Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex

Sullivan, Anita; Dafforn, Timothy R.; Hiemstra, Pieter S.; Stockley, Robert A.

doi:10.1186/1465-9921-9-60

Cited by 19 publications

(11 citation statements)

References 51 publications

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“…However, protease levels only accounted for a maximum of 23% of the variance in sputum SLPI levels, suggesting an important contribution from reduced SLPI production. In addition, our data demonstrates that elastase reduces release of SLPI from epithelial cells independent of its protease activity, as previous data suggested (21). Other studies have generated a variant of SLPI resistant to degradation by neutrophil elastase (32).…”

Section: Discussionsupporting

confidence: 85%

Antimicrobial peptides, disease severity and exacerbations in bronchiectasis

Sibila

Perea

Cantó

et al. 2019

Thorax

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RationaleRecently a frequent exacerbator phenotype has been described in bronchiectasis, but the underlying biological mechanisms are unknown. Antimicrobial peptides (AMPs) are important in host defence against microbes but can be proinflammatory in chronic lung disease.ObjectivesTo determine pulmonary and systemic levels of AMP and their relationship with disease severity and future risk of exacerbations in bronchiectasis.MethodsA total of 135 adults with bronchiectasis were prospectively enrolled at three European centres. Levels of cathelicidin LL-37, lactoferrin, lysozyme and secretory leucocyte protease inhibitor (SLPI) in serum and sputum were determined at baseline by ELISA. Patients were followed up for 12 months. We examined the ability of sputum AMP to predict future exacerbation risk.Measurements and main resultsAMP levels were higher in sputum than in serum, suggesting local AMP release. Patients with more severe disease at baseline had dysregulation of airway AMP. Higher LL-37 and lower SLPI levels were associated with Bronchiectasis Severity Index, lower FEV1 (forced expiratory volume in 1 s) and Pseudomonas aeruginosa infection. Low SLPI levels were also associated with the exacerbation frequency at baseline. During follow-up, higher LL-37 and lower SLPI levels were associated with a shorter time to the next exacerbation, whereas LL-37 alone predicted exacerbation frequency over the next 12 months.ConclusionsPatients with bronchiectasis showed dysregulated sputum AMP levels, characterised by elevated LL-37 and reduced SLPI levels in the frequent exacerbator phenotype. Elevated LL-37 and reduced SLPI levels are associated with Pseudomonas aeruginosa infection and can predict future risk of exacerbations in bronchiectasis.

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Section: Discussionsupporting

confidence: 85%

Antimicrobial peptides, disease severity and exacerbations in bronchiectasis

Sibila

Perea

Cantó

et al. 2019

Thorax

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“…Results from studies with these patients suggest that an inverse correlation exists between SLPI levels and the risk of developing an exacerbation [40]. Interestingly, our group has recently shown that 17β-oestradiol (E 2 ), the primary oestrogen in non-pregnant females, is capable of abrogating TLR (Toll-like receptor) responsiveness by up-regulating SLPI in CF bronchial epithelial cells (Figure 2).…”

Section: Slpi Inflammatory Lung Disease and The Female Gendermentioning

confidence: 93%

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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“…34 However, extracellular levels in tissue cultures and in respiratory secretions are low. 35 SLPI forms complexes with elastase, and such complexes are bound to negatively charged cell membranes, decreasing levels in free secretions. 35 Bacterial infection in COPD is a strong stimulus for increased proteolytic activity in the lower respiratory tract, which is the most likely mechanism of the decreased SLPI levels seen in this study.…”

Section: Effect Of Acquisition Of a New Bacterial Strain On Sputum Ammentioning

confidence: 99%