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!
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Power and Electrical Engineering
16.01.2017 | Information Technology
16.01.2017 | Power and Electrical Engineering