Acute injury to differentiating Clara cells in neonatal rabbits results inage-related failure of bronchiolar epithelial repair

Nonciliated bronchiolar (Clara) cells are progenitor cells during lung deve lopment. During differentiation, they have a heightened injury susceptibili ty to environmental toxicants bioactivated by cytochrome P450 monooxygenase . When neonatal rabbits are treated with the P450-mediated cytotoxicant 4-i pomeanol (IPO), abnormal bronchiolar epithelium results. This study establi shes the impact of IPO cytotoxicity on 3 stages of rabbit Clara cell differ entiation, early (2.5 and 5 days postnatal [DPN]), intermediate (7 and 9 DP N;), and late (15 and 21 DPN), and relates the cytotoxicity to the extent o f bronchiolar repair Neonates received a single dose of IPO (5 mg/kg) and w ere assessed by qualitative pathology 48 hours later for injury or at 3 wee ks for repair. IPO injured the 3 stages of Clara cell differentiation to th e same degree; epithelium was swollen, exfoliated, and squamated. Epithelia l repair differed among the 3 stages. Bronchioles of animals treated during early and intermediate stages had simple squamous and irregularly shaped c uboidal cells. Animals treated during late stages were similar to controls. Thus, differentiating Clara cells are susceptible to injury by the P450-me diated cytotoxicant IPO, but the extent of repair varies based on when the initial injury occurs.