Abstract
The lung alveoli slowly self-renew pneumocytes, but their facultative regeneration capacity is rapidly efficient after an injury, so fibrosis infrequently occurs. We recently observed Keratin 14 (KRT14) expression during diffuse alveolar damage (DAD), but not in controls. We wonder if KRT14 may be a marker of pneumocyte transition from quiescence to regeneration. Quantitative PCR and Western blot analyses highlighted the presence of KRT14 (mRNA and protein) only in human lung samples with DAD or interstitial lung disease (ILD). In the exponentially growing cell lines A549 and H441, the mRNA and protein levels of KRT14 peaked at day one after cell seeding and decreased at day two, opposite to what observed for the proliferation marker E2F1. The inverse relation of KRT14 versus E2F1 expression holds true also for other proliferative markers, such as cyclin E1 and cyclin D1. Of interest, we also found that E2F1 silencing caused cell cycle arrest and increased KRT14 expression, whilst E2F1 stimulation induced cell cycle progression and decreased KRT14. KRT14 also increased in proliferative pneumocytes (HPAEpiC) just before transdifferentiation. Overall, our results suggest that KRT14 is a viable biomarker of pneumocyte activation, and repair/regeneration. The involvement of KRT14 in regenerative process may suggest a novel pharmaceutical target to accelerate lung repair.
Highlights
The lung has a facultative regeneration ability: its reparative capacity is highly efficient, but the differentiated cells re-enter the cell cycle only when needed [1]
Considering that the magnitude of the ΔCt values is inversely proportional to the expression level, these results confirmed that Keratin 14 (KRT14) is actively expressed mainly in diffuse alveolar damage (DAD) patients, even if some patient with interstitial lung disease (ILD) may express it at low level
We have previously showed that Keratin 14 (KRT14) is overexpressed in human lung alveoli during diffuse alveolar damage (DAD), while normal lung do not [3]
Summary
The lung has a facultative regeneration ability: its reparative capacity is highly efficient, but the differentiated cells re-enter the cell cycle only when needed [1]. Type 2 pneumocytes proliferate and transdifferentiate into alveolar epithelial cells type 1 (pneumocytes type 1). This process is not usually reported by pathologists for the lack of effective biomarkers. In a recent immunohistochemical study in human lung biopsy/autopsy samples, we showed that lung alveoli express keratin 14 (KRT14) in DAD/ARDS [3]. This factor was never found to be expressed in normal lung during progenitor cell quiescence. We assessed KRT14 mRNA expression and protein levels in human fresh lung samples from patients/controls, and in primary isolated pneumocytes and cultured human pneumocyte cell lines under different experimental conditions
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