Role of cellular proteinases and their protein inhibitors in inflammation

Woessner, Jeff

doi:10.1007/978-94-011-2996-1_4

Cited by 10 publications

(5 citation statements)

References 197 publications

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“…A range of inhibitors active against cathepsins B, D and L, the most abundant cathepsins in differentiated macrophages [35] , were screened for their capacity to prevent loss of ΔΨ m , one of the first signs of irreversible cell death. Only inhibitors with activity against the aspartic protease cathepsin D (but not B or L) were able to prevent the dissipation of ΔΨ m ( Figure S4A ).…”

Section: Resultsmentioning

confidence: 99%

A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci

et al. 2011

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The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D−/− hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function.

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Section: Resultsmentioning

confidence: 99%

A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci

et al. 2011

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“…This prompted studies which showed that the use of structurally different elastase inhibitors was beneficial in models of acute lung inflammation (13). Indeed, the body produces different natural specific inhibitors to counteract the biological destructive activity of elastase (14,15). In lungs, one can consider two groups (16), the early or alarm inhibitors such as the secretory leukocyte proteinase inhibitor (SLPI) and elafin, and the secondary or acute-phase inhibitors such as α1proteinase inhibitor (α1-PI).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil DNA Contributes to the Antielastase Barrier during Acute Lung Inflammation

Balloy

Sallenave²,

Crestani³

et al. 2003

Am J Respir Cell Mol Biol

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During acute lung inflammation, the airspaces are invaded by circulating neutrophils. These may then injure tissues through the release of elastase. Different natural specific inhibitors such as alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin are nonetheless able to counteract the enzymatic activity of elastase. The present study was undertaken to assess the role of these different inhibitors in the intrinsic antielastase barrier during lipopolysaccharide-induced lung inflammation in mice. Upon intranasal administration of lipopolysaccharide to mice, the antielastase activity recovered from bronchoalveolar lavage fluids (BALF) increases progressively up to 48 h (7-fold) and returns to the basal level within 72 h. By contrast, when the same experiments are performed with neutropenic mice (pretreatment with an antigranulocyte antibody, or vinblastine), the increase is almost totally absent. Ultrafiltration of BALF through 100 kD cutoff membranes shows that the activity remains in the retentate, thus ruling out a role for native alpha1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin. Gel filtration and fraction analysis show that the material eluted with a Mr of 600 kD. Agarose gel electrophoresis and ethidium bromide staining reveal that the activity corresponds to the presence a large amount of DNA. Interestingly, DNase treatment of the active fraction suppresses the antielastase activity. Analysis of BALF from patients with acute lung inflammation shows the presence of DNA with antielastase activity. We therefore concluded that during acute lung inflammation, the recruitment of neutrophils in the airspaces accounts for the increased presence of DNA, which in turn contributes to the antielastase barrier.

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“…PMNs are necessary to contend against infections through phagocytosis and destruction of microorganisms, but paradoxically, they are also important effectors of inflammation, particularly through proteolytic enzymes that they release into the extracellular space during phagocytosis (2). One of these enzymes is human leukocyte elastase (HLE), a serine proteinase that has been linked to the pathogenesis of a variety of inflammatory diseases, including different lung pathologies such as bronchiectasis, cystic fibrosis, acute respiratory distress syndrome (ARDS), bronchitis, and emphysema (3,4).…”

Section: Introductionmentioning

confidence: 99%

Proteolysis of monocyte CD14 by human leukocyte elastase inhibits lipopolysaccharide-mediated cell activation

Le-Barillec¹,

Si‐Tahar²,

Balloy³

et al. 1999

J. Clin. Invest.

110

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Role of cellular proteinases and their protein inhibitors in inflammation

Cited by 10 publications

References 197 publications

A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci

A Cardinal Role for Cathepsin D in Co-Ordinating the Host-Mediated Apoptosis of Macrophages and Killing of Pneumococci

Neutrophil DNA Contributes to the Antielastase Barrier during Acute Lung Inflammation

Proteolysis of monocyte CD14 by human leukocyte elastase inhibits lipopolysaccharide-mediated cell activation

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