Cathepsins in bleomycin-induced lung injury in rat

Abstract

Cathepsins in bleomycin-induced lung injury in rat. R. Koslowski, K. Knoch, E. Kuhlisch, D. Seidel, M. Kasper. #ERS Journals Ltd 2003. ABSTRACT: 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.

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

“…41 This is indeed supported by our study, which demonstrates the upregulation of CB in ILD-PM (Figures 2 and 3). As a ubiquitous endopeptidase and ectodipeptidase, CB has a clear association with neutrophils and several inflammation markers especially TNF-a.…”

“…46 Macrophages represent the predominant cell type, contributing to elevated CB levels, but other cell types also participate. 41 CD8 þ T-cell responses are a critical arm of the immune response to respiratory virus infection and may have a role in the pathogenesis of ILD. The effect of TNF-a expressed by CD8 þ T cells is mediated not exclusively by cytotoxicity, but also through the activation of alveolar target cells and their expression of inflammatory mediators.…”

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

“…Collagen deposition has also been reported 14 days after BLM administration in rats (21,31). In the present study, an increase in parenchymal signal intensity in areas devoid of apparent edema-like signals was observed at week 2 after BLM exposure, from assessments in the right transversal and right coronal regions of MRI images of the lung.…”

“…The novelty of the current research is the demonstration that conventional proton MRI applied under conditions of spontaneous breathing can detect lung injury following BLM treatment. Intratracheal administration of BLM at a dose conventionally used in other, nonimaging studies (1,20,21), resulted in pronounced inflammation and edema leading to moderate fibrosis in the right lobes and severe fibrosis in the left lobe, processes that were accompanied by signal changes detected by proton MRI. We have shown a pronounced increase in MRI fluid signal volume one week following BLM instillation that correlated strongly with increased BAL cell count and MPO and EPO activities as well as with histology, denoting severe cellular infiltration and edema.…”

“…Evidence from the literature suggests that the major fibroproliferative phase induced by BLM in rats and mice occurs within the first week following its administration and that this process coexists with inflammation (14,21,29,30). Histological examinations of rats (1,26) have shown an elevated presence of inflammatory cells and cytokines at four days and a further increment at six days after BLM-treatment, as well as protein-rich granular-textured edema in the alveolar spaces.…”