Use of Secretory Leukoprotease Inhibitor to Augment Lung Antineutrophil Elastase Activity

Vogelmeier, Claus; Gillissen, A; Buhl, Roland

doi:10.1378/chest.110.6_supplement.261s

Cited by 54 publications

(36 citation statements)

References 52 publications

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“…SLPI is the major antielastase of the conducting airways [18]. SLPI is a 12-kDa, nonglycosylated, disulphide-linked antiprotease secreted by cells of mucosal surfaces including the epithelium of the airways [17].…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Jaumann¹,

Elssner²,

Mazur³

et al. 2000

Eur Respir J

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Obliterative bronchiolitis (OB) is the major long-term complication following lung and heart-lung transplantation. In bronchoalveolar lavage fluid samples obtained from patients suffering from OB, a marked increase in the number of neutrophils and elevated expression of transforming growth factor (TGF)-b 1 had been found. The goal of the study was to evaluate whether TGF-b 1 is capable of interfering with the expression of the secretory leukoprotease inhibitor (SLPI), the dominating defence of the conducting airways against neutrophil elastase (NE).The authors analysed the effects of TGF-b 1 on gene expression and protein release of SLPI by cultured human bronchial epithelial (BEAS-2B) cells. SLPI protein levels in the supernatants were quantified with a specific enzyme-linked immunosorbent assay; SLPI messenger ribonucleic acid (mRNA) levels were measured by reverse transcriptase polymerase chain reaction.Incubation with TGF-b 1 induced a marked decrease in SLPI protein levels (1 ng . mL and NE also caused a significant reduction in SLPI synthesis (10 ng . mL -1 TGF-b 1 + 7.5 U . mL -1 NE: mRNA SI = 0.61, p<0.05; protein SI = 0.65, p<0.05; 50 ng . mL -1 TGF-b 1 + 7.5 U . mL -1 NE: mRNA SI = 0.52, p<0.05; protein SI = 0.58, p<0.05; 10 ng . mL -1 TGF-b 1 : mRNA SI = 0.33, p<0.01; protein SI = 0.38, p<0.01). In conclusion, the data suggest that the coincidence of neutrophilia and upregulation of transforming growth factor-b 1 in obliterative bronchiolitis may lead to uninhibited neutrophil elastase activity by downregulation of secretory leukoprotease inhibitor, with the consequence of ongoing injury to the epithelium. Eur Respir J 2000; 15: 1052±1057.

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Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Jaumann¹,

Elssner²,

Mazur³

et al. 2000

Eur Respir J

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“…In our study a significant difference was observed in apparent permeabilities of free-rSLPI and DOPS-rSLPI across the Calu-3 monolayer indicating that transport occurred at a much faster rate for free-rSLPI compared to that for rSLPI encapsulated in DOPS-rSLPI liposomes (Figure 1). This rapid transport of free-rSLPI across the airway epithelial cells could explain the rapid clearance of the inhaled protein previously seen in in vivo studies (McElvaney et al, 1993, Vogelmeier et al, 1996. The encapsulation of rSLPI within this liposome carrier therefore appears to retard transport across the epithelium, which could signify increased rSLPI residence time within the lungs when encapsulated in DOPSrSLPI liposomes compared to free-rSLPI.…”

Section: Discussionmentioning

confidence: 80%

“…The success of inhaled rSLPI therapy has been limited, however, by rapid clearance and extensive degradation by proteases, particularly cathepsins. In vivo human studies involving the delivery of rSLPI locally to the lung indicated that rSLPI does not accumulate on the respiratory surface and instead moves rapidly from the epithelial surface to the interstitium of the lung after inhalation (Vogelmeier et al, 1996). It therefore requires repeated dosages every 12 hours in order to maintain therapeutic effectiveness (McElvaney et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model

et al. 2011

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NG, Cryan SA. The effect of liposome encapsulation on the pharmacokinetics of recombinant secretory leukocyte protease inhibitor (rSLPI) therapy after local delivery to a guinea pig asthma model. Pharmaceutical Research. 2011;28(9):2233-45. AuthorsAileen Gibbons, Danielle Padilla-Carlin, Ciara Kelly, Anthony J. Hickey, Clifford Taggart, Noel G. McElvaney, and Sally-Ann Cryan This article is available at e-publications@RCSI: http://epubs.rcsi.ie/spharmart/3 -Use LicenceAttribution-Non-Commercial-ShareAlike 1.0 You are free:• to copy, distribute, display, and perform the work.• to make derivative works. Under the following conditions:• Attribution -You must give the original author credit.• Non-Commercial -You may not use this work for commercial purposes.• Share Alike -If you alter, transform, or build upon this work, you may distribute the resulting work only under a licence identical to this one. Methods: Transport of DOPS-rSLPI and free-rSLPI across a polarised air-liquid epithelial monolayer was measured. An asthma guinea pig model was administered either DOPS-rSLPI liposomes or free-rSLPI by intratracheal instillation. Results: Apparent permeability (P app ) of free-rSLPI was significantly higher at 4.9 x10 -6 cm/s than for DOPS-rSLPI, P app of 2.05 x10 -7 cm/s. In vivo studies confirmed this result. Plasma rSLPI concentrations were highest in free-rSLPI treated animals compared with those treated with DOPS-rSLPI, there also appeared to be a trend for higher intracellular rSLPI content in animals dosed with DOPS-rSLPI compared to free-rSLPI. Eosinophil influx was recorded as a measure of inflammation. Pre-dosing with either free-rSLPI or DOPSrSLPI prevented inflammatory response to antigen challenge to levels comparable to control animals. Conclusion: Encapsulation of rSLPI in DOPS:Chol liposomes improves stability, reduces clearance and increases residence time in the lungs after local delivery.3

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“…SLPI plays a primary role in the regulation of neutrophil-mediated in¯ammation through proteolysis and subsequent inhibition of the leukocyte serine proteases, including the neutrophil proteases (cathepsin G and elastase) and the pancreatic proteases (trypsin and chymotrypsin) (Thompson and Ohlsson, 1986). Because of its potent antiprotease activity, SLPI serves as a potential therapeutic agent for the treatment of proteolytic tissue damage seen in degenerative and in¯ammatory diseases such as cystic ®brosis, allergic rhinitis and asthma (Lee et al, 1993); reviewed in Vogelmeier et al (1996). This nonglycosylated 11.7 kDa enzyme is produced by epithelial cells and resides in parotid secretions, bronchial, nasal and cervical mucus, and seminal¯uid (Thompson and Ohlsson, 1986).…”

Section: Discussionmentioning

confidence: 99%

Identification of the secretory leukocyte protease inhibitor (SLPI) as a target of IRF-1 regulation

et al. 1999

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Use of Secretory Leukoprotease Inhibitor to Augment Lung Antineutrophil Elastase Activity

Cited by 54 publications

References 52 publications

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

The Effect of Liposome Encapsulation on the Pharmacokinetics of Recombinant Secretory Leukocyte Protease Inhibitor (rSLPI) Therapy after Local Delivery to a Guinea Pig Asthma Model

Identification of the secretory leukocyte protease inhibitor (SLPI) as a target of IRF-1 regulation

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