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Researchers identify new weapon to fight deadly bacterial sepsis
October 10, 2006GALVESTON, Texas - One of the most dangerous risks of contracting a serious bacterial infection is that the victim may develop sepsis-an overreaction by the immune system causing destructive inflammation throughout the body, often leading to heart and other organ failure and death. Even the best hospital intensive care units may be helpless to save patients stricken by severe sepsis. According to a 2003 study by Emory University and the Centers for Disease Control and Prevention, sepsis killed 120,491 hospitalized people in 2000. The same study found cases of sepsis in the U.S. have risen dramatically in recent decades, nearly tripling from 82.7 cases out of every 100,000 Americans in 1979 to 240.4 cases per 100,000 in 2000. Muppets creator Jim Henson died of the disease in 1990 at age 53.
Epidemiologists blame this large increase on the explosive rise in antibiotic-resistant bacteria caused by overuse of antibiotics as well as on the increasing numbers of people living with immune systems weakened by HIV, using immune-suppressive therapy for organ and bone marrow transplants, and receiving high-dose chemotherapy for cancer. Young children and elderly people are also at a higher risk for the condition because of their weaker immune systems.
Now, Assistant Professor Kota V. Ramana and Professor Satish Srivastava of the University of Texas Medical Branch at Galveston (UTMB) and their collaborators have discovered that in laboratory mice, blocking the activity of a single enzyme known as aldose reductase can short-circuit sepsis, protecting heart function and greatly reducing sepsis deaths. Moreover, the scientists have accomplished this feat using a chemical compound very similar to a diabetes drug already in stage three clinical trials in the United States, the final level of human experimentation before a drug is considered for federal licensing approval.
If those diabetes trials prove successful and the drug is approved for use in diabetics, it's possible that such an "aldose reductase inhibitor" could be used by physicians relatively quickly for "off-label" emergency use against sepsis in humans, the scientists said. When a drug is approved for one human use, individual doctors may try it out against other conditions where it appears warranted.
Srivastastava, senior author of a paper on the sepsis discovery to be published online Oct. 9 in the journal Circulation, explained that in this disease, "You can treat an infection and kill off all the bacteria, but there are still two things causing damage - the inflammatory proteins released by the body's natural defenses, and the outer membranes of the dead bacteria, mainly composed of large toxic molecules called lipopolysaccharides, which go on inducing more inflammatory immune response even though the bacteria themselves are dead."
"This inflammatory response causes significant problems with cardiac contractility," Srivastava added, "and so instead of pumping blood properly, the heart just flutters, a condition leading to cardiomyopathy."
The drastic drop in the heart's ability to pump blood is dangerous in itself, the researcher continued, and it can also have disastrous effects on the lungs and kidneys, which depend on efficient blood circulation.
Srivastava, lead author Ramana and their collaborators injected mice with lipopolysaccharide (LPS) to produce the conditions of severe sepsis, leading to major declines in heart function and substantial increases in heart-damaging inflammatory signaling molecules. But when they treated the mice with an aldose reductase inhibitor, they found that blocking the enzyme's activity restored the heart's ability to pump blood normally and allowed mice injected with otherwise lethal levels of LPS to survive.
Other experiments conducted in cell cultures traced the specific biochemical pathways by which LPS triggers an inflammatory cycle that damages the cells of the heart. By blocking aldose reductase activity with pharmacological inhibitors or using small interfering RNAs (pieces of genetic material that specifically stop the production of particular cellular proteins) to prevent the cells from producing the enzyme in the first place, the researchers demonstrated that aldose reductase is essential to that cycle.
Previous work by Srivastava and his UTMB collaborators (including research described in a paper published Oct. 1 in Cancer Research) has demonstrated that blocking aldose reductase similarly can dramatically reduce the inflammation-driven processes of colorectal cancer and complications of diabetes.
"There are so many inflammatory signaling processes that depend on this enzyme, and so it made sense to look into with regard to sepsis, which we knew was a runaway inflammatory process," Srivastava said. "We're hoping that when an aldose reductase inhibitor is approved as a drug in the U.S. - one is already in use in Japan for diabetes, by the way - we can interest clinicians in studying its use against sepsis."
University of Texas Medical Branch at Galveston
If those diabetes trials prove successful and the drug is approved for use in diabetics, it's possible that such an "aldose reductase inhibitor" could be used by physicians relatively quickly for "off-label" emergency use against sepsis in humans, the scientists said. When a drug is approved for one human use, individual doctors may try it out against other conditions where it appears warranted.
Srivastastava, senior author of a paper on the sepsis discovery to be published online Oct. 9 in the journal Circulation, explained that in this disease, "You can treat an infection and kill off all the bacteria, but there are still two things causing damage - the inflammatory proteins released by the body's natural defenses, and the outer membranes of the dead bacteria, mainly composed of large toxic molecules called lipopolysaccharides, which go on inducing more inflammatory immune response even though the bacteria themselves are dead."
"This inflammatory response causes significant problems with cardiac contractility," Srivastava added, "and so instead of pumping blood properly, the heart just flutters, a condition leading to cardiomyopathy."
The drastic drop in the heart's ability to pump blood is dangerous in itself, the researcher continued, and it can also have disastrous effects on the lungs and kidneys, which depend on efficient blood circulation.
Srivastava, lead author Ramana and their collaborators injected mice with lipopolysaccharide (LPS) to produce the conditions of severe sepsis, leading to major declines in heart function and substantial increases in heart-damaging inflammatory signaling molecules. But when they treated the mice with an aldose reductase inhibitor, they found that blocking the enzyme's activity restored the heart's ability to pump blood normally and allowed mice injected with otherwise lethal levels of LPS to survive.
Other experiments conducted in cell cultures traced the specific biochemical pathways by which LPS triggers an inflammatory cycle that damages the cells of the heart. By blocking aldose reductase activity with pharmacological inhibitors or using small interfering RNAs (pieces of genetic material that specifically stop the production of particular cellular proteins) to prevent the cells from producing the enzyme in the first place, the researchers demonstrated that aldose reductase is essential to that cycle.
Previous work by Srivastava and his UTMB collaborators (including research described in a paper published Oct. 1 in Cancer Research) has demonstrated that blocking aldose reductase similarly can dramatically reduce the inflammation-driven processes of colorectal cancer and complications of diabetes.
"There are so many inflammatory signaling processes that depend on this enzyme, and so it made sense to look into with regard to sepsis, which we knew was a runaway inflammatory process," Srivastava said. "We're hoping that when an aldose reductase inhibitor is approved as a drug in the U.S. - one is already in use in Japan for diabetes, by the way - we can interest clinicians in studying its use against sepsis."
University of Texas Medical Branch at Galveston
Sepsis Current Events and Sepsis News RSSProgress made on group B streptococcus vaccine
Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have completed a Phase II clinical study that indicates a vaccine to prevent Group B Streptococcus (GBS) infection is possible.
Canadian scientists link fat hormone to death from potentially deadly blood infection
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OMRF scientists discover promising new path for treating traumas
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Compound shows potential for slowing progression of ALS
A chemical cousin of a drug currently used to treat sepsis dramatically slows the progression of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease, in mice.
Review: Pneumococcal conjugate vaccines effective at preventing child deaths
A study published in The Cochrane Review this month concludes that pneumococcal conjugate vaccines (PCV), already known to prevent invasive pneumococcal disease (IPD) and x-ray defined pneumonia, was also effective against child deaths.
Key feature of immune system survived in humans, other primates for 60 million years
A new study has concluded that one key part of the immune system, the ability of vitamin D to regulate anti-bactericidal proteins, is so important that is has been conserved through almost 60 million years of evolution and is shared only by primates, including humans - but no other known animal species.
Discovery may lead to powerful new therapy for asthma
University of Texas Medical Branch at Galveston researchers have found that a single enzyme is apparently critical to most allergen-provoked asthma attacks - and that activity of the enzyme, known as aldose reductase, can be significantly reduced by compounds that have already undergone clinical trials as treatments for complications of diabetes.
Abnormal Brain Circuits May Prevent Movement Disorder
Most people who carry a genetic mutation for a movement disorder called dystonia will never develop symptoms, a phenomenon that has puzzled scientists since the first genetic mutation was identified in the 1990's.
Scientists uncork a potential secret of red wine's health benefits
Scientists from Scotland and Singapore have unraveled a mystery that has perplexed scientists since red wine was first discovered to have health benefits: how does resveratrol control inflammation?
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