The surfactant protein C mutation A116D alters cellular processing, stress tolerance, surfactant lipid composition, and immune cell activation

BMC Pulmonary Medicine

Research Article

Markus Woischnik¹  Matthias Griese¹  Tobias Thurm¹  Sunčana Kern¹  Dominik Hartl¹  Eva Kaltenborn¹  Ralf Zarbock¹  Christiane Sparr¹  Andreas Hector¹  Gerd Schmitz²  Gerhard Liebisch² 

[1] Childrens' Hospital of the Ludwig-Maximilians-University, Lindwurmstr. 4, 80337, Munich, Germany;University of Regensburg, Institute for Clinical Chemistry and Laboratory Medicine, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany;

关键词: Interstitial Lung Disease;    Hydroxychloroquine;    Alveolar Epithelial Cell;    Lamellar Body;    Lung Surfactant;   

DOI  :  10.1186/1471-2466-12-15

 received in 2011-04-20, accepted in 2012-03-29,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundSurfactant protein C (SP-C) is important for the function of pulmonary surfactant. Heterozygous mutations in SFTPC, the gene encoding SP-C, cause sporadic and familial interstitial lung disease (ILD) in children and adults. Mutations mapping to the BRICHOS domain located within the SP-C proprotein result in perinuclear aggregation of the proprotein. In this study, we investigated the effects of the mutation A116D in the BRICHOS domain of SP-C on cellular homeostasis. We also evaluated the ability of drugs currently used in ILD therapy to counteract these effects.MethodsSP-CA116D was expressed in MLE-12 alveolar epithelial cells. We assessed in vitro the consequences for cellular homeostasis, immune response and effects of azathioprine, hydroxychloroquine, methylprednisolone and cyclophosphamide.ResultsStable expression of SP-CA116D in MLE-12 alveolar epithelial cells resulted in increased intracellular accumulation of proSP-C processing intermediates. SP-CA116D expression further led to reduced cell viability and increased levels of the chaperones Hsp90, Hsp70, calreticulin and calnexin. Lipid analysis revealed decreased intracellular levels of phosphatidylcholine (PC) and increased lyso-PC levels. Treatment with methylprednisolone or hydroxychloroquine partially restored these lipid alterations. Furthermore, SP-CA116D cells secreted soluble factors into the medium that modulated surface expression of CCR2 or CXCR1 receptors on CD4+ lymphocytes and neutrophils, suggesting a direct paracrine effect of SP-CA116D on neighboring cells in the alveolar space.ConclusionsWe show that the A116D mutation leads to impaired processing of proSP-C in alveolar epithelial cells, alters cell viability and lipid composition, and also activates cells of the immune system. In addition, we show that some of the effects of the mutation on cellular homeostasis can be antagonized by application of pharmaceuticals commonly applied in ILD therapy. Our findings shed new light on the pathomechanisms underlying SP-C deficiency associated ILD and provide insight into the mechanisms by which drugs currently used in ILD therapy act.

【 授权许可】

Unknown   
© Zarbock et al; licensee BioMed Central Ltd. 2012. 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.