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Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant
Chikara Otsubo1, Sivakama Bharathi1, Radha Uppala1
1From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
The Journal of Biological Chemistry
|August 5, 2015
Summary
Mitochondrial dysfunction causes lipid buildup in lungs, impairing surfactant function and reducing lung function. Inhibiting lipid synthesis improves lung health in a mouse model, suggesting a new therapeutic target for lung injury.
Area of Science:
- Mitochondrial biology
- Pulmonary medicine
- Lipid metabolism
Background:
- Mitochondrial energy metabolism is crucial for lung function, but its precise role remains unclear.
- Mice lacking long-chain acyl-CoA dehydrogenase (LCAD) exhibit reduced lung function.
- Dysfunctional fatty acid oxidation is linked to impaired lung health.
Purpose of the Study:
- To investigate the role of mitochondrial lipid metabolism in lung function.
- To determine the impact of long-chain acylcarnitines on pulmonary surfactant.
- To explore therapeutic strategies for lung dysfunction related to fatty acid oxidation defects.
Main Methods:
- Analysis of acylcarnitine accumulation in LCAD knockout mice lungs.
- In vitro studies on the effect of palmitoylcarnitine on pulmonary surfactant.
- Pharmacological intervention with mildronate in LCAD knockout mice.
- Detection of acylcarnitines in human bronchoalveolar lavage fluid.
Main Results:
- Long-chain acylcarnitines accumulate at the air-fluid interface in LCAD(-/-) lungs, exacerbated by stress or l-carnitine supplementation.
- Acylcarnitines co-localize with pulmonary surfactant and inhibit its surface tension-reducing properties.
- Mildronate treatment reduced acylcarnitines and improved lung function in LCAD(-/-) mice.
- Acylcarnitines are present in normal human lavage fluid.
Conclusions:
- Long-chain acylcarnitines disrupt pulmonary surfactant function, contributing to lung dysfunction.
- Dysfunctional fatty acid oxidation and subsequent acylcarnitine accumulation may be a risk factor for human lung injury.
- Targeting carnitine synthesis could be a therapeutic approach for lung conditions associated with impaired fatty acid oxidation.
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