Nrf2 gene 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-induced emphysema 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.