Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis

James Reihill; Kelly Moffitt; Lisa Douglas; Stuart Elborn; Andrew Jones; Lorraine Martin

doi:10.1016/j.jcf.2019.12.014

Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis

James Reihill, Kelly Moffitt, Lisa Douglas, Stuart Elborn, Andrew Jones, Lorraine Martin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLP) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TL proteolytic activity and clinical outcome has not been studied.

Methods: We analysed supernatant (sol) prepared from CF sputum from 29 and 33 adult CF patients in two study cohorts, respectively. Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis.

Results: TLP activity inversely correlated with percent predicted FEV1 (r=-0.4, p=0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p=0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 (per log unit TLP activity (p=0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in a second study cohort.

Conclusions: Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.

Original language	English
Journal	Journal of Cystic Fibrosis
Early online date	11 Jan 2020
DOIs	https://doi.org/10.1016/j.jcf.2019.12.014
Publication status	Early online date - 11 Jan 2020

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Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis
Copyright 2020 Elsevier. This manuscript is distributed under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
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@article{5bf2ae712aaf4cc1b4d271fcabd9a0fa,

title = "Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis",

abstract = "Background: In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLP) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TL proteolytic activity and clinical outcome has not been studied. Methods: We analysed supernatant (sol) prepared from CF sputum from 29 and 33 adult CF patients in two study cohorts, respectively. Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis.Results: TLP activity inversely correlated with percent predicted FEV1 (r=-0.4, p=0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p=0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 (per log unit TLP activity (p=0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in a second study cohort. Conclusions: Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease. ",

author = "James Reihill and Kelly Moffitt and Lisa Douglas and Stuart Elborn and Andrew Jones and Lorraine Martin",

year = "2020",

month = jan,

day = "11",

doi = "10.1016/j.jcf.2019.12.014",

language = "English",

journal = "Journal of Cystic Fibrosis",

issn = "1569-1993",

publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis

AU - Reihill, James

AU - Moffitt, Kelly

AU - Douglas, Lisa

AU - Elborn, Stuart

AU - Jones, Andrew

AU - Martin, Lorraine

PY - 2020/1/11

Y1 - 2020/1/11

N2 - Background: In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLP) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TL proteolytic activity and clinical outcome has not been studied. Methods: We analysed supernatant (sol) prepared from CF sputum from 29 and 33 adult CF patients in two study cohorts, respectively. Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis.Results: TLP activity inversely correlated with percent predicted FEV1 (r=-0.4, p=0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p=0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 (per log unit TLP activity (p=0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in a second study cohort. Conclusions: Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.

AB - Background: In cystic fibrosis (CF) airways excessive levels of serine trypsin-like proteases (TLP) activate the epithelial sodium channel (ENaC) resulting in airways dehydration and promotion of mucus secretion. Despite this the relationship of TL proteolytic activity and clinical outcome has not been studied. Methods: We analysed supernatant (sol) prepared from CF sputum from 29 and 33 adult CF patients in two study cohorts, respectively. Protease activities were determined by measuring the hydrolysis of peptide-based substrates or by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis.Results: TLP activity inversely correlated with percent predicted FEV1 (r=-0.4, p=0.03) and was greater in individuals who did not survive beyond 5-years from the time of sample collection. A Kaplan-Meier analysis demonstrated significantly reduced survival (p=0.04) for individuals with high TLP activity [hazard ratio (HR) of 7.21 (per log unit TLP activity (p=0.03)]. In contrast, neutrophil elastase displayed no significant associations with lung function or patient survival. Similar findings were evident in a second study cohort. Conclusions: Sputum TLP activity may represent a novel non-invasive biomarker and/or therapeutic target for CF lung disease.

U2 - 10.1016/j.jcf.2019.12.014

DO - 10.1016/j.jcf.2019.12.014

M3 - Article

SN - 1569-1993

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

ER -

Sputum trypsin-like protease activity relates to clinical outcome in cystic fibrosis

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