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Quantitative Trait Loci That Regulate Susceptibility to Both Butylated Hydroxytoluene-Induced Pulmonary Inflammation and Lung Tumor Promotion in CXB Recombinant Inbred Mice* FREE TO VIEW

Al Malkinson, PhD; Richard Radcliffe, PhD; Alison Bauer, PhD; Lori Dwyer-Nield, PhD; Steven Kleeberger, PhD
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*From the Departments of Pharmaceutical Sciences and Pharmacology (Drs. Malkinson, Radcliffe, Bauer, and Dwyer-Nield), University of Colorado Health Sciences Center, Denver, CO; and the Department of Environmental Health Sciences (Dr. Kleeberger), Johns Hopkins University, Baltimore, MD.

Correspondence to: Al Malkinson, PhD, Campus Box C238, 4200 East Ninth Ave, Denver, CO 80262; e-mail: Al.Malkinson@UCHSC.edu

Chest. 2002;121(3_suppl):82S. doi:10.1378/chest.121.3_suppl.82S
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It is not obvious whether the inflammation adjacent to human lung neoplasms is a response to local invasion, occurred early during tumorigenesis to enhance neoplastic growth, or both. COPD and asthma are associated with increased lung cancer risk, but experimental verification of a role for inflammation in lung tumorigenesis is lacking. Individuals vary in responsiveness to environmental carcinogens, allergens, and infection; identifying genes governing susceptibility to multiple inciting agents would provide pathogenic insight. Butylated hydroxytoluene (BHT), the most common synthetic food additive, is metabolized in mouse lungs into pneumotoxic oxidative species. Assessing the pneumopathologies induced by BHT in the 13 CXB recombinant strains allows linkage comparisons with previously mapped markers that are polymorphic between their C57BL/6J and BALB/cByJ progenitors. Two-stage carcinogenesis is initiated by a single administration of either urethane or 3-methylcholanthrene followed by multiple weekly BHT injections; promotion is defined as the increased lung tumor multiplicity caused by BHT over that induced by the carcinogen alone. Inflammatory parameters assessed included vascular hyperpermeability, macrophage and lymphocyte markers of chronic exudate, and the cyclooxygenase pulmonary contents. Our study confirms previous gene assignments for lung inflammation and lung carcinogenesis induced by other agents, emphasizes the commonality of some of these quantitative trait loci for both inflammation and carcinogenesis, and suggests new chromosomal regions whose function in these pathologic conditions should be examined.

Abbreviation: BHT = butylated hydroxytoluene

Supported by US Public Health Service grant CA33497.




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