Since the lung is repeatedly subjected to injury by pathogens and toxicants, maintenance of pulmonary homeostasis requires rapid repair of its epithelial surfaces. Ciliated bronchiolar epithelial cells, previously considered as terminally differentiated, underwent squamous cell metaplasia within hours after bronchiolar injury with naphthalene. Expression of transcription factors active in morphogenesis and differentiation of the embryonic lung, including -catenin, Foxa2, Foxj1, and Sox family members (Sox17 and Sox2), was dynamically regulated during repair and redifferentiation of the bronchiolar epithelium after naphthalene injury. Squamous cells derived from ciliated cells spread beneath injured Clara cells within 6-12 h after injury, maintaining the integrity of the epithelium. Dynamic changes in cell shape and gene expression, indicating cell plasticity, accompanied the transition from squamous to cuboidal to columnar cell types as differentiation-specific cell markers typical of the mature airway were restored. Similar dynamic changes in the expression of these transcription factors occurred in ciliated and Clara cells during regeneration of the lung after unilateral pneumonectomy. Taken together, these findings demonstrate that ciliated epithelial cells spread and transdifferentiate into distinct epithelial cell types to repair the airway epithelium.
Keywords: naphthalene; lung injury; transcription; pneumonectomy; bronchioleThe respiratory tract has an extensive cell surface that is directly exposed to inhaled gases, particles, and pathogens. A complex epithelium lines the airways, mediating gas exchange, mucociliary clearance, host defense, and surfactant homeostasis to maintain lung sterility and stability. While the adult lung is not mitotically active, respiratory epithelial cells can proliferate rapidly after injury to maintain lung structure and function.Models in which relatively rare subsets of nonciliated respiratory epithelial cells located in unique environments play critical roles in lung repair have been proposed (1-5). Krause and coworkers have provided evidence that extrapulmonary, bone marrow-derived cells migrate to the lung, contributing to the repair of the respiratory epithelium after injury (6). From a stochastic view, however, models in which rare progenitor cells account for the rapid and extensive repair of the lung are not compatible with the observed short period of proliferation and rapid restoration of epithelial surfaces that is observed after catastrophic injury caused by infection or toxicants. Rather, the remarkable repair capacity of the lung is more consistent with a model in (Received in original form August 30, 2005 and in final form September 30, 2005) This study was supported by NIH HL56387 (J.A.W.) and HL61646 (J
