Lack of a key enzyme dramatically increases resistance to sepsisApril 24, 2006
According to the new study, the presence of caspase-12, which appears to modulate inflammation and innate immunity in humans, increases the body's "vulnerability to bacterial infection and septic shock" while a deficiency confers strong resistance to sepsis. This new discovery suggests that caspase-12 antagonists could be a potentially useful in the treatment of sepsis and other inflammatory and immune disorders.
The study was published in the April 20 edition of the journal Nature (Volume 440, Number 7087).
Richard Ulevitch, chair of the Scripps Research Immunology Department and an author of the paper, says, "The results of the study make clear that caspase-12 plays a critical role in the elimination of bacterial pathogens, and that a deficiency allows systemic and abdominal infections to be better resolved. It's known that the presence of caspase-12 as a full length protein occurs in a small percentage of people of African descent. As a result, some of these individuals are far more susceptible to severe sepsis and have a significantly increased risk of dying from it."
Sepsis, the body's inflammatory response to severe infection, is one of the leading causes of death in the United States, killing more than 200,000 people each year, according to the Society of Critical Care Medicine. A 2003 study by The Centers for Disease Control and Emory University School of Medicine showed that the incidence of sepsis in the United States has increased almost nine percent a year since 1979.
The new study showed that caspase-12 deficient mice were resistant to peritonitis and septic shock and were able to clear pathogenic bacteria more efficiently than mice with the enzyme. The presence of caspase-12 also reduced production of several pro-inflammatory cytokines, increasing vulnerability to bacterial infection and septic mortality.
"Without the experimental model of peritonitis perfected by John Mathison from Scripps Research, we would not have been able to differentiate between the two mouse phenotypes," Ulevitch said. "Because of his work, we were able to use a surgically implanted stent in the colon that allowed a gradual occurrence of sepsis and easy identification."
A majority of mice with caspace-12 died from sepsis within the first 48 hours after onset, while 60 percent of the caspase-12 deficient mice survived. The deficient mice also showed a significantly lower number of bacterial colony-forming units per milliliter of blood, suggesting that more efficient bacterial clearance occurs in the absence of caspase-12.
Caspase-12 is also an inhibitor of caspase-1, a related enzyme involved in the inflammation process. Caspase-1 deficient mice are two-to-three times more susceptible to lethal Escherichia coli infection than normal mice. Consequently, the study said, sepsis resistance in caspase-12 deficient mice was most likely due to an initial hyper-production of cytokines that fight the infection.
"The resulting beneficial effect of cytokine hyper-production runs contrary to some of the current thinking in sepsis research," Ulevitch said. "The general thinking is that this initial cytokine 'storm' is harmful, and that belief has been the basis of a number of unsuccessful clinical studies. In our study, cells containing caspase-12 appear to weaken the activity of caspase-1 that is normally essential for bacterial clearance and sepsis survival."
In another finding, researchers showed that both mouse models had similar levels of stress-induced apoptosis or programmed cell death. While caspase-12 was previously thought to be a key mediator of endoplasmic reticulum apoptosis, the new study found that the presence or absence of caspase-12 had no effect on apoptotic sensitivity whatsoever.
Others authors of the study include Maya Saleh (currently with McGill University), Melissa K. Wolinski, Steve J. Bensinger, Patrick Fitzgerald, Nathalie Droin, Douglas R. Green (La Jolla Institute of Allergy and Immunology and St. Jude Children's Research Hospital); Donald W. Nicholson of Merck Research Laboratories, and; John C. Mathison of Scripps Research.
Scripps Research Institute
Related Sepsis Current Events and Sepsis News Articles
Influenza and sepsis: Mayo expert describes warning signs of severe sepsis, septic shock
Sepsis can be a dangerous complication of almost any type of infection, including influenza, pneumonia and food poisoning; urinary tract infections; bloodstream infections from wounds; and abdominal infections.
Alterations in fatty acid synthesis linked to sepsis inflammation
Sepsis is a leading cause of death for patients in intensive care units. The excessive systemic inflammation in individuals with sepsis damages organs and can lead to death.
Surprise: High-dose testosterone therapy helps some men with advanced prostate cancer
In a surprising paradox, the male hormone testosterone, generally thought to be a feeder of prostate cancer, has been found to suppress some advanced prostate cancers and also may reverse resistance to testosterone-blocking drugs used to treat prostate cancer.
Ben-Gurion University researchers discover that AAT drug may prevent deadly infections
Ben Gurion University of the Negev (BGU) researchers have discovered that alpha1-antitrypsin (AAT) could prevent deadly infections in immune system-compromised patients.
Fat isn't all bad: Skin adipocytes help protect against infections
When it comes to skin infections, a healthy and robust immune response may depend greatly upon what lies beneath.
New version of common antibiotic could eliminate risk of hearing loss
On Christmas Eve, 2002, Bryce Faber was diagnosed with a deadly cancer called neuroblastoma. The 2-year-old's treatment, which, in addition to surgery, included massive amounts of radiation followed by even more massive amounts of antibiotics, no doubt saved his life.
A human enzyme (CD 39) targets the Achilles heel of sepsis
There may never be a way to completely prevent infection, but sepsis may have an Achilles heel that would allow for more effective treatment of the condition.
Overly conservative FDA label likely prevents use of metformin in many type 2 diabetics
Many patients with type 2 diabetes in the United States may be discouraged from taking metformin--a proven, oral diabetes medicine--because the U.S. Food and Drug Administration inappropriately labels the drug unsafe for some patients also suffering from kidney problems, researchers from Penn Medicine and Weill Cornel Medical College report this week in a research letter published in JAMA Internal Medicine.
Study: Novel agent decreases neuropathic pain in patients with type 2 diabetes
Molecular Medicine, a peer-reviewed biomedical journal published by the Feinstein Institute Press, published the results of a new study reporting clinically significant pain reduction in type 2 diabetic patients.
A matter of birth and death: Unsafe conditions still killing new mothers and newborns
WaterAid and the London School of Hygiene &Tropical Medicine today join the World Health Organization, UNICEF, UNFPA, SHARE Research Consortium and other organisations in a call to protect the lives of new mothers and their babies, by improving access to safe water, basic sanitation and hygiene in healthcare facilities and homes.
More Sepsis Current Events and Sepsis News Articles