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Release: Sept. 2, 1999

UI study suggests genetics, gender affect human response to endotoxin

IOWA CITY, Iowa -- Endotoxin -- a common contaminant of agricultural dust, air pollution and household dust -- causes or exacerbates asthma and other lung problems in some, but not all, people with respiratory conditions. A recent University of Iowa Health Care study provides evidence that when it comes to healthy individuals, pulmonary responses to endotoxin can also differ markedly, yet consistently.

The study is the first to examine endotoxin response in nonsmoking, nonasthmatic and nonallergic individuals whose jobs do not put them in contact with the contaminant. The researchers found that some people had significant bronchospasm (narrowing of the airway) following slight endotoxin exposure, while others were resistant to even high dosages. Women were much more likely than men to show declined airway function after breathing even small amounts of the contaminant.

"The wide response difference in people who have no apparent predisposition to lung disease suggests a genetic cause of endotoxin susceptibility and resistance," said Joel N. Kline, M.D., UI assistant professor of internal medicine and lead investigator. "The gender-based response difference also suggests there are cellular differences. The finding may have implications for the prevention or treatment of endotoxin-associated disease in susceptible individuals."

Previous research, including studies led by David A. Schwartz, M.D., UI professor of internal medicine and a senior author for the current study, showed that the inhalation of dust containing endotoxin can cause problems for individuals with asthma or other lung conditions. A poisonous byproduct of bacterial infection or other microorganisms, endotoxin is known chemically as lipopolysaccharide. It is extremely prevalent in agricultural dust, such as that found in grain silos.

In the recent study, 72 individuals, 26 men and 46 women, inhaled incrementally increasing amounts of endotoxin. After each dose, the researchers measured the participants' pulmonary function. Kline described the highest endotoxin dosage, 40 micrograms, as "the total amount a worker inhales during an eight-hour shift in a heavy dust-exposure site such as a grain elevator."

Eight of the participants were highly sensitive and developed "profound bronchospasm" following exposure to miniscule doses -- 6.5 micrograms -- of endotoxin. The majority of participants (53) were intermediate in their response, while 11 were hyporesponsive, meaning they showed little response even at the highest dosage. Seven of the eight highly sensitive individuals were women, while eight of the 11 hyporesponsive individuals were men, pointing to a sex-based link.

The researchers were able to reproduce the results with a sub-group of the original participant pool. In addition, to further document the response differences, the researchers studied blood cell samples taken from some of the sensitive and nonresponsive individuals. The cells from sensitive individuals had more inflammatory mediators than cells taken from the nonresponsive individuals. This cellular finding supported the physiology results of the breathing tests, Kline said.

He added that it is not entirely clear how endotoxin causes breathing problems, but the contaminant seems to cause inflammation through a "cascade" effect.

"The endotoxin causes macrophages, the most numerous inflammatory cells in the normal lung, to release mediators of inflammation such as cytokines," Kline explained. "These proteins have multiple effects including attracting other inflammatory cells."

Overall, the research adds to the "growing acceptance" that endotoxin is an important component of environmental influences on asthma and other airway obstructions, he said.

The findings were published in the July issue of the American Journal of Respiratory and Critical Care Medicine. The research team included members of the UI College of Medicine departments of internal medicine and pediatrics and the former department of preventive medicine (now the UI College of Public Health) and the Veterans Affairs Medical Center in Iowa City. The study was supported by grants from the federal Department of Veterans Affairs, the National Institute of Environmental Health Sciences and the National Heart, Lung and Blood Institute.