Lung damage induced by butylated hydroxytoluene in mice. Biochemical, cellular, and morphologic characterization.
This study was designed to characterize the biochemical, cellular, and morphologic events produced in mice by butylated hydroxytoluene (BHT) and to relate these events to changes in extracellular angiotensin-converting enzyme (ACE) activity. On Day 1 after the administration of BHT, bronchoalveolar lavage (BAL) ACE activity increased 4-fold (p less than 0.001), its specific activity relative to BAL protein increased 3-fold (p less than 0.001), and both type 1 cell damage and endothelial cell damage were detected by electron microscopy. The early increase in BAL ACE activity preceded changes in plasma ACE levels, BAL cell number, protein, lactate, and lactate dehydrogenase (LDH) activity in both plasma and BAL, and the ACE content of alveolar macrophages. On Day 2, BAL ACE activity increased 9-fold, BAL protein increased 4-fold (p less than 0.001), BAL LDH activity increased 34% (p less than 0.05), and the BAL cell count doubled (p less than 0.01). Changes in each animal's appearance, body weight, wet and dry lung weights, and plasma ACE levels occurred between Days 3 and 5. The BAL differential cell count, which consisted of greater than 95% macrophages in uninjured mice, did not change until Day 5 when there was a small increase in polymorphonuclear leukocytes (PMN). On Day 7, the number of PMN peaked, and some of the other measures of lung injury began returning toward normal. These results indicate that BAL ACE activity is a sensitive, early marker of BHT-induced lung injury, which appears to reflect damage to the cells of the alveolar-capillary barrier. In addition, PMN do not appear to play a major role in this model of lung injury. Because of its effects on angiotensin, bradykinin, and prostaglandins, the early release of ACE from damaged cells may modulate the subsequent injury.
D000818:Animals; D002084:Butylated Hydroxytoluene; D002452:Cell Count; D004727:Endothelium / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008171:Lung Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D009504:Neutrophils / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology
D007773:Lactates; D011506:Proteins; D002084:Butylated Hydroxytoluene; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D007703:Peptidyl-Dipeptidase A