Therapeutic effects of cysteine protease inhibition in allergic lung inflammation: Inhibition of allergen-specific T lymphocyte migration

Layton, Guy T.; Harris, S.; Bland, F.A.; Lee, S.R.; Fearn, Sarah; Kaleta, J.; Wood, M.L.; Bond, Allen; Ward, George W.

doi:10.1007/pl00000262

Cited by 13 publications

(12 citation statements)

References 42 publications

(33 reference statements)

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“…Since previously published reports address that CB mediates human lung epithelial cell death stimulated by lipopolysaccharides (Tang et al, 2006) or human lung endothelial cell death in allergic lung inflammation (Layton et al, 2001) or cell death in tumor cell lines (Bröker et al, 2004), our investigation implicates that CB may play a dominant role in executing FATIIC death under the condition of hyperoxia as well.…”

Section: Discussionmentioning

confidence: 80%

“…In particular, the role of CB in inducing cell death has been revealed in other cell lines and conditions (Layton et al, 2001;Bröker et al, 2004;Tang et al, 2006). Although oxygen radical species generated by hyperoxia is a stimulus for lysosomal permeabilization, whether FATIIC death is mediated by the non-caspase protease, CB, has never been explored yet.…”

Section: Introductionmentioning

confidence: 99%

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Cathepsin B is activated as an executive protease in fetal rat alveolar type II cells exposed to hyperoxia

Lee

Kim

2011

Exp Mol Med

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Alveolar type II cells are main target of hyperoxia-induced lung injury. The authors investigated whether lysosomal protease, cathepsin B (CB), is activated in fetal alveolar type II cells in the transitional period from the canalicular to saccular stages during 65%-hyperoxia and whether CB is related to fetal alveolar type II cell (FATIIC) death secondary to hyperoxia. FATIICs were isolated from embryonic day 19 rats and exposed to 65%-oxygen for 24 h and 36 h. The cells exposed to room air were used as controls. Cell cytotoxicity was assessed by lactate dehydrogenase-release and flow cytometry, and apoptosis was analyzed by TUNEL assay and flow cytometry. CB activity was assessed by colorimetric assay, qRT-PCR and western blots. 65%-hyperoxia induced FATIIC death via necrosis and apoptosis. Interestingly, caspase-3 activities were not enhanced in FATIICs during 65%-hyperoxia, whereas CB activities were greatly increased during 65%-hyperoxia in a time-dependent manner, and similar findings were observed with qRT-PCR and western blots. In addition, the preincubation of CB inhibitor prior to 65%-hyperoxia reduced FATIIC death significantly. Our studies suggest that CB activation secondary to hyperoxia might have a relevant role in executing the cell death program in FATIICs during the acute stage of 65%-hyperoxia.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Cathepsin B is activated as an executive protease in fetal rat alveolar type II cells exposed to hyperoxia

Lee

Kim

2011

Exp Mol Med

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“…Many autophagy inhibitors act on post-sequestration steps and agents, such as bafilomycin A1, that blocks autophagy activity are known to cause accumulation of autophagosomes [31]. Chloroquine is a compound that elevates lysosomal pH, and E64d is an effective inhibitor of lysosomal enzymes [32]. After 3-NP treatment, more LAMP2-positive vacuoles were observed.…”

Section: Resultsmentioning

confidence: 99%

DRAM1 Regulates Autophagy Flux through Lysosomes

Zhang

et al. 2013

PLoS ONE

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We have previously reported that the mitochondria inhibitor 3-nitropropionic acid (3-NP), induces the expression of DNA damage-regulated autophagy modulator1 (DRAM1) and activation of autophagy in rat striatum. Although the role of DRAM1 in autophagy has been previously characterized, the detailed mechanism by which DRAM1 regulates autophagy activity has not been fully understood. The present study investigated the role of DRAM1 in regulating autophagy flux. In A549 cells expressing wilt-type TP53, 3-NP increased the protein levels of DRAM1 and LC3-II, whereas decreased the levels of SQSTM1 (sequestosome 1). The increase in LC3-II and decrease in SQSTM1 were blocked by the autophagy inhibitor 3-methyl-adenine. Lack of TP53 or knock-down of TP53 in cells impaired the induction of DRAM1. Knock-down of DRAM1 with siRNA significantly reduced 3-NP-induced upregulation of LC3-II and downregulation of SQSTM1, indicating DRAM1 contributes to autophagy activation. Knock-down of DRAM1 robustly decreased rate of disappearance of induced autophagosomes, increased RFP-LC3 fluorescence dots and decreased the decline of LC3-II after withdraw of rapamycin, indicating DRAM1 promotes autophagy flux. DRAM1 siRNA inhibited lysosomal V-ATPase and acidification of lysosomes. As a result, DRAM1 siRNA reduced activation of lysosomal cathepsin D. Similar to DRAM1 siRNA, lysosomal inhibitors E64d and chloroquine also inhibited clearance of autophagosomes and activation of lysosomal cathapsin D after 3-NP treatment. These data suggest that DRAM1 plays important roles in autophagy activation induced by mitochondria dysfunction. DRAM1 affects autophagy through argument of lysosomal acidification, fusion of lysosomes with autophagosomes and clearance of autophagosomes.

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“…KNT1 and KNT2, inhibitors of cysteine proteinases, have been shown to participate in inflammatory processes. For example, the allergic lung inflammation of human asthma in a mouse model can be prevented by using the extracellular cysteine protease inhibitor E64 (22). KNT also played a role in immunosenescence through inhibition of extracellular signal-regulated kinase (ERK)-dependent T cell proliferation (23).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling of a Respiratory Syncytial Virus-Infected Rat Pneumonia Model

Wang

Zhang

Gao³

et al. 2016

Jpn J Infect Dis

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SUMMARY:Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in pediatric patients. Our goal was to obtain a detailed understanding of the molecular pathogenesis of RSV infections by studying the protein expression profiles in rats with pneumonia. First, we successfully established a pneumonia rat model by intranasally injecting RSV. The differentially expressed proteins in lung tissues of RSV-infected rats compared with those of the controls were analyzed by using 2-dimensional fluorescence difference gel electrophoresis and MALDI-TOF/TOF MS. In total. 41 differentially expressed protein spots representing 20 unique proteins were successfully identified. Classification analysis showed that most of these proteins are implicated in metabolic processes, cellular processes, cellular component organization or biogenesis, and immune system processes. The significantly elevated expressions levels of 4 proteins namely, T-kininogen 1, T-kininogen 2, haptoglobin, and hemopexin, which might serve as the potential biomarkers of RSV-infected pneumonia, were further validated in RSV-infected rats using western blot and immunohistochemistry. These results provide new insights into the pathogenesis of RSV infection-induced pneumonia and provide important future directions for functional studies and therapeutic design.

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Therapeutic effects of cysteine protease inhibition in allergic lung inflammation: Inhibition of allergen-specific T lymphocyte migration

Abstract: Since E64 is not cell permeable and does not inhibit antigen-induced T cell proliferation in vitro or in vivo, the data indicate that membrane-associated cysteine proteases, possibly cathepsin B, may regulate T lymphocyte migration in vivo.

Cited by 13 publications

References 42 publications

Cathepsin B is activated as an executive protease in fetal rat alveolar type II cells exposed to hyperoxia

Cathepsin B is activated as an executive protease in fetal rat alveolar type II cells exposed to hyperoxia

DRAM1 Regulates Autophagy Flux through Lysosomes

Proteomic Profiling of a Respiratory Syncytial Virus-Infected Rat Pneumonia Model

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