Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion.
Chronic pulmonary inflammatory diseases predispose towards lung cancer by unknown mechanisms. Butylated hydroxytoluene (BHT) administration to mice causes lung injury and a subsequent inflammatory response, and when administered chronically to certain inbred strains following carcinogen treatment, increases lung tumor multiplicity. We hypothesize that inflammation promotes lung tumor growth in this model system and have begun to examine this hypothesis by assessing inflammatory parameters in inbred strains that vary in their susceptibility to promotion. Positive correlations were found between susceptibilities to tumor promotion and BHT induction of alveolar macrophage and lymphocyte infiltration into alveolar airspaces, and increased vascular permeability (P < .03, P < .04, and P < .005, respectively). The amounts of pulmonary cyclooxygenase (COX)-1 and COX-2 did not strongly correlate with promotion. Because persistent elevation of macrophage content is the hallmark of a chronic inflammatory response, the alveolar macrophage population was depleted by adding chlorine to the drinking water prior to carcinogenesis. This treatment reduced lung tumor multiplicity following 2-stage carcinogenesis (P < .05). These correlations between inflammatory and tumorigenic responses to BHT, along with decreased tumorigenesis after macrophage depletion, are consistent with a role of inflammation in promotion. Inflammatory mediators may provide targets for early diagnosis and chemoprevention.
Bauer
A K
AK
Department of Pharmacology, University of Colorado Health Sciences Center, C238, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Dwyer-Nield
L D
LD
Keil
K
K
Koski
K
K
Malkinson
A M
AM
D000818:Animals; D002084:Butylated Hydroxytoluene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D005260:Female; D007249:Inflammation / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000209:etiology*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000139:chemically induced*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013045:Species Specificity
D002273:Carcinogens; D002084:Butylated Hydroxytoluene; D011451:Prostaglandin-Endoperoxide Synthases