New angle on treating sepsis

Enzyme that plays role in inflammation may be suitable drug target

By blocking an enzyme that appears to incite inflammation in sepsis, researchers can reverse the deadly condition in mice, a study in the June 4 Science shows.

Sepsis is a massive inflammatory state typically triggered by a bacterial infection. The reaction can cause blood vessel leakage, organ failure and heart problems. Death rates from sepsis can be as high as 60 percent.

The enzyme that researchers blocked, called sphingosine kinase 1, or SphK1, is known to spur production of inflammatory proteins. That led researchers to investigate a potential link to sepsis. Such a connection hadn’t previously been made, says study coauthor Alirio Melendez, a physician at the University of Glasgow in Scotland.

“This is a long way from getting into a clinical setting, but I think it’s promising,” says Derek Wheeler, a pediatric intensive care physician at Cincinnati Children’s Hospital Medical Center and the University of Cincinnati.

Melendez teamed with researchers in Singapore and Europe to explore the role of SphK1 in sepsis by first examining blood from sepsis patients. Those samples showed that while most cells in the body make the enzyme, it is mass-produced by certain immune cells during sepsis.

In lab-dish tests in cells, the researchers inhibited SphK1 by silencing a key gene or by adding an experimental compound called 5c that neutralizes SphK1. Cells’ production of several inflammatory compounds, including one called nuclear factor Kappa-B that plays a central role in inflammation and immunity, decreased substantially.

Next the researchers injected a bacterial toxin into mice to induce sepsis. Mice whose ability to make SphK1 had been blocked were able to avoid sepsis. In another test, mice that got sepsis from intestinal surgery survived longer if they had been pretreated with SphK1 blockers.

“Patients undergoing bowel surgery are prone to developing sepsis,” Melendez says. “We can potentially prevent patients from developing overwhelming inflammation.”

In other tests of mice getting intestinal surgery, the SphK1-blockers boosted the effectiveness of antibiotic treatment, possibly because less inflammation left a normal quota of immune cells in the blood to do the job of clearing the bacteria, he says.

What’s more, compound 5c improved mouse survival even when given to the animals after sepsis had already set in. This approach has parallels to treating sepsis in people. “Most patients that come to us with sepsis probably developed it over the course of 12 to 24 hours before getting to a health setting,” Wheeler says.

The new study’s surgical test in mice also has the advantage of approximating the effects of a burst appendix in people, he says.

Doctors tread a fine line in suppressing inflammation in sepsis, because overdoing it can compromise the immune system, leaving a patient vulnerable to bacterial infections.

Timothy Hla, a vascular biologist at the Weill Cornell Medical College in New York City, says the SphK1 inhibitors used in this study need to be tested more extensively. “You can give compounds to animals and cure them, but that doesn’t tell you the mechanisms at work,” he says. “I’m pretty sure this compound [5c] is blocking many things — not just SphK1.” Hla also raises questions about the safety of decreasing levels of the inflammatory compound nuclear factor kappa-B. Doing so “generally has a lot of side effects,” he says.

Overall, Hla says the study offers “an interesting finding, but I think it’s very preliminary.”

Even so, the authors maintain that using SphK1 inhibitors, alone or with antibiotics, “might offer a suitable new therapeutic tool for the treatment of septic shock.” Compound 5c is a synthetically modified version of a compound called sphingosine, found naturally in cells. Melendez and his team plan to develop 5c as a drug for treating sepsis patients.

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