Fanucchi M V, Buckpitt A R, Murphy M E, Plopper C G
Department of Veterinary Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis 95616, USA.
Toxicol Appl Pharmacol. 1997 May;144(1):96-104. doi: 10.1006/taap.1997.8119.
Selective Clara cell injury produced by many bioactivated lung toxicants is thought to result from high levels of activating enzymes found in differentiated Clara cells. A recent study found an elevated susceptibility to the Clara cell toxicant 4-ipomeanol in neonatal rabbits when Clara cell P450 activity is low. To determine whether differentiating Clara cells in another species (mouse) are more susceptible to injury by a different bioactivated Clara cell toxicant (naphthalene), adult, 14-day postnatal (DPN) and 7DPN male mice were given a single intraperitoneal dose (25, 50, or 100 mg/kg) of naphthalene and killed 24 hr later. Epithelial damage, as assessed by quantitative histopathology, included cellular swelling, vacuolization, and exfoliation. In 7DPN mice, bronchiolar epithelium was severely injured at the lowest dose of naphthalene tested, 25 mg/kg. Bronchiolar epithelium in 14DPN mice was moderately injured at 25 mg/kg; injury severity was greatest at 50 and 100 mg/kg. Minimal bronchiolar epithelial injury occurred in adult mice at 50 mg/kg and moderate injury at 100 mg/kg. In proximal bronchi, epithelium of 7DPN mice showed signs of injury only at 100 mg/kg. Bronchial epithelium of adult mice was not injured at any dose. Isolated distal airways from 7DPN and 14DPN mice were more sensitive to naphthalene exposure than isolated distal airways from adult mice. Despite the low levels of P450 activity, differentiating Clara cells in neonatal mice are more susceptible to injury by the bioactivated cytotoxicant naphthalene than are differentiated Clara cells in adult mice.
许多生物活化的肺毒物所导致的选择性克拉拉细胞损伤，被认为是由于分化的克拉拉细胞中存在高水平的活化酶所致。最近一项研究发现，当克拉拉细胞的P450活性较低时，新生兔对克拉拉细胞毒物4-异戊烯醇的易感性会升高。为了确定另一种物种（小鼠）中正在分化的克拉拉细胞是否对另一种生物活化的克拉拉细胞毒物（萘）更易受损伤，给成年、出生后14天（DPN）和7天DPN的雄性小鼠腹腔注射单次剂量（25、50或100mg/kg）的萘，并在24小时后处死。通过定量组织病理学评估的上皮损伤包括细胞肿胀、空泡化和脱落。在7天DPN的小鼠中，测试的最低萘剂量25mg/kg时细支气管上皮就受到了严重损伤。14天DPN小鼠的细支气管上皮在25mg/kg时受到中度损伤；在50和100mg/kg时损伤程度最大。成年小鼠在50mg/kg时细支气管上皮仅有轻微损伤，在100mg/kg时为中度损伤。在近端支气管中，7天DPN小鼠的上皮仅在100mg/kg时出现损伤迹象。成年小鼠的支气管上皮在任何剂量下均未受损。与成年小鼠分离的远端气道相比，7天DPN和14天DPN小鼠分离的远端气道对萘暴露更敏感。尽管P450活性水平较低，但新生小鼠中正在分化的克拉拉细胞比成年小鼠中已分化的克拉拉细胞对生物活化的细胞毒性剂萘更易受损伤。
