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AMPK-driven Macrophage Responses are Autophagy-dependent in Experimental Bronchopulmonary Dysplasia

The pathogenesis of bronchopulmonary dysplasia (BPD) remains incompletely understood. Recent studies suggest insufficient adenosine monophosphate-activated protein kinase (AMPK) activation as a potential cause of impaired autophagy in rodent and non-human primate (NHP) models of BPD. Impaired autophagy is associated with enhanced inflammatory signaling in alveolar macrophages (AM) and increased severity of murine BPD induced by neonatal hyperoxia exposure. The goal of this study was to determine the role of autophagy and AMPK activation in macrophage responses in murine BPD. C57BL/6J mice were exposed to neonatal hyperoxia starting on postnatal day (P)1 and treated with the AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) between P3 and P6. Mice were euthanized on P7 and markers of AMPK activation and autophagy were assessed by immunoblotting. Alveolarization was assessed using radial alveolar counts, mean linear intercept measurements, and quantification of alveolar septal myofibroblasts. Relative mRNA expression of M1-like and M2-like genes was assessed in AMs isolated from bronchoalveolar lavage (BAL) fluid from WT, LysMCre--Becn1fl/fl and LysMCre+-Becn1fl/fl mice following neonatal hyperoxia exposure. AICAR treatment resulted in AMPK activation and induction of autophagic activity in whole lung and BAL cell lysates and attenuated hyperoxia-induced alveolar simplification in neonatal lungs. AICAR-treated control but not Beclin1-deficient AMs demonstrated significantly decreased expression of M1-like markers and significantly increased expression of M2-like markers. In conclusion, pharmacologic activation of AMPK by AICAR resulted in induction of autophagy and played a protective role, at least in part, through attenuation of pro-inflammatory signaling in AMs via autophagy-dependent mechanisms in a murine model of BPD.

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S1802 AICAR (Acadesine) AICAR (Acadesine, NSC105823, AICA Riboside), an AMPK activator, results in accumulation of ZMP, which mimics the stimulating effect of AMP on AMPK and AMPK kinase. AICAR (Acadesine) induces mitophagy. Phase 3.

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AMPK Mitophagy