Matthias Griese1, Francesco Bonella2, Ulrich Costabel2, Jacques de Blic3, Nguyen-Binh Tran1, Gerhard Liebisch4. 1. German Center for Lung Research, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany. 2. Center for Interstitial and Rare Lung Diseases, Department of Pneumology, Ruhrlandklinik University Hospital, Essen, Germany. 3. Hôpital Necker-Enfants Malades, Paris, France; and. 4. Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany.
Abstract
Rationale: Pulmonary alveolar proteinosis (PAP) is characterized by filling of the alveolar spaces by lipoprotein-rich material of ill-defined composition, and is caused by molecularly different and often rare diseases that occur from birth to old age. Objectives: To perform a quantitative lipidomic analysis of lipids and the surfactant proteins A, B, and C in lavage fluids from patients with proteinosis of different causes in comparison with healthy control subjects. Methods: During the last two decades, we have collected BAL samples from patients with PAP due to autoantibodies against granulocyte-macrophage colony-stimulating factor; genetic mutations in CSF2RA (colony-stimulating factor 2 receptor α-subunit), MARS (methionyl aminoacyl-tRNA synthetase), FARSB (phenylalanine-tRNA synthetase, β-subunit), and NPC2 (Niemann-Pick disease type C2); and secondary to myeloid leukemia. Their lipid composition was quantified.Measurements and Main Results: Free cholesterol was largely increased by 60-fold and cholesteryl esters were increased by 24-fold. There was an excessive, more than 130-fold increase in ceramide and other sphingolipids. In particular, the long-chain ceramides d18:1/20:0 and d18:1/24:0 were elevated and likely contributed to the proapoptotic environment observed in PAP. Cellular debris lipids such as phosphatidylethanolamine and phosphatidylserine were only moderately increased, by four- to sevenfold. The surfactant lipid class phosphatidylcholine expanded 17-fold, lysophosphatidylcholine expanded 54-fold, and the surfactant proteins A, B, and C expanded 144-, 4-, and 17-fold, respectively. These changes did not differ among the various diseases that cause PAP.Conclusions: This insight into the alveolar lipidome may provide monitoring tools and lead to new therapeutic strategies for PAP.
Rationale: Pulmonary alveolar proteinosis (PAP) is characterized by filling of the alveolar spaces by lipoprotein-rich material of ill-defined composition, and is caused by molecularly different and often rare diseases that occur from birth to old age. Objectives: To perform a quantitative lipidomic analysis of lipids and the surfactant proteins A, B, and C in lavage fluids from patients with proteinosis of different causes in comparison with healthy control subjects. Methods: During the last two decades, we have collected BAL samples from patients with PAP due to autoantibodies against granulocyte-macrophage colony-stimulating factor; genetic mutations in CSF2RA (colony-stimulating factor 2 receptor α-subunit), MARS (methionyl aminoacyl-tRNA synthetase), FARSB (phenylalanine-tRNA synthetase, β-subunit), and NPC2 (Niemann-Pick disease type C2); and secondary to myeloid leukemia. Their lipid composition was quantified.Measurements and Main Results: Free cholesterol was largely increased by 60-fold and cholesteryl esters were increased by 24-fold. There was an excessive, more than 130-fold increase in ceramide and other sphingolipids. In particular, the long-chain ceramides d18:1/20:0 and d18:1/24:0 were elevated and likely contributed to the proapoptotic environment observed in PAP. Cellular debris lipids such as phosphatidylethanolamine and phosphatidylserine were only moderately increased, by four- to sevenfold. The surfactant lipid class phosphatidylcholine expanded 17-fold, lysophosphatidylcholine expanded 54-fold, and the surfactant proteins A, B, and C expanded 144-, 4-, and 17-fold, respectively. These changes did not differ among the various diseases that cause PAP.Conclusions: This insight into the alveolar lipidome may provide monitoring tools and lead to new therapeutic strategies for PAP.
Authors: Seunghyi Kook; Ping Wang; Shufang Meng; Christopher S Jetter; Jennifer M S Sucre; John T Benjamin; Jason J Gokey; Hayley A Hanby; Alexa Jaume; Laura Goetzl; Michael S Marks; Susan H Guttentag Journal: Proc Natl Acad Sci U S A Date: 2021-05-18 Impact factor: 12.779
Authors: Christina W Agudelo; Britta K Kumley; Estela Area-Gomez; Yimeng Xu; Abdoulaye J Dabo; Patrick Geraghty; Michael Campos; Robert Foronjy; Itsaso Garcia-Arcos Journal: PLoS One Date: 2020-02-06 Impact factor: 3.240