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

Naphthalene exposure kills lung airway epithelial (Clara) cells, but is rapidly followed by Clara cell reconstitution coincident with proliferation of pulmonary neuroendocrine cells (PNEC). Although a role for mature PNEC in the reconstitution process has been excluded, the reconstituting progenitor cells have been suggested to enter a transient neuroendocrine (NE) differentiation phase before differentiating to Clara cells. Furthermore, these progenitors were suggested to be the target population for transformation to a NE tumor; small cell lung cancer (SCLC). Although the NE phenotype is central to SCLC oncogenesis, the relevance of NE differentiation to post naphthalene reconstitution remains to be determined. The Growth factor independent-1 (Gfi1) transcription factor is expressed in SCLC and is required for the NE differentiation of PNEC. Gfi1(-/-) mice display a 70% reduction in airway cells that express NE markers, and cells that stain for NE markers show weak expression of some markers. Therefore, to determine the relevance of the NE phenotype to post-naphthalene reconstitution, we examined post-naphthalene reconstitution in Gfi1(-/-) mice. Our analyses indicate that the post-naphthalene regeneration process includes both airway epithelial proliferation and apoptosis. Gfi1 deletion lowered both airway epithelial proliferation and apoptosis; however, the post-naphthalene rate of increase in growth and apoptosis was not significantly different between Gfi1(-/-) mice and wild-type littermates. Moreover, the timing and extent of CC10+ cell regeneration was unaffected by Gfi1 deletion. These data suggest that neither Gfi1 nor the NE phenotype play a dominant role in the regeneration process. However, the few Gfi1(-/-) cells capable of NE differentiation show a significant reduction in post-naphthalene proliferation. The modest proliferation seen in Gfi1(-/-) NE cells is consistent with the previously proposed role for Gfi1 in controlling neuroendocrine cancer growth.