Alteration of Pulmonary Neuroendocrine Cells during Epithelial Repair of Naphthalene-Induced Airway Injury

Abstract

Whole-mount airway preparations isolated from the lungs of mice treated by intraperitoneal injection of naphthalene and allowed to recover for 5 days were examined for the distribution and abundance of solitary pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) along the main axial pathway of the right middle lobe. Sham mice treated with corn oil vehicle were examined in a similar manner. An antibody to calcitonin gene-related peptide, a neuroendocrine cell marker, was used to identify the location, size, and number of PNECs and NEBs in the airways. After naphthalene treatment and epithelial repair, NEBs were significantly increased along the walls of the airways as well as on branch point ridges. The surface area covered by NEBs composed of 20 or fewer PNECs was significantly enlarged after naphthalene treatment compared with control NEBs of an equivalent cell number. The PNEC number per square millimeter was also increased more than threefold above control values after naphthalene treatment. These findings provide further support for a key role of neuroendocrine cells in the reparative process of airway epithelial cell renewal after injury.

Basal Cells Are a Multipotent Progenitor Capable of Renewing the Bronchial Epithelium

“…3,41 In contrast, bronchiolar airways are lined by a simple cuboidal to columnar epithelium which includes nonciliated secretory (Clara) and ciliated cells with sparsely distributed neuroepithelial cells that are either solitary or organized into clusters. 3,42 The notion of regional differences in the type and differentiation potential of progenitor cells is supported by studies using purified cell populations to reconstitute denuded rat tracheal xenografts. 43,44 In these studies, bronchiolar Clara cells isolated from the rabbit lung reconstituted an epithelium resembling bronchiolar epithelium, yet a mixed population of rabbit tracheal epithelial cells re-established a pseudostratified epithelium similar to that found in the trachea.…”

Loss of GFI1 impairs pulmonary neuroendorine cell proliferation, but the neuroendocrine phenotype has limited impact on post-naphthalene airway repair

“…Clara cell reconstitution post-naphthalene induced ablation is associated with PNEC and NEB hyperplasia. 6,11,12 Lung injury as a result of naphthalene administration provides a model to study the dynamics of reconstitution and to characterize progenitor cells responsible for the repair of injured lungs. 6,9,[11][12][13][14][15] The naphthalene injury and repair model has been utilized to define progenitors responsible for injury recovery and reconstitution of depleted epithelial cells.…”

“…6,11,12 Lung injury as a result of naphthalene administration provides a model to study the dynamics of reconstitution and to characterize progenitor cells responsible for the repair of injured lungs. 6,9,[11][12][13][14][15] The naphthalene injury and repair model has been utilized to define progenitors responsible for injury recovery and reconstitution of depleted epithelial cells. 11,12,[16][17][18][19][20] The NEB hyperplasia associated with naphthalene injury suggests a possible role for the PNEC in the reconstitution process.…”

“…6,9,[11][12][13][14][15] The naphthalene injury and repair model has been utilized to define progenitors responsible for injury recovery and reconstitution of depleted epithelial cells. 11,12,[16][17][18][19][20] The NEB hyperplasia associated with naphthalene injury suggests a possible role for the PNEC in the reconstitution process. 11,12,16 However, more recent data indicate that PNEC themselves are incapable of Clara cell reconstitution of the airways.…”

“…11,12,[16][17][18][19][20] The NEB hyperplasia associated with naphthalene injury suggests a possible role for the PNEC in the reconstitution process. 11,12,16 However, more recent data indicate that PNEC themselves are incapable of Clara cell reconstitution of the airways. 16,17,19 It has been suggested that the NEB microenvironment serves as a reservoir for a variant Clara cell that (1) lacks cytochrome P450-2F2-isozyme activity rendering it resistant to naphthalene toxicity and (2) may be capable of proliferating and repopulating the injured lungs.…”