Endothelial Adenosine Monophosphate-Activated Protein Kinase-alpha (AMPKα) Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension

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ESPR196
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Abstract: :

Background & Objective:

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of preterm infants, with pulmonary hypertension (PH) being a common life-threatening sequela of the disease. Further, BPD-associated PH lacks curative therapies. We showed that hyperoxia increases lung AMPKα activation in neonatal mice.  Whether this alteration is a compensatory or contributory phenomenon in hyperoxia-induced experimental BPD is unclear. Thus, we hypothesized that endothelial AMPKα-deficient neonatal mice would be more susceptible to hyperoxia-induced experimental BPD and PH than their wild-type littermates. 


Methods:

To determine the necessary role of endothelial AMPKα signaling in neonatal lung injury, we decreased endothelial AMPKα expression by breeding AMPKα-1flox/flox mice with Tie-Cre mice, and exposed endothelial AMPKα-1 sufficient or deficient mouse pups to air (21% FiO2) or hyperoxia (70% O2) from PND1 to PND14. Lung morphometric studies and echocardiographic (echo) studies were done on PND28 to determine the effects of AMPKα-1 gene and hyperoxia on alveolarization, pulmonary vascularization, pulmonary vascular remodeling, and PH. To determine the sufficient role of AMPK signaling in neonatal lung injury, C57BL6J wild-type mice were treated with daily i.p. injections of 1 mg/kg of the AMPK agonist, aminoimidazole-4-carboxamide ribonucleotide (AICAR), or the vehicle, while they were exposed to air or hyperoxia through PND1-PND14. Lung morphometric studies were done on PND14 to determine the effects of hyperoxia and AMPKα activation on alveolarization and pulmonary vascularization. 


Results:

Hyperoxia induced alveolar simplification, as evidenced by decreased radial alveolar counts and increased mean linear intercepts. Additionally, hyperoxia decreased lung angiogenesis. Further, hyperoxia induced pulmonary vascular remodeling and PH, as evidenced by increased medial wall thickness index of resistance lung vessels, decreased pulmonary acceleration time/ejection time ratio, and increased right ventricular systolic pressure. However, these effects of hyperoxia were augmented in the presence of endothelial AMPKα-1 deficiency. By contrast, AICAR-mediated AMPKα activation attenuated hyperoxia-induced lung injury. 


Conclusion:

These findings support our hypothesis that AMPKα signaling mitigates hyperoxia-induced experimental BPD and PH in neonatal mice. We propose that AMPKα is a potential therapeutic target for BPD infants with PH.


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