Tackling infection and inflammation in the Cystic Fibrosis lung: novel CAP inhibitors & Pseudomonas aeruginosa.

Research output: Contribution to conferencePaper

Abstract

Cystic fibrosis (CF) is a debilitating, inheritable disease, characterised by impaired mucociliary clearance (MCC) and dehydration of the airway surface liquid. This results from absence or reduced functionality of the CF transmembrane conductance regulator (CFTR) and linked dysregulation of epithelial sodium channel (ENaC) activation via trypsin-like channel activating proteases (CAPs). Airways mucus becomes thickened and is retained in the lung, allowing for persistent pathogen colonisation and chronic inflammation. MCC may be corrected through inhibition of CAPs1.
Pseudomonas aeruginosa (Pa) is the most common pathogen associated with CF lung infection and persists due to the conditions within the CF lung and its own evasive and defensive systems (biofilm formation, secretion of proteases and toxins e.g. Exotoxin A). Infection persists despite a heightened host inflammatory response and cells undergo apoptosis and remodelling, leading to airway destruction. Protease activated receptor 2 (PAR2) is a key mediator of inflammatory processes, and is selectively activated by trypsin and trypsin-like proteases causing increased production of inflammatory cytokines.
A novel CAP inhibitor, QUBTL1, has been shown to restore MCC, and may also have a synergistic effect on inflammatory and infective processes in the lungs1. The aim of this study is to investigate the effect of QUBTL1 and other novel CAP inhibitors’ on bacterial proteases and the implications of this on inflammation in CF.
QUBTL1 alone has been shown to reduce by 50% TNFa-mediated cytokine release (IL-6 and IL-8) in CF airways epithelial cells. PAR2 function in response to stimuli and as measured by Ca2+ mobilisation was shown to be reduced following preincubation with the compound for 48 hours. A lysate of a virulent Pa strain, PA0219, isolated from a CF patient, was cultured and profiled, and found to contain CAP-like activity, suggesting a putative role for Pa in ENaC activation. This activity is significantly inhibited by a range of novel inhibitors in vitro. Pa Exotoxin A-mediated cytotoxicity was also reduced in the presence of CAP inhibitors.
QUB-TL1 suppresses ENaC and rehydrates CF airway epithelia. Our studies also now show an ability of the compound to modulate inflammation. These multiple activities could potentially offer a mechanism to improve quality of life and reduce hospitalization for CF patients.
1. Reihill JA et al (2016) Am J Respir Crit Care Med, 194, 701-710
Original languageEnglish
Number of pages1
Publication statusPublished - 28 Oct 2017
Event10th General Meeting of the International Proteolysis Society - Banff Centre, Banff, Canada
Duration: 28 Oct 201702 Oct 2018
http://www.ips2017.org

Conference

Conference10th General Meeting of the International Proteolysis Society
CountryCanada
CityBanff
Period28/10/201702/10/2018
Internet address

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    Maye, J., Reihill, J., & Martin, L. (2017). Tackling infection and inflammation in the Cystic Fibrosis lung: novel CAP inhibitors & Pseudomonas aeruginosa.. Paper presented at 10th General Meeting of the International Proteolysis Society, Banff, Canada.