Previous data from experiments generated by our lab indicate a potential involvement of miR-154-3p and miR-154-5p in the context of lung development, or more precisely in the Fgf and Tgf-beta signaling cascades, which are known to be important for both, prenatal and postnatal lung development. It has been shown that both miRNAs are rather expressed in the embryonic lung than in the postnatal lung. We have decided to examine the role of miR-154-3p and miR-154-5p in the context of postnatal lung development and BPD. For these purposes we applied high oxygen concentrations using a BPD mouse model and used an inducible transgenic mouse line overexpressing both isomiRNAs in the murine airway epithelium, in order 1. to examine the temporo-spatial expression pattern of miR-154-3p and miR-154-5p in the model of hyperoxic lung injury, 2. to show the impact of airway epithelial-specific miR-154-3p (and miR-154-5p) overexpression on lung histology and gene expression in mutants compared to wildtype and under hyperoxia compared to normoxia, and 3. to describe the potential role of miR-154-3p in the BPD mouse model as a potentially protective factor.1. miR-154-3p appeared to be expressed in the proximal and distal airway epithelial cells. Applying hyperoxia to the murine lungs after birth enhanced miR-154-3p (and to a lesser extent miR-154-5p) expression in the distal airway epithelium, especially in AECII cells. 2. A deterioration of alveolar formation was found after hyperoxic lung injury, indicated by increased MLI (mean linear intercept of the alveoli) and septal wall thickness, beside a dynamic change of genetic expression levels for mRNAs, which are involved in Fgf and Tgf-beta signaling. Also AECI cells and alveolar myofibroblasts appeared to be affected. Overexpression of miR-154-3p and miR-154-5p leads to a similar alveolar phenotype and similar alterations of the genetic expression profile as previously seen after hyperoxia. 3. In isolated AECII cells, a more AECI specific transcription profile was found after miR-154-3p and miR-154-5p overexpression compared to controls, potentially indicating a transition from AECII to AECI cells upon miR-154-3p and miR-154-5p induction. Interestingly, this AECII-to-AECI transition has already been described in the context of hyperoxia in rats.As seen in the results of the current study hyperoxia is able to enhance miR-154-3p expression in the AECII cells and both, hyperoxia and miRNA overexpression, lead to similar injurious effects in the murine lung, it appears to be plausible that miR-154-3p might be a mediator of hyperoxic lung injury. In literature we were able to find that AECII-to-AECI transdifferentiation is activated upon hyperoxia. Our findings are possibly indicative for the initiation of the very same process after miR-154-3p and miR-154-5p overexpression.Thus, we hypothesize, that hyperoxia may induce an augmented AECII-to-AECI transdifferentiation in the murine lung epithelium by activating miR-154-3p.
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