The goals of this proposal are to determine whether the airway response to inhaled endotoxin is a genetically based trait in humans and to assess to what extent the expression of this trait is influenced by gender. Occupational and environmental exposure to grain dust can cause asthma and bronchitis. Endotoxin appears to be one of the primary components of grain dust (and other organic dusts) that causes airway inflammation and airflow obstruction. Lipopolysaccharide (LPS) is a specific type of endotoxin found in the cell wall of gram-negative bacteria. In a murine model, we have confirmed that LPS resistance is determined by a single gene (Lps response gene), and we have localized this gene to a 220,000 base pair region on chromosome 4. In preliminary human studies, we have shown that most health, non-asthmatic, non-apoptotic, life-timer non-cigarette smoking volunteers develop airflow obstruction with challenged with increasing concentrations of inhaled LPS. However, approximately 10% of subjects developed marked airflow obstruction after inhaling trivial amounts of LPS and 15% of subjects appear to be hyporesponsive after inhaling over 40 micrograms of LPS. In addition, females demonstrate greater bronchial sensitivity to inhaled LPS than males. These results lead us to hypothesize that the airway response to inhaled LPS is a genetically determined complex trait in humans. Moreover, gender appears to substantially influence the airway response to inhaled LPS. We will use a familial cohort design to determine whether the airway response to inhaled endotoxin is a genetically based trait in humans, and to assess to what extent the expression of this trait is influence by gender. The study design is dependent on two interactive stages. In the first stage, we will screen a relatively large population of healthy, unrelated volunteers (n=200) with incremental doses of inhaled LPS. This will allow us to identify approximately 50 study subjects who will serve as "sensitive" or "hyporesponsive" probands. These sensitive and hyporesponsive probands will be used to identify families for the second stage of this investigation. In the second stage of the study, we will evaluate the airway response to incremental doses of inhaled LPS among 100 first degree relatives of up to 50 sensitive and hyporesponsive probands. Finds from this study will help us to determine why only a small portion of workers develop airway disease when exposed to organic dust.

R01HL062628

1999-02-10

2002-12-31