Acute sensitivity of BHT-induced alveolar toxicity to a diquat challenge in murine lungs

In this study we investigated the effects of a mild toxic challenge at selected points in time on the nonspecific cellular events that occurred in acutely damaged pulmonary alveoli. Swiss-Webster mice were treated with butylated hydroxytoluene (BHT, 400 mg/kg ip) and sacrificed at Days 1, 3, and 5 thereafter; either 24 or 48 hr prior to each sacrifice, the herbicide diquat was administered (4 mg/kg ip) as a challenge to the ongoing cellular events in the pulmonary alveoli. Standard morphometric techniques were used at both the levels of light and electron microscopy to evaluate the alveolar response to BHT and diquat treatments. Following BHT, early type I epithelial and endothelial damage triggered inflammatory changes in alveolar septa. Proliferation and differentiation of type II pneumocytes, aiming at the regeneration of the respiratory epithelium, ensued and peaked at Day 3. Treatment with diquat alone caused mild inflammatory changes and hypertrophy of type II pneumocytes, in the absence of necrosis of any alveolar cell type. The pinpoint administration of diquat in the early days following treatment with BHT significantly disorganized the temporal pattern of alveolar reaction. Diquat enhanced epithelial and endothelial damage only if administered before the onset of BHT-induced injury. Afterwards, the alveolar response to the combined effects of BHT and diquat could not be predicted from their known individual effects. Treatment with diquat modified either proliferation or differentiation of type II pneumocytes, depending upon time along the BHT schedule. Inflammatory and interstitial reactions were lowered when diquat was given at Days 1 and 3 post-BHT, but potentiated when given at Day 4. The results document time-related changes in the sensitivity of damaged and regenerating alveolar cells to a mild exogenous chemical challenge. They may further indicate that low levels of urban and industrial toxicants might influence pulmonary alveolar events in individuals made more susceptible by acute or chronic respiratory diseases.