Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researches Discover Gene Critical for Protection Against Septic-Shock-Induced Death

04.04.2006
Findings May Offer Therapeutic Potential for Sepsis Treatment

Disruption of a single gene, Nrf2, plays a critical role in regulating the body’s innate immune response to sepsis and septic shock, according to a study by a research team led by Shyam Biswal, PhD, at the Johns Hopkins Bloomberg School of Public Health. The researchers found that the absence of Nrf2 caused a dramatic increase in mortality due to septic shock in mice. The study’s findings, which will be published in the April 2006 issue of the Journal of Clinical Investigation, may hold potential for the treatment of life-threatening sepsis.

Sepsis is a complex disease characterized by an increased inflammatory response in the body’s attempt to combat an infection from microorganisms such as bacteria, fungi or viruses. A weak host inflammatory response can lead to greater infection, whereas an excessive inflammatory response may lead to tissue damage, myocardial injury, acute respiratory failure, multiple organ failure or death. Controlling inflammation is thus a central focus of treating sepsis. Researchers have been hunting for novel host genes that regulate inflammation as potential targets for the next generation of sepsis therapies. The incidence of sepsis in the United States ranges from 400,000 to 750,000 cases per year. Mortality due to sepsis is around 30 percent and increases with age from 10 percent in children to 40 percent in the elderly. Mortality is 50 percent or greater in patients with the more severe syndrome, septic shock.

Suspecting that a dysregulation in the body’s inflammatory response exacerbates sepsis, the research team began looking into the genetic factors that might contribute to this syndrome. In 2002, Biswal and his colleagues discovered that Nrf2 acts as a primary regulator of most of the cellular antioxidant pathways and detoxifying enzymes that protect the body from a wide variety of environmental toxicants. In subsequent studies, they discovered that Nrf2 is a pleiotropic protein that regulates a broad spectrum of genes used by the host to defend against a variety of stresses, including oxidative and inflammatory diseases such as cigarette-smoke-inducedemphysema and allergic asthma in mice models.

Biswal’s team found that the deletion of the Nrf2 gene increased the inflammatory response and caused early death in mice subjected to septic peritonitis or endotoxin shock or both. Mice deficient in Nrf2 gene expressed dramatically increased levels of effector molecules (cytokines) that mediate innate immune response, the body’s first line of defense. “Sepsis syndrome is like a speeding car with a brake failure. Nrf2 may function like a brake that regulates the speed,” said Biswal, senior author of the study and assistant professor in the Bloomberg School’s Department of Environmental Health Sciences. Biswal speculates that suboptimal function of Nrf2 may be one reason why some intensive-care patients progress into severe sepsis and die.

“Nrf2 protects from septic shock by two mechanisms,” explained lead author Rajesh Thimmulappa, PhD, a postdoctoral fellow at Environmental Health Sciences, Bloomberg School of Public Health. “First, Nrf2 protects from dysregulation of host inflammatory response, which is a characteristic feature of septic shock. Secondly, Nrf2 protects from oxidative pathological damage, the main cause of multi-organ failure during septic shock. Hence, Nrf2 can be a promising therapeutic target for attenuating septic-related deaths.”

According to Biswal, the findings provide a better understanding of the human body’s defense mechanisms to sepsis and septic shock, and may provide clues to designing novel therapies that could minimize mortality. The researchers are now trying to find if activation of Nrf2 by a small-molecule drug can minimize pathological damage and improve survival during sepsis caused by bacteria or viruses. Future studies will determine the therapeutic potential of targeting Nrf2 for treatment of sepsis and other inflammatory diseases that impact public health.

The other coauthors of the study are Hannah Lee, Tirumalai Rangasamy, Sekhar P. Reddy, Masayuki Yamamoto , Thomas W. Kensler.

This work was supported by NIH grants- HL081205 (S. Biswal), P50 CA058184, NIEHS center grant P30 ES 038819, Young Clinical Scientist award from Flight Attendant Research Institute (S. Biswal), The Maryland Cigarette Restitution Fund (S. Biswal); CA94076 (T.W. Kensler) and P50 HL073994 (S.P. Reddy)”.

Tim Parsons | EurekAlert!
Further information:
http://www.jhsph.edu

More articles from Life Sciences:

nachricht Seeing on the Quick: New Insights into Active Vision in the Brain
15.08.2018 | Eberhard Karls Universität Tübingen

nachricht New Approach to Treating Chronic Itch
15.08.2018 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

Im Focus: Lining up surprising behaviors of superconductor with one of the world's strongest magnets

Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur

What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

2018 Work Research Conference

25.07.2018 | Event News

 
Latest News

Unraveling the nature of 'whistlers' from space in the lab

15.08.2018 | Physics and Astronomy

Diving robots find Antarctic winter seas exhale surprising amounts of carbon dioxide

15.08.2018 | Earth Sciences

Early opaque universe linked to galaxy scarcity

15.08.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>