a master switch to control the effects of G-CSF on neutrophil production.

While neutrophils are the key offenders of acute lung injury, completely blocking them from entering the lung is not a practical treatment.

"You need enough neutrophils in the lung to fight infection or repair lung damage but when there are too many, they cause irreversible injury," Gelman says. "It's a delicate balancing act."

Instead, the investigators showed they could prevent post-transplant lung injury by blocking G-CSF in mice that lacked blc3 in their bone marrow.

"This reduced the number of neutrophils that entered the lung," Gelman explains. "Other inflammatory cytokines, including GM-CSF and IL-3, still produced neutrophils but not enough to cause acute lung injury."

The researchers also showed they could prevent acute lung injury in a mouse model of sepsis by blocking G-CSF in mice that lacked bcl3.

Interestingly, G-CSF is routinely given to cancer patients undergoing chemotherapy to help them fight infections.

"There's been a lot of effort to stimulate neutrophil production in cancer patients because chemotherapy kills cancer cells and prevents the production of white blood cells, including neutrophils," Gelman says. "But what we're saying is that under acute stress to the lung, the effect of G-CSF on neutrophil production needs to be limited but certainly not eliminated."

In follow-up studies, Gelman and his colleagues want to get a better handle on how mutations in the bcl3 gene affect a person's susceptibility to acute lung injury from an infection or a transplant, he says.

The research was funded by a grant from the National Heart, Lung, and Blood Institute.

Kreisel D, Sugimoto S, Tietjens J, Zhu J, Yamamoto S, Krupnick AS, Carmody RJ, Gelman AE. Bcl3 prevents acute inflammatory lung injury by restraining emergency granulopoiesis. Journal of Clinical Investigation. January 2011.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Caroline Arbanas | EurekAlert!
Further information:
http://www.wustl.edu

More articles from Life Sciences:

nachricht For a chimpanzee, one good turn deserves another
27.06.2017 | Max-Planck-Institut für Mathematik in den Naturwissenschaften (MPIMIS)

nachricht New method to rapidly map the 'social networks' of proteins
27.06.2017 | Salk Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Touch Displays WAY-AX and WAY-DX by WayCon

27.06.2017 | Power and Electrical Engineering

Drones that drive

27.06.2017 | Information Technology

Ultra-compact phase modulators based on graphene plasmons

27.06.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>