A non-BRICHOS surfactant protein c mutation disrupts epithelial cell function and intercellular signaling

BMC Cell Biology

Research Article

Markus Woischnik¹  Matthias Griese¹  Tobias Thurm¹  Sunčana Kern¹  Dominik Hartl¹  Christiane Sparr¹  Andreas Hector¹  Gerd Schmitz²  Gerhard Liebisch²  Surafel Mulugeta³  Michael F Beers³ 

[1] Department of Pneumology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Lindwurmstr. 4, 80337, Munich, Germany;Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany;Pulmonary and Critical Care Division, University of Pennsylvania School of Medicine, 380 S. University Avenue, 19104, Philadelphia, PA, USA;

关键词: Interstitial Lung Disease;    Hydroxychloroquine;    Lamellar Body;    I73T Mutation;    Cytoprotective Mechanism;   

DOI  :  10.1186/1471-2121-11-88

 received in 2010-05-07, accepted in 2010-11-20,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundHeterozygous mutations of SFTPC, the gene encoding surfactant protein C (SP-C), cause sporadic and familial interstitial lung disease (ILD) in children and adults. The most frequent SFTPC mutation in ILD patients leads to a threonine for isoleucine substitution at position 73 (I73T) of the SP-C preprotein (proSP-C), however little is known about the cellular consequences of SP-CI73T expression.ResultsTo address this, we stably expressed SP-CI73T in cultured MLE-12 alveolar epithelial cells. This resulted in increased intracellular accumulation of proSP-C processing intermediates, which matched proSP-C species recovered in bronchial lavage fluid from patients with this mutation. Exposure of SP-CI73T cells to drugs currently used empirically in ILD therapy, cyclophosphamide, azathioprine, hydroxychloroquine or methylprednisolone, enhanced expression of the chaperones HSP90, HSP70, calreticulin and calnexin. SP-CI73T mutants had decreased intracellular phosphatidylcholine level (PC) and increased lyso-PC level without appreciable changes of other phospholipids. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-CI73T cells secreted into the medium soluble factors that modulated surface expression of CCR2 or CXCR1 receptors on CD4+ lymphocytes and neutrophils, suggesting a direct paracrine influence of SP-CI73T on neighboring cells in the alveolar space.ConclusionWe show that I73T mutation leads to impaired processing of proSP-C in alveolar type II cells, alters their stress tolerance and surfactant lipid composition, and activates cells of the immune system. In addition, we show that some of the mentioned cellular aspects behind the disease can be modulated by application of pharmaceutical drugs commonly applied in the ILD therapy.

【 授权许可】

Unknown   
© Woischnik et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.