GP130-STAT3 Regulates Epithelial Cell Migration and Is Required for Repair of the Bronchiolar Epithelium

Abstract

Following injury, bronchiolar cells undergo rapid squamous metaplasia, followed by proliferation and re-establishment of the complex columnar epithelium that is characteristic of the normal airway. Mechanisms that regulate the repair of bronchiolar epithelium are of considerable relevance for understanding the pathogenesis of both acute and chronic lung diseases associated with airway remodeling. This study was designed to identify the role of the GP130-STAT3 signaling pathway during repair of the bronchiolar epithelium. STAT3 ( The respiratory epithelium is recurrently subject to injury by pathogens, particles, and toxicants. Following extensive bronchiolar injury, remaining cells undergo squamous metaplasia to maintain the epithelial barrier. Thereafter, epithelial cell proliferation and differentiation restore the normal populations of ciliated and nonciliated cells lining the bronchioles. Since acute and chronic airway injuries are associated with many pulmonary diseases, the mechanisms and cellular processes regulating repair of the respiratory epithelium are of considerable interest. Repair of the bronchiolar epithelium has been studied using various agents to cause epithelial cell injury, including naphthalene, respiratory pathogens, and inhaled toxicants (see review 1 ). Naphthalene has been used to selectively kill nonciliated bronchiolar cells in the mouse lung in vivo.2-4 Within 24 hours after naphthalene exposure, Clara cells are sloughed from the bronchiolar surface. Remaining cells, consisting primarily of ciliated cells and nonciliated, naphthalene-resistant cells, undergo squamous metaplasia and spread to maintain the epithelial lining. Dynamic changes in cell shape are accompanied by the expression of a number of transcription factors and cellular markers that are also associated with the differentiation of respiratory epithelial cells during

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

“…Although we used the ciliated cell marker, b-Tubulin IV, which is expressed relatively late in the differentiation of ciliated cells, others have also previously shown that ciliated cells do not proliferate during repair of the naphthalene-injured bronchiolar epithelium using the ciliated cell marker, FoxJ1, which is expressed earlier than b-Tubulin IV in the differentiation of ciliated cells. 33 These findings are in accordance with a previous study, which utilized transgenic lineage tracing experiments in order to follow the fate of ciliated cells and provided strong evidence that ciliated cells do not proliferate or transdifferentiate into different epithelial cell types during repair of the naphthalene-injured mouse airway epithelium. 10 In addition, we found that many of the proliferating (ie, Ki-67-positive) cells detected within the regenerating airway epithelium were also dually positive for CC10/CCSP in both Elf3 þ / þ and Elf3À/À mice.…”

“…Regulation of gene expression is a very important aspect of many physiological and pathological processes, and there have only been few studies examining the role of various transcription factors in the pulmonary regenerative response to naphthalene-induced Clara cell damage. 4,6,9,33,40,41 In the present study, our findings suggest that Elf3 may play an important role in regulating airway epithelial repair kinetics, as the rate of bronchiolar epithelial cell proliferation and mitosis as well as Clara cell renewal was delayed in Elf3À/À mice after treatment with naphthalene. The absence of Elf3 appeared to have no observable effect on the extent of Clara cell injury in Elf3À/À mice, as there was no significant difference in the mean necrosis score between Elf3 þ / þ and Elf3À/À mice at any time point after naphthalene exposure.…”

“…30 In addition, we have previously shown reduced expression of the proinflammatory cytokine, interleukin-6 (IL-6), in the lungs of Elf3À/À mice when compared with their wild-type littermates after intranasal instillation of lipopolysaccharide, 31 suggesting a possible role for Elf3 in the regulation of IL-6 expression. Both TGF-b RII (see Zhao et al 32 ) and IL-6 (see Kida et al 33 ) have also been shown to be involved in the process of lung injury and repair.…”

The building blocks of mammalian lung development

“…Alternatively, interpreting the roles of signaling pathways in adult progenitors may require more subtle cell-type specific manipulation of signaling levels. It would be very surprising if there were no common regulatory mechanisms between the embryonic and adult lung progenitors, particularly during lung repair when the adult progenitors take on some of the morphogenetic functions performed by the embryonic cells (for example, migration, cell shape changes, cellsubstrate interaction changes, more rapid proliferation; see Kida et al, 2008). However, even if the regulation is different, the published lung embryonic progenitor experiments provide a framework for adult experimental design.…”

Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling

“…Although retinoid deficiency is a well-known cause of squamous metaplasia in cultured cells, the mechanisms by which different levels of retinoids and/or EGF-mediated signaling alter BC behavior and the fate of their immediate progeny remains poorly understood. Loss-of-function studies in the mouse have demonstrated that signaling of the cytokine IL-6 through gp130 and STAT3 is required for repair of the bronchiolar epithelium following Clara cell depletion (Kida et al, 2008). In the absence of gp130 or STAT3, reparative cells failed to generate a normal pseudostratified epithelium and, instead, areas of flattened epithelial cells persisted.…”