Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 314, Issue 5, Pages L860-L870Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00365.2017
Keywords
acute lung injury; AKAP121; Akap1; autophagy; hyperoxia; mitochondria; oxygen treatment
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Funding
- American Heart Association (AHA) National Scientist Development Grant [09SDG2260957]
- National Heart, Lung, and Blood Institute Grant [R01-HL-105932]
- Joy McCann Culverhouse Endowment
- AHA [14POST18200004]
- AHA National Scientist Development Grant [17SDG32780002]
- University Grants Commission, Raman Postdoctoral Fellowship Award in USA, New Delhi, India [F-90/2016 (IC)]
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Critically ill patients are commonly treated with high levels of oxygen, hyperoxia, for prolonged periods of time. Unfortunately, extended exposure to hyperoxia can exacerbate respiratory failure and lead to a high mortality rate. Mitochondrial A-kinase anchoring protein (Akap) has been shown to regulate mitochondrial function. It has been reported that, under hypoxic conditions, Akap121 undergoes proteolytic degradation and promotes cardiac injury. However, the role of Akap1 in hyperoxia-induced acute lung injury (ALI) is largely unknown. To address this gap in our understanding of Akap1, we exposed wild-type (wt) and Akap1(-/-) mice to 100% oxygen for 48 h, a time point associated with lung damage in the murine model of ALI. We found that under hyperoxia, Akap1(-/-) mice display increased levels of proinflammatory cytokines, immune cell infiltration, and protein leakage in lungs, as well as increased alveolar capillary permeability compared with wt controls. Further analysis revealed that Akap1 deletion enhances lung NF-kappa B p65 activity as assessed by immunoblotting and DNA-binding assay and mitochondrial autophagy-related markers, PINK1 and Parkin. Ultrastructural analysis using electron microscopy revealed that Akap1 deletion was associated with remarkably aberrant mitochondria and lamellar bodies in type II alveolar epithelial cells. Taken together, these results demonstrate that Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice.
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