Leukotriene A<sub>4</sub> Hydrolase: The Janus Enzyme Shows Its Ugly Side in Smokers

Snelgrove, Robert J.; Kheradmand, Farrah

doi:10.1164/rccm.201405-0975ed

Cited by 7 publications

(7 citation statements)

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“…Unfortunately the list of correct steps varies greatly between studies, the most recent being from the American Thoracic Society [ 16 ], from which our criteria have been adapted together with the manufacturers’ advice to keep the head straight. The choice of critical steps was a selection from those recommended by Newman [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…All interviewers received prior instruction and scored the performance on a check list. A 12 point checklist was used for metered dose inhaler with or without spacer use adapted from the American Thoracic Society [ 16 ], adding the manufacturers’ advice to keep the head straight. The choice of critical steps was a selection from those recommended by Newman [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

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Predictors of correct technique in patients using pressurized metered dose inhalers

et al. 2017

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BackgroundCorret inhaler technique is recommended by guidelines for optimum asthma care. The objective of the study is to determine real life predictors of correct pressurized metered dose inhaler (pMDI) technique in Asthma and COPD patients.MethodsTwo hundred eight adult patients aged 18+ from respiratory outpatients (69.2%) and the community on regular pMDI for a diagnosis of Asthma (78.9%) or COPD, were recruited. A questionnaire containing 31 possible predictors was administered and pMDI technique with or without spacer was observed by trained researchers on 12 point steps, of which 4 were considered critical.Results23.1% of patients had no errors in inhaler technique and 32.2% had no critical errors. Patients had a median of 10 correct steps (IQR9-11), and 3(IQR2-4) correct critical steps. Using binary logistic regression the predictors of 10 correct steps were, other healthcare professional (pharmacist, nurse, physiotherapist) explained OR 3.73(1.63–8.54, p = 0.001), male gender 2.70(1.35–5.39, p = 0.004), self-score 1–10 1.21(1.05–1.39, p = 0.007), spacer use 0.38(0.19–0.79, p = 0.007), inhaled steroid 3.71(1.34–10.25, p = 0.01), heart disease 0.31(0.13–0.77, p = 0.01), pneumococcal vaccine 2.48(1.0–6.15, p = 0.043), education level 1–4 1.44(1.00–2.06, p = 0.05) and respiratory physician explained 0–7 times, 1.11(0.99–1.26, p = 0.08). Using ordinal logistic regression, predictors for correct critical steps 0–4, were: technique self-score 1–10 1.2(1.05–1.42, p = 0.006), inhaled corticosteroid use 2.78(1.1–7.31, p = 0.03) and education level 1–4 1.41(1.02–1.95, p = 0.03 Times respiratory physician explained inhaler technique 0–7 1.1(0.98–1.24, p = 0.1), married status 1.55(0.85–2.82, p = 0.15), hypercholesterolaemia 0.52(0.25–1.01, p = 0.054) and male gender 1.76(0.97–3.18, p = 0.06).ConclusionsKnown predictors of correct pMDI use, such as gender and education level were confirmed, while age and concomitant use of dry powder inhaler were not. Pneumococcal vaccination and awareness of steroid side effects were possible novel positive predictors, while the use of a spacer and co-morbidity with heart disease were found to be negative predictors. Patients’ self-assessment correlated well with actual performance. This information may be useful in defining approaches to optimize inhaler techniques which are so susceptible to human error.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-017-0386-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Predictors of correct technique in patients using pressurized metered dose inhalers

et al. 2017

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“…amounts of reactive aldehydes that chemically acetylate PGP, enhancing its chemotactic activity and protecting it from degradation by LTA 4 H [19,23,26]. Additionally, cigarette smoke selectively abrogates the peptidase activity of LTA 4 H [19,35,41], again seemingly driven by intrinsic reactive aldehydes.…”

Section: Pgp In Chronic Lung Diseasementioning

confidence: 99%

The multifaceted roles of the matrikine Pro-Gly-Pro in pulmonary health and disease

Patel

Snelgrove

2018

Eur Respir Rev

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Matrikines are bioactive fragments of the extracellular matrix (ECM) that are fundamental in regulating a diverse array of physiological processes. The tripeptide Proline-Glycine-Proline (PGP) is a collagen-derived matrikine that has classically been described as a neutrophil chemoattractant. In this article, we describe our current understanding of the pathways that generate, degrade and modify PGP to dictate its bioavailability and stability. Additionally, we discuss our expanding appreciation of the capacity of PGP to regulate diverse cell types and biological processes, independent of its activity on neutrophils, including a putative role in wound repair. We argue that PGP functions as a primitive and conserved damage-associated molecular pattern, which is generated during infection or injury and subsequently acts to shape ensuing inflammatory and repair processes. As a fragment of the ECM that accumulates at the epicentre of the action, PGP is perfectly positioned to focus neutrophils to the exact site required and direct a localised repair response. However, it is essential that PGP is efficiently degraded, as if this matrikine is allowed to persist then pathology can ensue. Accordingly, we discuss how this pathway is subverted in chronic lung diseases giving rise to persistent inflammation and pathological tissue remodelling.

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“…Accordingly, it seems that the LTA 4 H-PGP degradation pathway is perturbed in these chronic diseases to enable PGP to accumulate and drive inflammation91518. Together, these studies highlight the critical importance of the secondary PGP-degrading activity of LTA 4 H.…”

mentioning

confidence: 93%

“…Significant quantities of PGP are found in patients with chronic neutrophilic lung diseases such as chronic obstructive pulmonary disease (COPD), Cystic Fibrosis (CF) and bronchiolitis obliterans syndrome (BOS), peaking with exacerbation of disease and inversely correlating with lung function 10 11 14 15 16 17 . Accordingly, it seems that the LTA 4 H-PGP degradation pathway is perturbed in these chronic diseases to enable PGP to accumulate and drive inflammation 9 15 18 . Together, these studies highlight the critical importance of the secondary PGP-degrading activity of LTA 4 H.…”

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confidence: 99%

The development of novel LTA4H modulators to selectively target LTB4 generation

Low

Akthar

Patel

et al. 2017

Sci Rep

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The pro-inflammatory mediator leukotriene B4 (LTB4) is implicated in the pathologies of an array of diseases and thus represents an attractive therapeutic target. The enzyme leukotriene A4 hydrolase (LTA4H) catalyses the distal step in LTB4 synthesis and hence inhibitors of this enzyme have been actively pursued. Despite potent LTA4H inhibitors entering clinical trials all have failed to show efficacy. We recently identified a secondary anti-inflammatory role for LTA4H in degrading the neutrophil chemoattractant Pro-Gly-Pro (PGP) and rationalized that the failure of conventional LTA4H inhibitors may be that they inadvertently prevented PGP degradation. We demonstrate that these inhibitors do indeed fail to discriminate between the dual activities of LTA4H, and enable PGP accumulation in mice. Accordingly, we have developed novel compounds that potently inhibit LTB4 generation whilst leaving PGP degradation unperturbed. These novel compounds could represent a safer and superior class of LTA4H inhibitors for translation into the clinic.

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Leukotriene A₄ Hydrolase: The Janus Enzyme Shows Its Ugly Side in Smokers

Cited by 7 publications

References 15 publications

Predictors of correct technique in patients using pressurized metered dose inhalers

Predictors of correct technique in patients using pressurized metered dose inhalers

The multifaceted roles of the matrikine Pro-Gly-Pro in pulmonary health and disease

The development of novel LTA4H modulators to selectively target LTB4 generation

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Leukotriene A4 Hydrolase: The Janus Enzyme Shows Its Ugly Side in Smokers

Cited by 7 publications

References 15 publications

Predictors of correct technique in patients using pressurized metered dose inhalers

Predictors of correct technique in patients using pressurized metered dose inhalers

The multifaceted roles of the matrikine Pro-Gly-Pro in pulmonary health and disease

The development of novel LTA4H modulators to selectively target LTB4 generation

Contact Info

Product

Resources

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Leukotriene A₄ Hydrolase: The Janus Enzyme Shows Its Ugly Side in Smokers