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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 RSSSafety data favor norepinephrine over dopamine for shock
Physicians treating patients with shock should consider norepinephrine instead of dopamine as a tool for stabilizing blood pressure, according to an editorial in the March 4, 2010, issue of the New England Journal of Medicine (NEJM).
Kidney injury linked to greater risk of death among pneumonia patients
Patients hospitalized with even mild to moderate community-acquired pneumonia who develop acute kidney injury (AKI) are more likely to die after discharge than pneumonia patients whose kidneys remain healthy, according to a University of Pittsburgh School of Medicine study in the February issue of Kidney International.
Study finds that 2 treatment strategies for severe sepsis show similar survival rates
A comparison of two strategies for treating severe sepsis or septic shock finds that using lactate levels measured in blood samples showed a similar short-term survival rate compared to a treatment regimen using central venous oxygen saturation measured using a specialized catheter.
Treating neonatal meningitis -- is nitric oxide a foe or a friend to bacteria?
Current research suggests that nitric oxide may play a role in the pathogenesis of neonatal meningitis.
New study shows sepsis and pneumonia caused by hospital-acquired infections kill 48,000 patients
Two common conditions caused by hospital-acquired infections (HAIs) killed 48,000 people and ramped up health care costs by $8.1 billion in 2006 alone, according to a study released today in the Archives of Internal Medicine.
Cholesterol-lowering drug shows promise against serious infections in sickle cell disease
New research suggests a family of widely used cholesterol-lowering drugs might help protect individuals from serious illness following bacterial infection, including the pneumococcal infections that pose a deadly threat to those with sickle cell disease.
Fish oil not snake oil
A randomised controlled trial of fish oil given intravenously to patients in intensive care has found that it improves gas exchange, reduces inflammatory chemicals and results in a shorter length of hospital stay.
Naturally occurring lipid blocks RSV infection in lungs
Researchers at National Jewish Health have discovered that a naturally occurring lipid in the lung can prevent RSV infection and inhibit spread of the virus after an infection is established. RSV is the major cause of hospitalization for children in the first two years of life, and is increasingly recognized as a dangerous pathogen in adults with chronic lung diseases, the elderly, and immunocompromised individuals.
Septic shock: Nitric oxide beneficial after all
Scientists at VIB and Ghent University in Flanders, Belgium have found an unexpected ally for the treatment of septic shock, the major cause of death in intensive care units. By inducing the release of nitric oxide (NO) gas in mice with septic shock, researchers Anje Cauwels and Peter Brouckaert discovered that the animal's organs showed much less damage, while their chances of survival increased significantly.
Fatty food can weaken the immune system
Fresh evidence that fatty food is bad for our health has come to light: mice fed a lard-based diet over a long period got worse at fighting bacteria in the blood, reveals a thesis from the Sahlgrenska Academy.
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