Woischnik, Markus and Sparr, Christiane and Kern, Suncana and Thurm, Tobias and Hector, Andreas and Hartl, Dominik and Liebisch, Gerhard and Mulugeta, Surafel and Beers, Michael F. and Schmitz, Gerd and Griese, Matthias (2010) A non-BRICHOS surfactant protein c mutation disrupts epithelial cell function and intercellular signaling. BMC CELL BIOLOGY, 11: 88. ISSN 1471-2121,
Full text not available from this repository. (Request a copy)Abstract
Background: Heterozygous 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-C-I73T expression. Results: To address this, we stably expressed SP-C-I73T 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-C-I73T 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-C-I73T 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-C-I73T 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-C-I73T on neighboring cells in the alveolar space. Conclusion: We 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TANDEM MASS-SPECTROMETRY; INTERSTITIAL LUNG-DISEASE; PULMONARY ALVEOLAR PROTEINOSIS; HIGH-THROUGHPUT QUANTIFICATION; ENDOPLASMIC-RETICULUM STRESS; II CELLS; SP-B; CHILDREN; CHEMOKINES; EXPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Jul 2020 10:53 |
| Last Modified: | 06 Jul 2020 10:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/23859 |
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