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Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function

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Reynolds_et_al-2018-American_Journal_of_Respiratory_Cell_and_Molecular_Biology.pdfAccepted version5.36 MBAdobe PDFView/Open
Title: Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function
Authors: Reynolds, CJ
Quigley, K
Cheng, X
Suresh, A
Tahir, S
Ahmed-Jushuf, F
Nawab, K
Choy, K
Walker, SA
Mathie, SA
Sim, M
Stowell, J
Manji, J
Pollard, T
Altmann, DM
Boyton, RJ
Item Type: Journal Article
Abstract: RATIONALE: IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung. OBJECTIVES: To better understand the duality of IL-8 dependent host immunity to bacterial infection and lung pathology, we targeted human IL-8 to express transgenically in murine bronchial epithelium, investigating the impact of over-expression on lung bacterial clearance, host immunity, lung pathology and function. MEASUREMENTS AND MAIN RESULTS: Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation, activation and chemtoaxis. There was enhanced protection from challenge with Pseudomonas aeruginosa and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL2 and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen, OprF, indicating a regulatory T cell phenotype. However, this enhanced bacterial immunity comes at the high price of progressive lung remodelling, with increased inflammation, mucus hyper-secretion, and fibrosis. There is increased expression of Ccl3 and reduced expressioh of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all resulting in impaired lung function with reduced compliance, increased resistance and bronchial hyperreactivity measured by whole body plethysmography. CONCLUSIONS: IL-8 over-expression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodelling and damaged tight junctions, leading to impaired lung function.
Issue Date: 1-Nov-2018
Date of Acceptance: 12-Jun-2018
URI: http://hdl.handle.net/10044/1/60795
DOI: https://dx.doi.org/10.1165/rcmb.2018-0007OC
ISSN: 1044-1549
Publisher: American Thoracic Society
Start Page: 557
End Page: 571
Journal / Book Title: American Journal of Respiratory Cell and Molecular Biology
Volume: 59
Issue: 5
Copyright Statement: © 2018 by the American Thoracic Society.
Sponsor/Funder: Welton Foundation
Medical Research Council (MRC)
Asthma UK
Welton Foundation
Medical Research Council (MRC)
National Institutes of Health
Wellcome Trust
Wellcome Trust
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: PC3015TWF
G108/495
05/045
N/A
MRC Ref G0400503
HHSN272200900046C
095472/Z/11/Z
100046/Z/12/Z
RDF01 79560
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Respiratory System
bacterial infection
host immunity
IL-8
lung remodeling
tight junction
AIRWAY SMOOTH-MUSCLE
NEUTROPHIL CHEMOTACTIC FACTOR
HUMAN INTERLEUKIN-8 RECEPTORS
TUMOR-NECROSIS-FACTOR
PSEUDOMONAS-AERUGINOSA
MESENCHYMAL TRANSITION
ENDOTHELIAL-CELLS
BARRIER FUNCTION
LAVAGE FLUID
EXPRESSION
IL-8
bacterial infection
host immunity
lung remodeling
tight junction
Animals
Chronic Disease
Humans
Immunity, Innate
Interleukin-8
Lung
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pneumonia
Pseudomonas Infections
Pseudomonas aeruginosa
Pulmonary Fibrosis
Lung
Animals
Mice, Inbred C57BL
Mice, Transgenic
Humans
Mice
Pseudomonas aeruginosa
Pseudomonas Infections
Pulmonary Fibrosis
Pneumonia
Chronic Disease
Interleukin-8
Immunity, Innate
bacterial infection
host immunity
interleukin 8
lung function
lung remodelling
Respiratory System
1102 Cardiorespiratory Medicine and Haematology
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-06-12
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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