LUNG DAMAGE INDUCED BY BUTYLATED HYDROXYTOLUENE IN MICE - BIOCHEMICAL, CELLULAR, AND MORPHOLOGIC CHARACTERIZATION

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Abstract
Biochemical, cellular and morphologic events produced in mice by butylated hydroxytoluene (BHT) were characterized and related to changes in extracellular angiotensin-converting enzyme (ACE) activity. On day 1 after BHT administration, bronchoalveolar lavage (BAL) ACE activity increased 4-fold (P < 0.001), its specific activity relative to BAL protein increased 3-fold (P < 0.001) and both type 1 cell damage and endothelial cell damage were detected by EM. 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 alveolar macrophage ACE content. On day 2, BAL ACE activity increased 9-fold, BAL protein increased 4-fold (P < 0.001), BAL LDH activity increased 34% (P < 0.05) and the BAL cell count doubled (P < 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, PMN number peaked and some other lung injury measures began returning toward normal. BAL ACE activity is a sensitive, early BHT-induced lung injury marker, which appears to reflect damage to the alveolar-capillary barrier cells. PMN do not appear to play a major role in this lung injury model. Because of its effects on angiotensin, bradykinin and prostaglandins, early ACE release from damaged cells may modulate the subsequent injury.