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 possib le 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."
Source:University of Texas Medical Branch at Galveston
Related biology news :
1. Researchers discover way to make cells in the eye sensitive to light
2. Researchers find how protein allows insects to detect and respond to pheromones
3. Researchers Uncover Key Step In Manufacture of Memory Protein
4. Researchers reveal the infectious impact of salmon farms on wild salmon
5. Researchers identify target for cancer drugs
6. Researchers discover molecule that causes secondary stroke
7. Researchers find missing genes of ancient organism
8. Researchers trace evolution to relatively simple genetic changes
9. Researchers add new tool to tumor-treatment arsenal
10. UF Researchers Map Bacterial Proteins That Cause Tooth Loss
11. VCU Researchers Identify Networks Of Genes Responding To Alcohol In The Brain