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Cathepsins in bleomycin-induced lung injury in rat

¹ Institute of Physiological Chemistry, ² Experimental Diabetology Group, ³ Institute of Medical Informatics and Biometrics and ⁴ Institute of Anatomy, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany

CORRESPONDENCE: R. Koslowski, Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Fiedlerstr 42, 01307, Dresden, Germany. Fax: 49 3514586305. E-mail: koslowsk@rcs.urz.tu-dresde.de

Keywords: bleomycin, cathepsins, cysteine proteinase inhibitors, lung fibrosis

Received: December 5, 2002
Accepted April 14, 2003

This study was supported by the Ministry of Education and Research, Bonn, Germany (FKZ 01ZZ5904).

Endogenous inhibitors tightly control the activity of proteinases in the extracellular space. Proteinase/antiproteinase imbalance may be caused by predominance of proteinases, resulting in severe tissue damage or abundance of proteinase inhibitors, leading to a shift in the balance of synthesis and degradation of extracellular matrix proteins and accumulation of these matrix components. Lung fibrosis is characterised by accumulation of fibrous matrix proteins in the alveolar interstitium.

The activity of cathepsin D and amounts of cathepsins D and B in bleomycin-injured rat lung tissue and alveolar macrophages were examined. In addition, the activities of cathepsins and cysteine proteinase inhibitors (CPIs) in bronchoalveolar lavage fluid (BALF) were determined.

No cathepsin but high CPI activity and large amounts of procathepsin B were detected in the BALF. In the alveolar lumen, the disturbed proteinase/antiproteinase balance for cysteine proteinases was clearly dominated by CPIs. In alveolar macrophages, the main source of increased cathepsin levels, large changes in cathepsin B and D content were observed during the inflammatory phase, corresponding to the occurrence of procathepsin B in BALF. With the end of the phase of tissue remodelling, imbalances in cathepsin and CPI activities were largely eliminated. Immunoblot data, revealing an increase in cathepsin D levels in myofibroblast-like cells compared to fibroblasts and in resting fibroblasts compared to proliferating cells, implicate this proteinase in the differentiation and conversion processes occurring at the beginning of the fibrotic phase of lung injury.

The results show that cathepsin amounts and activities are increased transiently in lung tissue during regeneration processes in bleomycin-induced lung injury. Imbalances of cathepsin and cysteine proteinase inhibitors activities are also a phenomenon of the phase of tissue remodelling initiated by lung injury.

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