%0 Journal Article
%T The surfactant protein C mutation A116D alters cellular processing, stress tolerance, surfactant lipid composition, and immune cell activation
%A Ralf Zarbock
%A Markus Woischnik
%A Christiane Sparr
%A Tobias Thurm
%A Sun£¿ana Kern
%A Eva Kaltenborn
%A Andreas Hector
%A Dominik Hartl
%A Gerhard Liebisch
%A Gerd Schmitz
%A Matthias Griese
%J BMC Pulmonary Medicine
%D 2012
%I BioMed Central
%R 10.1186/1471-2466-12-15
%X SP-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.Stable 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.We 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.Pulmonary surfactant is a phospholipid/protein mixture secreted to the alveolar surface by alveolar type 2 (AT2) cells [1]. It reduces surface tension and prevents alveolar collapse at the end of expiration [2]. A normal composition and homeostasis of pulmonary surfactant is critical for its surface-tension-reducing properties and gas exchange in the alveoles of the lung. Surfactant protein C (SP-C) is a hydrophobic, lung-specific protein that coisolat
%U http://www.biomedcentral.com/1471-2466/12/15