Cleaved secretory leucocyte protease inhibitor as a biomarker of chymase activity in allergic airway disease

Belkowski, Stanley M.; Boot, J. D.; Mascelli, Mary Ann; Diamant, Zuzana; Garavilla, Lawrence de; Hertzog, Brenda; Polkovitch, Deborah; Towers, Marcia; Batheja, Ameesha; D’Andrea, Michael R.

doi:10.1111/j.1365-2222.2009.03247.x

Cited by 20 publications

(10 citation statements)

References 30 publications

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“…Recent studies have shown that patients with allergic asthma express substantially higher levels of SLPI compared with healthy controls, and that SLPI may have a role in protecting the airways from asthma-induced inflammation ( Figure 2) [44,45]. Expression of SLPI actually protects against allergic asthma in a mouse ovalbumin model of asthma, and this may be related to the earlier observations that SLPI can block tryptase-induced bronchoconstriction and hyper-responsiveness [46].…”

Section: Slpi Inflammatory Lung Disease and The Female Gendermentioning

confidence: 87%

SLPI and inflammatory lung disease in females

McKiernan

McElvaney

Greene

2011

Biochemical Society Transactions

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During the course of certain inflammatory lung diseases, SLPI (secretory leucoprotease inhibitor) plays a number of important roles. As a serine antiprotease it functions to protect the airways from proteolytic damage due to neutrophil and other immune cell-derived serine proteases. With respect to infection it has known antimicrobial and anti-viral properties that are likely to contribute to host defence. Another of its properties is the ability to control inflammation within the lung where it can interfere with the transcriptional induction of pro-inflammatory gene expression induced by NF-κB (nuclear factor κB). Thus, factors that regulate the expression of SLPI in the airways can impact on disease severity and outcome. Gender represents once such idiosyncratic factor. In females with CF (cystic fibrosis), it is now thought that circulating oestrogen contributes, in part, to the observed gender gap whereby females have worse disease and poorer prognosis than males. Conversely, in asthma, sufferers who are females have more frequent exacerbations at times of low-circulating oestrogen. In the present paper, we discuss how SLPI participates in these events and speculate on whether regulatory mechanisms such as post-transcriptional modulation by miRNAs (microRNAs) are important in the control of SLPI expression in inflammatory lung disease.

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Section: Slpi Inflammatory Lung Disease and The Female Gendermentioning

confidence: 87%

SLPI and inflammatory lung disease in females

McKiernan

McElvaney

Greene

2011

Biochemical Society Transactions

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“…Extracellular SLPI can be cleaved by respiratory proteases such as cathepsin L, matrix metalloproteinase 12 (MMP12), and NE, and can serve as a biomarker for airway disease (5,6,30,40,46). It has been shown that cathepsins and MMPs are induced in smokers as well as in chronic cigarette smoke exposure models (9,28).…”

Section: Discussionmentioning

confidence: 99%

Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers

Meyer

Bauer

Letang

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI remain unclear. We examined SLPI mRNA and protein secretion in differentiated nasal epithelial cells (NECs) and nasal lavage fluid (NLF) from nonsmokers and smokers and demonstrated that SLPI expression is increased in NECs and NLF from smokers. Transcriptional regulation of SLPI expression was confirmed using SLPI promoter reporter assays followed by chromatin immunoprecipitation. The role of STAT1 in regulating SLPI expression was further elucidated using WT and stat1(-/-) mice. Our data demonstrate that STAT1 regulates SLPI transcription in epithelial cells and slpi protein in the lungs of mice. Additionally, we reveal that NECs from smokers have increased STAT1 mRNA/protein expression. Finally, we demonstrate that SLPI contained in the nasal mucosa of smokers is proteolytically cleaved but retains functional activity against neutrophil elastase. These results demonstrate that smoking enhances expression of SLPI in NECs in vitro and in vivo, and that this response is regulated by STAT1. In addition, despite posttranslational cleavage of SLPI, antiprotease activity against neutrophil elastase is enhanced in smokers. Together, our findings show that SLPI regulation and activity is altered in the nasal mucosa of smokers, which could have broad implications in the context of respiratory inflammation and infection.

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“…However, a limitation is the lack of a marker reflecting chymase inhibition in vivo. Belkowski et al 77 demonstrated that cleaved secretory leucocyte protease may be a useful marker of chymase activity in the sputum of asthmatic patients. However, there is no established marker in plasma, which is necessary to evaluate in vivo chymase activity.…”

Section: Role Of Chymase On Pressure Loaded-and Volume Loaded-cardiacmentioning

confidence: 99%

Improvement of cardiovascular remodelling by chymase inhibitor

Jin

2016

Clin Exp Pharma Physio

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SUMMARYChymase has been identified as an angiotensin II-forming enzyme found in cardiovascular tissues. Angiotensin II is involved not only in the regulation of blood pressure, but also in the progression of cardiovascular remodelling. Interestingly, chymase inhibitors prevent cardiovascular remodelling without lowering blood pressure. The reason why chymase inhibitors do not affect blood pressure may depend on the localization of chymase in vivo. In normal tissues, chymase is stored in mast cell granules and has no enzymatic function; whereas, in damaged tissues, chymase exhibits enzymatic activity immediately following its release from the granules. Chymase also activates transforming growth factor-b and matrix metalloproteinase-9, both of which are involved in cardiovascular remodelling, and their enzymatic functions are also observed only in damaged tissues. In animal models of hypertension, diabetes and hypercholesterolaemia, chymase inhibitors improve cardiovascular remodelling without a general circulatory effect, including blood pressure. Thus, it is proposed that chymase is a potentially important target for preventing cardiovascular diseases.

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Cleaved secretory leucocyte protease inhibitor as a biomarker of chymase activity in allergic airway disease

Abstract: Our data indicate that cSLPI reflects chymase activity in AR and asthma. Hence, cSLPI may serve as a biomarker for disease activity and for monitoring the efficacy of novel anti-inflammatory treatments in chymase-mediated diseases.

Cited by 20 publications

References 30 publications

SLPI and inflammatory lung disease in females

SLPI and inflammatory lung disease in females

Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers

Improvement of cardiovascular remodelling by chymase inhibitor

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