title: Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction.
abstract: Long-chain acyl-CoA dehydrogenase (LCAD) is a mitochondrial fatty acid oxidation enzyme whose expression in humans is low or absent in organs known to utilize fatty acids for energy such as heart, muscle, and liver. This study demonstrates localization of LCAD to human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. The physiological role of LCAD and the fatty acid oxidation pathway in lung was subsequently studied using LCAD knock-out mice. Lung fatty acid oxidation was reduced in LCAD(-/-) mice. LCAD(-/-) mice demonstrated reduced pulmonary compliance, but histological examination of lung tissue revealed no obvious signs of inflammation or pathology. The changes in lung mechanics were found to be due to pulmonary surfactant dysfunction. Large aggregate surfactant isolated from LCAD(-/-) mouse lavage fluid had significantly reduced phospholipid content as well as alterations in the acyl chain composition of phosphatidylcholine and phosphatidylglycerol. LCAD(-/-) surfactant demonstrated functional abnormalities when subjected to dynamic compression-expansion cycling on a constrained drop surfactometer. Serum albumin, which has been shown to degrade and inactivate pulmonary surfactant, was significantly increased in LCAD(-/-) lavage fluid, suggesting increased epithelial permeability. Finally, we identified two cases of sudden unexplained infant death where no lung LCAD antigen was detectable. Both infants were homozygous for an amino acid changing polymorphism (K333Q). These findings for the first time identify the fatty acid oxidation pathway and LCAD in particular as factors contributing to the pathophysiology of pulmonary disease.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213. Electronic address: eric.goetzman@chp.edu.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Goetzman
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Sivakama S
authors.initials: SS
authors.lastname: Bharathi
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Radha
authors.initials: R
authors.lastname: Uppala
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McHugh
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado 80206.
authors.forename: Beata
authors.initials: B
authors.lastname: Kosmider
authors.affiliation: Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822.
authors.forename: Rimei
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822.
authors.forename: Yi Y
authors.initials: YY
authors.lastname: Zuo
authors.affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Beck
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Richard W
authors.initials: RW
authors.lastname: McKinney
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Helen
authors.initials: H
authors.lastname: Skilling
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Suhrie
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Karunanidhi
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Renita
authors.initials: R
authors.lastname: Yeasted
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Chikara
authors.initials: C
authors.lastname: Otsubo
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Bryon
authors.initials: B
authors.lastname: Ellis
authors.affiliation: Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
authors.forename: Yulia Y
authors.initials: YY
authors.lastname: Tyurina
authors.affiliation: Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Medical Specialty Service Line, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15213.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mallampalli
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000378:metabolism; D000328:Adult; D000818:Animals; D001980:Bronchi / Q000378:metabolism; D045744:Cell Line, Tumor; D003065:Coenzyme A / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010100:Oxygen / Q000378:metabolism; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D011110:Polymorphism, Genetic; D011650:Pulmonary Alveoli / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D011663:Pulmonary Surfactants; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D010100:Oxygen; D003065:Coenzyme A
keywords: Acyl-CoA Dehydrogenase; Fatty Acid Oxidation; Genetic Diseases; Lung; Mitochondrial Metabolism; Pulmonary Surfactant