title: The lung tumor promoter, butylated hydroxytoluene (BHT), causes chronic inflammation in promotion-sensitive BALB/cByJ mice but not in promotion-resistant CXB4 mice.
abstract: An inflammatory response accompanies the reversible pneumotoxicity caused by butylated hydroxytoluene (BHT) administration to mice. Lung tumor formation is promoted by BHT administration following an initiating agent in BALB/cByJ mice, but not in CXB4 mice. To assess the contribution of inflammation to this differential susceptibility, we quantitatively characterized inflammation after one 150 mg/kg body weight, followed by three weekly 200 mg/kg ip injections of BHT into male mice of both strains. This examination included inflammatory cell infiltrate and protein contents in bronchoalveolar lavage (BAL) fluid, cyclooxygenase (COX)-1 and COX-2 expression in lung extracts, and PGE(2) and PGI(2) production by isolated bronchiolar Clara cells. BAL macrophage and lymphocyte numbers increased in BALB mice (P<0.0007 and 0.02, respectively), as did BAL protein content (P<0.05), COX-1 and COX-2 expression (P<0.05 for each), and PGI(2) production (P<0.05); conversely, these indices were not perturbed by BHT in CXB4 mice. BALB mice fed aspirin (400 mg/kg of chow) for two weeks prior to BHT treatment had reduced inflammatory cell infiltration. Our results support a hypothesis that resistance to BHT-induced inflammation in CXB4 mice accounts, at least in part, for the lack of effect of BHT on lung tumor multiplicity in this strain.
authors.affiliation: Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Bauer
authors.forename: L D
authors.initials: LD
authors.lastname: Dwyer-Nield
authors.forename: J A
authors.initials: JA
authors.lastname: Hankin
authors.forename: R C
authors.initials: RC
authors.lastname: Murphy
authors.forename: A M
authors.initials: AM
authors.lastname: Malkinson
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology* / Q000633:toxicity; D001241:Aspirin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002084:Butylated Hydroxytoluene / Q000494:pharmacology* / Q000633:toxicity; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D018709:Statistics, Nonparametric
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D002273:Carcinogens; D007527:Isoenzymes; D008565:Membrane Proteins; D002084:Butylated Hydroxytoluene; D015121:6-Ketoprostaglandin F1 alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D001241:Aspirin