Sepsis is a complex, serious condition that affects more than 400,000 people in the US each year. It begins when a bacterial infection produces endotoxins called lipopolysaccharides that bind to endothelial cells lining the insides of blood vessels. This binding causes oxidative stress and an influx of calcium, activating the endothelial cells and increasing the expression of pro-inflammatory molecules. This activation, in turn, kicks off a chain of cellular events in which the normal immune reaction is overstimulated and the immune system attacks the body's own organs and tissues, culminating in unchecked inflammation. Lung inflammation, a common feature of sepsis, can lead to edema (fluid in the lungs) and possibly death. Sepsis is currently treated with antibiotic therapy, but its efficacy is limited.

“While antibiotics are improving, more than 25 percent of those who develop sepsis will die from it. This is partly because we don't fully understand the mechanisms behind the widespread inflammation it causes,” says Muniswamy Madesh, a biochemist at Temple University (Philadelphia, PA). Madesh and his collaborators recently reported that blocking the activity of a protein called STIM1 in endothelial cells can halt the sepsis cascade and protect against lung damage. “We've provided evidence indicating that without STIM1 driving calcium signaling, the exacerbation of inflammation can't occur,” Madesh explains. The study results provide new insight into the cellular processes underlying sepsis and may lead to new treatment strategies.

STIM1 is involved in calcium sensing and signaling, which is important in cellular communication, including the sequence of events that takes place in sepsis. To learn more about its role in sepsis, Madesh's group knocked out expression of STIM1 in endothelial cells of mice and compared them with wild-type mice after exposure to lipopolysaccharides. Calcium transport was disrupted in STIM1-deficient mice, interrupting the sepsis cascade and preventing lung injury (J. Clin. Invest. doi:10.1172/JCI65647; published online 25 January 2013). Blocking STIM1-driven calcium signaling using a small molecule called BTP2 also prevented lung damage. “Eliminating STIM1 or blocking the channel both reduced the permeability of the lungs' blood vessels and lessened lung edema. We can block this pathway using both genetic and pharmacological approaches, and both protected against endotoxin-induced lung inflammation,” Madesh summarized.

His team's future work includes developing new molecules that target STIM1 activation as potential therapeutic strategies. In addition to sepsis, such treatments could be useful in other diseases and conditions that involve STIM-driven calcium signaling, such as stroke.