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Gene targeting of the cysteine peptidase cathepsin H impairs lung surfactant in mice

 
: Bühling, F.; Kouadio, M.; Chwieralski, C.E.; Kern, U.; Hohlfeld, J.M.; Klemm, N.; Friedrichs, N.; Roth, W.; Deussing, J.M.; Peters, C.; Reinheckel, T.

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PLoS one. Online journal 6 (2011), No.10, Art. e26247
http://www.pubmedcentral.nih.gov/tocrender.fcgi?action=archive&journal=440
ISSN: 1932-6203
English
Journal Article, Electronic Publication
Fraunhofer ITEM ()

Abstract
Background: The 11 human cysteine cathepsins are proteases mainly located in the endolysosomal compartment of all cells and within the exocytosis pathways of some secretory cell types. Cathepsin H (Ctsh) has amino- and endopeptidase activities. In vitro studies have demonstrated Ctsh involvement in the processing and secretion of the pulmonary surfactant protein B (SP-B). Furthermore, Ctsh is highly expressed in the secretory organelles of alveolar type II pneumocytes where the surfactant proteins are processed. Methodology/Principal Findings: Hence, we generated Ctsh null mice by gene targeting in embryonic stem cells to investigate the role of this protease in surfactant processing in vivo. The targeting construct contains a ß-galactosidase (lacZ) reporter enabling the visualisation of Ctsh expression sites. Ctsh-deficiency was verified by northern blot, western blot, and measurement of the Ctsh aminopeptidase activity. Ctsh-/- mice show no gross phenotype and their d evelopment is normal without growth retardation. Broncho-alveolar lavage (BAL) from Ctsh-/- mice contained lower levels of SP-B indicating reduced SP-B secretion. The BAL phospholipid concentration was not different in Ctsh+/+ and Ctsh-/- mice, but measurement of surface tension by pulsating bubble surfactometry revealed an impairment of the tension reducing function of lung surfactant of Ctsh-/- mice. Conclusions/Significance: We conclude that cathepsin H is involved in the SP-B production and reduced SP-B levels impair the physical properties of the lung surfactant. However, Ctsh defiency does not reproduce the severe phenotype of SP-B deficient mice. Hence, other proteases of the secretory pathway of type II pneumocytes, i.e. cathepsins C or E, are still able to produce surfactant of sufficient quality in absence of Ctsh.

: http://publica.fraunhofer.de/documents/N-189055.html