In a surprise finding, scientists have discovered that histamine, the inflammatory compound released during allergic reactions that causes runny nose, watery eyes, and wheezing, can be produced in large amounts in the lung by neutrophils, the white blood cells that are the major component of pus.
Pus, a fluid found in infected tissue, is produced as a result of inflammation.
The study in mice is the first to show that lung neutrophils can produce histamine in significant quantities, according to principal investigator George Caughey, MD, chief of pulmonary/critical care medicine at the San Francisco VA Medical Center.
"Previously it was thought that the primary sources of lung histamine, in health as well as disease, was mast cells, which are classically associated with allergy," notes Caughey, who is also a professor of medicine at the University of California, San Francisco.
Caughey says the result could mean that histamine acts as a link between airway infections and asthma and bronchitis, which are associated with allergy. "In both, we observe inflammation ---- swelling, blood vessel leak, and muscle contraction that narrows the airway."
The study appears in the January 2007 issue of the Journal of Experimental Medicine.
Caughey was investigating the well-known fact that upper respiratory infections often trigger acute asthma attacks. "We hypothesized that an infection in the airway would release histamine from mast cells, and that would be one of the reasons," he explains.
To test the hypothesis, Caughey and his team exposed two different populations of mice to mycoplasma, a common respiratory infection in rodents and humans. One population had a genetic abnormality that causes a total lack of mast cells; the other population was made up of normal, wild-type mice. Both populations of infected mice developed pneumonia.
"We thought the mice without mast cells would do better than the wild-type mice, because the infection wouldn't be provoking mast cells to release histamine," recalls Caughey. "In fact, they did much worse. Even though there were no mast cells, histamine levels rose up to 50 times normal."
The reason was straightforward, Caughey says. Neutrophil numbers increased in response to infection, and neutrophils in turn produced histamine. "It's a direct effect of the mycoplasma bacteria on neutrophils. They induce neutrophils to produce the enzyme that produces histamine."
Individual neutrophils produce much less histamine than individual mast cells, says Caughey, but "because pus contains millions if not billions of neutrophils, the overall amount they make is very considerable."
The neutrophil-histamine effect was similar in the wild-type mice, reports Caughey: "Histamine levels from neutrophils blew right past the histamine levels contributed by mast cells."
The wild-type mice suffered less severe infections overall because "as a number of recent studies, including ours, have shown, mast cells actually play a role in protecting against bacteria," Caughey explains. "For example, a mouse without mast cells with the equivalent of a ruptured appendix will die of the resulting infection, while a mouse with mast cells can survive."
When the infected mice without mast cells were given antihistamines, the level of histamine, and therefore the severity of the pneumonia, dropped in proportion to the amount of antihistamine given.
"This is a study in mice, so we cannot freely extrapolate the results to human beings," cautions Caughey. "Nonetheless, antihistamines may deserve more of a look as therapeutic options in lung and airway infection."
He says the study also has implications for other types of airway infection "in which there are a lot of white blood cells ---- cystic fibrosis, for example, which can be associated with asthma-like airway contraction."
The next steps for Caughey and his research team are to investigate "how general this result might be. Does only one type of bacteria cause the effect, or do others, also? Is it limited to rodents, or does it carry forward to humans? And if it does, is the amount of histamine produced by neutrophils enough to make a clinical difference?"
Co-authors of the study were Xiang Xu, MD, PhD, Dongji Zhang, MD, PhD, Hong Zhang, PhD, Paul J. Wolters, MD, Nigel P. Killeen, PhD, Brandon M. Sullivan, Richard M. Locksley, MD, and Clifford A. Lowell, MD, PhD, of UCSF.
The study was supported by funds from the National Institutes of Health, the Diamond Family Foundation, and an Elizabeth Nash memorial fellowship from Cystic Fibrosis Research, Inc. A part of the NIH funds was administered by the Northern California Institute for Research and Education.
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