Development of a model of neonatal pulmonary cytotoxicity

Although the lung of humans continues to develop for 8 to 10 years postnatally, response of developing lungs to toxicants is not well known. This is critical since children are exposed to a number of environmental pulmonary toxicants. We have focused on one of the lung's primary target cells, the Clara cell, which has high P450 activity and differentiates postnatally. Previous studies found that developing rabbit Clara cells are more susceptible to the P450-mediated toxicant, 4-ipomeanol (IPO), than mature Clara cells of adults at the same dose despite having less P450 acitivity. The purpose of this study was to answer two questions: 1) Are specific stages of Clara cell differentiation more susceptible to injury than others? 2) Does the ability of the Clara cell to repair vary with the stage of of differentiation during which the injury takes place? 3,5,7,9, and 21 day-old rabbits were given a single i.p. injection of IPO. Animals were killed 48 hrs post-injection for injury susceptibility evaluation and killed at 4 wks of age for repair potential evaluation. Injury susceptibility was: 7 and 9 > 5 and 3 > 21 days old. Repair potential was: 7 and 9 < 5 and 3 < 21 days old. We conclude that specific stages of Clara cell differentiation are more susceptible to IPO-induced injury and that the repair potential does vary with the stage of Clara cell differentiation at the time of injury This provides a model of neonatal pulmonary cytotoxicity that can be used to elucidate the mechanisms behind the stage-specific patterns of Clara cell injury and repair following exposure to the P450-mediated cytotoxicant, IPO.