Van Winkle L S, Isaac J M, Plopper C G
Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California-Davis 95616-8732, USA.
Am J Pathol. 1997 Aug;151(2):443-59.
Clara cells are primary targets for metabolically activated pulmonary toxicants because they contain an abundance of the cytochrome P450 monooxygenases required for generation of toxic metabolites. The factors that regulate bronchiolar regeneration after Clara cell injury are not known. Previous studies of naphthalene-induced bronchiolar injury and repair in the mouse have shown that epithelial cell proliferation is maximal 1 to 2 days after injury and complete 4 days after injury. Proliferation is followed by epithelial re-differentiation (4 to 14 days). In this study, mice were treated with the environmental pollutant naphthalene to induce massive Clara cell injury. The distribution and abundance of three growth-regulatory peptides (epidermal growth factor receptor (EGFR), epidermal growth factor (EGF), and transforming growth factor (TGF)-alpha) was determined immunochemically during repair of this acute bronchiolar injury. EGFR and its ligands were detected at low levels in cells throughout the lung including peribronchiolar interstitial cells, blood vessels, and conducting airway epithelium. Immediately after naphthalene injury (1 to 2 days), EGFR, EGF, and TGF-alpha are expressed in increased abundance in squamous epithelial cells of the injury target zone, distal bronchioles. These immunopositive squamous cells are detected in clumps in the distal bronchioles at the time when cell proliferation is maximal. EGFR protein expression is decreased slightly 4 to 7 days after injury and continues to decrease below control levels of abundance 14 to 21 days after injury. This down-regulation of EGFR is not reflected in a corresponding decrease in EGF and TGF-alpha protein expression, indicating that control of cell proliferation is regulated at the receptor level. Co-localization of EGFR and bromodeoxyuridine-positive proliferating cells in the same bronchiole indicates that EGFR is up-regulated within the proliferative microenvironment as well as in specific proliferating cells within the injury target zone. The coincident localization within terminal bronchioles of EGFR, EGF, and TGF-alpha to groups of squamous epithelial cells 2 days after naphthalene injury suggests that these peptides are important in up-regulating cell proliferation after Clara cell injury in the mouse.
克拉拉细胞是代谢活化的肺毒物的主要靶细胞，因为它们含有大量生成毒性代谢物所需的细胞色素P450单加氧酶。克拉拉细胞损伤后调节细支气管再生的因素尚不清楚。先前对萘诱导的小鼠细支气管损伤和修复的研究表明，上皮细胞增殖在损伤后1至2天达到最大值，并在损伤后4天完成。增殖之后是上皮细胞重新分化（4至14天）。在本研究中，用环境污染物萘处理小鼠以诱导大量克拉拉细胞损伤。在这种急性细支气管损伤的修复过程中，通过免疫化学方法确定了三种生长调节肽（表皮生长因子受体（EGFR）、表皮生长因子（EGF）和转化生长因子（TGF）-α）的分布和丰度。在整个肺的细胞中，包括细支气管周围间质细胞、血管和传导气道上皮细胞，EGFR及其配体的表达水平较低。萘损伤后立即（1至2天），EGFR、EGF和TGF-α在损伤靶区远端细支气管的鳞状上皮细胞中表达丰度增加。在细胞增殖达到最大值时，在远端细支气管中可检测到这些免疫阳性的鳞状细胞团块。损伤后4至7天，EGFR蛋白表达略有下降，并在损伤后14至21天继续下降至低于对照丰度水平。EGFR的这种下调并未反映在EGF和TGF-α蛋白表达的相应下降中，表明细胞增殖的控制在受体水平上进行调节。同一细支气管中EGFR与溴脱氧尿苷阳性增殖细胞的共定位表明，EGFR在增殖微环境以及损伤靶区内的特定增殖细胞中上调。萘损伤后2天，EGFR、EGF和TGF-α在终末细支气管内与鳞状上皮细胞群的一致定位表明，这些肽在小鼠克拉拉细胞损伤后上调细胞增殖中起重要作用。
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