November 14, 2004
STANFORD, Calif. – Mast cells are immune cells known mostly for their unwanted effects: they cause the wheezing of asthma, the itching of eczema, the sneezing and runny nose of hay fever and, in extreme cases, the life-threatening shock of anaphylaxis. But researchers at the Stanford University School of Medicine have found that these cells also have some very beneficial effects.
Stephen Galli, MD, the Mary Hewitt Loveless, MD, Professor and chair of pathology, and his colleagues have shown for the first time that mast cells can provide protection from a potentially deadly condition known as sepsis by destroying a molecule that contributes to the pathology and death associated with this bacterial infection. Their results are to be published in the Nov. 14 advance online edition of Nature. The first authors, Marcus Maurer, MD, and Jochen Wedemeyer, MD, were postdoctoral fellows in Galli’s laboratory during the study.
“What we have uncovered in this study is a new role for the mast cell, which is to limit the amount of damage caused by endothelin-1, a molecule that is produced in high amounts by the body during severe sepsis, as well as in association with other disorders,” said Galli.
Sepsis is a severe illness caused by overwhelming infection of toxin-producing bacteria in the bloodstream. The effects of sepsis in humans include a high fever, hyperventilation and diarrhea and can be life threatening, especially in patients with other medical problems.
During some infections, endothelin-1 levels can go very high, contributing to some of the severe problems of sepsis. At the start of the study, the scientists already knew that, in cell culture, mast cells are activated by endothelin-1. In turn, the mast cells also can produce endothelin-1 and break it down.
“However, it was not possible to guess what the net effect of the mast cells on the endothelin system would be, because mast cells can both degrade it and produce it,” said Galli.
To see the mast cells in action rather than in a culture dish, senior research scientist Mindy Tsai, DMSc, helped produce genetically engineered mast cells that could or could not respond normally to endothelin-1. The researchers could then selectively transplant these mast cells to mice that lacked the cells and thus see how it affected the ability to respond to endothelin-1 or bacterial infection.
Most of the mice without mast cells died as a result of bacterial infection. But survival during sepsis was greatly improved in the mice with mast cells that could respond normally to endothelin-1. The scientists found that endothelin-1 can activate mast cells in the mice and, once triggered, the cells produced another protein that breaks down endothelin-1, reducing its toxic effects. In other words, said Galli, the mast cells help to restore normal physiological balance in the mice with high levels of endothelin-1.
High levels of endothelin-1 have been reported in a number of human diseases, such as high blood pressure, pulmonary hypertension, asthma, congestive heart failure, renal failure and gastric ulcers, said Galli. Moreover, mast cells have been implicated in many of the same disorders.
“Although we have studied a bacterial infection as a kind of first test case, we hope to be able to develop models that would allow us to study this phenomenon in other diseases as well,” he said. “We are too early in this work to see clearly what the therapeutic potential will be.”
Other scientists have considered the possibility of eliminating mast cells as a possible treatment for diseases such as asthma. However, Galli said his team’s results offer an example of a beneficial function that would be lost if those cells were eliminated.
“It’s reassuring that evolution has produced cells that under some circumstances have significant benefit, even though when they are activated inappropriately, such as in asthma, they produce harm,” Galli said.
Interestingly, he said, a component of a particular snake venom, that of the Israeli mole viper, contains a compound similar to endothelin-1. Animals bitten by the snake develop some effects that are similar to those observed in sepsis. It is possible that mast cells also counteract this venom component, breaking it down and reducing the toxicity of the protein. Galli’s group is looking at this now.
Other Stanford researchers who contributed to this work are Martin Metz, Adrian Piliponsky and Davavani Chatterjea. The National Institutes of Health funded the study.
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