Nicotine’s Good Side: Substance curbs sepsis in mice

Small doses of nicotine can halt the progression of the often-fatal condition called sepsis, according to experiments in mice. The finding, coupled with tests of nicotine on cultured human cells, suggests a pathway to more-effective therapies for the infection-triggered problem.

Twice as many mice injected with nicotine survived at least 3 weeks after sepsis set in than did mice receiving inert injections. Luis Ulloa of the Institute for Medical Research at North Shore-Long Island Jewish Health System in Manhasset, N.Y., and his coinvestigators conclude that the treatment works by inhibiting overproduction of an immune system molecule that promotes inflammation.

Other studies have suggested that nicotine may be effective against inflammatory diseases such as ulcerative colitis, which is chronic inflammation of the large intestine.

When Ulloa and his colleagues began experimenting in lab dishes with human macrophages, a type of immune system cell, they discovered that the biochemical acetylcholine put the brakes on the cells’ production of the protein called high mobility group box 1 (HMBG1). This protein is one of the family of immune chemicals called cytokines, which play a role in infection-fighting inflammation. In sepsis, however, HMBG1 overstimulates inflammation.

Knowing that acetylcholine acts through immune-cell receptors that also bind nicotine, the researchers tested that chemical on the human cells. It triggered a strong anti-inflammatory effect.

The researchers then injected doses of nicotine into one of two sets of mice in which they had induced sepsis by infecting the animals with bacteria. After 24 hours, the mice receiving nicotine had lower concentrations of HMBG1 proteins in their bloodstreams than the other mice did, the team reports in the November Nature Medicine.

To find out whether this effect can improve survival, the researchers induced sepsis in mice and then injected one group of mice with nine doses of nicotine over 3 days and gave another group an inert solution. After 3 weeks, 81 percent of the mice that had received the nicotine were still alive, compared with 44 percent in the group getting inert injections.

Ulloa expects the findings to lead to the development of new, nicotinelike compounds that can reduce inflammatory diseases while avoiding the side effects of nicotine, which include nausea and heart and blood vessel problems. “However, these are preclinical studies, and future studies are needed to evaluate potential effects of human use” of such compounds, he adds.

Effective new therapies for sepsis could have tremendous medical benefits. In the United States, sepsis kills a third of the 750,000 people who experience it each year, accounting for 9 percent of U.S. deaths. Current treatment consists of antibiotics and critical care to prevent organ failure, but sepsis often spreads too rapidly for physicians to halt its damage.

Pathologist Peter A. Ward of the University of Michigan Health System in Ann Arbor says, “There’s every reason to think [the new finding] might ultimately have clinical implications.” The goal for treatment of sepsis and other inflammatory conditions, he explains, is to find ways of enlisting the body’s natural regulators.

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