Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Goetzman, Eric S.; Alcorn, John F.; Bharathi, Sivakama S.; Uppala, Radha; McHugh, Kevin J.; Kośmider, Beata; Chen, Rimei; Zuo, Yi Y.; Beck, Megan E.; McKinney, Richard W.; Skilling, Helen; Suhrie, Kristen; Karunanidhi, Anuradha; Yeasted, Renita; Otsubo, Chikara; Ellis, Bryon; Tyurina, Yulia Y.; Kagan, Valerian E.; Mallampalli, Rama K.; Vockley, Jerry

doi:10.1074/jbc.m113.540260

Cited by 50 publications

(55 citation statements)

References 69 publications

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“…MLE12 and ATII Cell Studies-Mouse lung epithelial cells (MLE12; American Type Culture Collection, Manassas, VA) were cultured as described (1). Primary human ATII cells were isolated and cultured as described (14).…”

Section: Animals-lcadmentioning

confidence: 99%

“…The human lungs, from de-identified organ donors whose lungs were not suitable for transplantation, were obtained through the International Institute for the Advancement of Medicine (Edison, NJ) and the Center for Organ Recovery (Pittsburgh, PA). Both MLE12 and primary ATII cells were grown in 24- (1).…”

Section: Animals-lcadmentioning

confidence: 99%

“…Palmitate Oxidation in Mouse Lung Tissues-Minced tissues were incubated in 350 l of PBS with 5 mM glucose, 1 mM carnitine, and 125 M final concentration of [ 3 H]palmitate-BSA at 37°C for 1 h as described (1). After homogenization using a Bullet Blender (Next Advance, Averill Park, NY), the aqueous layer was separated using chloroform/methanol extraction and counted.…”

Section: Animals-lcadmentioning

confidence: 99%

“…We previously observed high rates of FAO in mouse lung and showed that LCAD is the dominant long-chain ACAD enzyme in both murine and human lung (1). LCAD is specifically expressed in alveolar type II (ATII) pneumocytes (1). ATII cells, which only comprise 5% of the alveolar surface, fulfill several critical roles in the lung.…”

mentioning

confidence: 99%

“…They are rich in mitochondria suggesting a high demand for energy (3). LCAD knock-out mice have reduced lung FAO, reduced levels of active pulmonary surfactant, and altered breathing mechanics characterized by reduced pulmonary compliance, or in other words, stiffer, less elastic lungs (1).…”

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confidence: 99%

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Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant

Otsubo

Bharathi

Uppala

et al. 2015

Journal of Biological Chemistry

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Background: Mice with a defect in mitochondrial fatty acid oxidation (FAO) have reduced lung function but the mechanism is not known. Results: Acylcarnitines accumulate in FAO-deficient lungs and inhibit pulmonary surfactant. Conclusion: Acylcarnitines contribute to reduced lung function in FAO-deficient mice. Significance: Humans with FAO deficiencies may be at risk for lung injury due to acylcarnitine inhibition of pulmonary surfactant.

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Section: Animals-lcadmentioning

confidence: 99%

Section: Animals-lcadmentioning

confidence: 99%

Section: Animals-lcadmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant

Otsubo

Bharathi

Uppala

et al. 2015

Journal of Biological Chemistry

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Pervasive inflammatory activation in patients with deficiency in very‐long‐chain acyl‐coA dehydrogenase (VLCADD)

et al. 2021

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Objectives Very‐long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD) is a disorder of fatty acid oxidation. Symptoms are managed by dietary supplementation with medium‐chain fatty acids that bypass the metabolic block. However, patients remain vulnerable to hospitalisations because of rhabdomyolysis, suggesting pathologic processes other than energy deficit. Since rhabdomyolysis is a self‐destructive process that can signal inflammatory/immune cascades, we tested the hypothesis that inflammation is a physiologic dimension of VLCADD. Methods All subjects ( n = 18) underwent informed consent/assent. Plasma cytokine and cytometry analyses were performed. A prospective case analysis was carried out on a patient with recurrent hospitalisation. Health data were extracted from patient medical records. Results Patients showed systemic upregulation of nine inflammatory mediators during symptomatic and asymptomatic periods. There was also overall abundance of immune cells with high intracellular expression of IFNγ, IL‐6, MIP‐1β (CCL4) and TNFα, and the transcription factors p65‐NFκB and STAT1 linked to inflammatory pathways. A case analysis of a patient exhibited already elevated plasma cytokine levels during diagnosis in early infancy, evolving into sustained high systemic levels during recurrent rhabdomyolysis‐related hospitalisations. There were corresponding activated leukocytes, with higher intracellular stores of inflammatory molecules in monocytes compared to T cells. Exposure of monocytes to long‐chain free fatty acids recapitulated the cytokine signature of patients. Conclusion Pervasive plasma cytokine upregulation and pre‐activated immune cells indicate chronic inflammatory state in VLCADD. Thus, there is rationale for practical implementation of clinical assessment of inflammation and/or translational testing, or adoption, of anti‐inflammatory intervention(s) for personalised disease management.

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AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

Zieger

Keeler

Flotte

et al. 2019

J of Inher Metab Disea

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Very‐long chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD−/−), and (2) to determine if AAV9‐mediated gene therapy improves respiratory function. For the first aim, VLCAD−/− and wild‐type (WT) mice underwent an exercise/fast “stress protocol” and awake spontaneous breathing was evaluated using whole‐body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO2: 0.21; FiCO2: 0.07; nitrogen balance). During hypercapnia, VLCAD −/− mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD −/− animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9‐VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno‐staining with anti‐human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD−/− mice and a single injection with AAV9‐VLCAD gene therapy ameliorates breathing.

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Long-chain Acyl-CoA Dehydrogenase Deficiency as a Cause of Pulmonary Surfactant Dysfunction

Cited by 50 publications

References 69 publications

Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant

Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant

Pervasive inflammatory activation in patients with deficiency in very‐long‐chain acyl‐coA dehydrogenase (VLCADD)

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

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