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Increased expression of p22phox mediates airway hyperresponsiveness in an experimental model of asthma

Increased expression of p22phox mediates airway hyperresponsiveness in an experimental model of asthma
Increased expression of p22phox mediates airway hyperresponsiveness in an experimental model of asthma

AIM: Chronic airway diseases such as asthma are associated with increased production of reactive oxygen species (ROS) and oxidative stress. Endogenous NADPH oxidases are a major source of superoxide in lung, but their underlying role in asthma pathology is poorly understood. We sought to characterize the involvement of NADPH oxidase in allergic asthma by studying the role of CYBA (p22phox) in human asthma and murine house dust mite (HDM)-induced allergic airway inflammation.

RESULTS: Increased expression and localisation of p22-PHOX was observed in biopsies of asthmatic patients. HDM treated wild-type mice possessed elevated p22phox expression, corresponded with elevated superoxide production. p22phox knockout (KO) mice did not induce superoxide and were protected against HDM-induced goblet cell hyperplasia and mucus production and HDM-induced airway-hyperreactivity (AHR). IL-13 induced tracheal hyperreactivity and Signal transducer and activator of transcription (STAT)6 phosphorylation was attenuated in the absence of p22phox or catalase pretreatment.

INNOVATION: Our study identifies increased expression of p22phox in lungs of asthmatic patients and in experimental model. The induced AHR and mucus hypersecretion is result of an increased ROS from the p22phox dependent NADPH oxidase, which in turn activates STAT6 for the pathological feature of Asthma.

CONCLUSIONS: Together with the increased p22phox expression in lungs of asthmatic patients, these findings demonstrate a crucial role of p22phox dependent NADPH oxidase for the development of mucus hypersecretion and AHR in HDM-induced model of asthma. This suggests inhibition of functional NADPH oxidase by selective interference of p22phox might hold promising therapeutic strategy for the management of asthma.

Journal Article
1523-0864
1460-1472
Nagaraj, Chandran
580a09fb-1b5c-457f-afa2-58724109f69e
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Heinemann, Akos
5a8ac4ee-ea5c-4197-934f-b0a8da6a5a19
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Olschewski, Andrea
30851e9c-364f-4837-a7b3-116a634f0da9
Marsh, Leigh M
a5d4a74c-6453-49c6-ba4a-08a37f32ae96
Nagaraj, Chandran
580a09fb-1b5c-457f-afa2-58724109f69e
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Heinemann, Akos
5a8ac4ee-ea5c-4197-934f-b0a8da6a5a19
Howarth, Peter
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Olschewski, Andrea
30851e9c-364f-4837-a7b3-116a634f0da9
Marsh, Leigh M
a5d4a74c-6453-49c6-ba4a-08a37f32ae96

Nagaraj, Chandran, Haitchi, Hans Michael, Heinemann, Akos, Howarth, Peter, Olschewski, Andrea and Marsh, Leigh M (2017) Increased expression of p22phox mediates airway hyperresponsiveness in an experimental model of asthma. Antioxidants & Redox Signaling, 27 (18), 1460-1472. (doi:10.1089/ars.2016.6863).

Record type: Article

Abstract

AIM: Chronic airway diseases such as asthma are associated with increased production of reactive oxygen species (ROS) and oxidative stress. Endogenous NADPH oxidases are a major source of superoxide in lung, but their underlying role in asthma pathology is poorly understood. We sought to characterize the involvement of NADPH oxidase in allergic asthma by studying the role of CYBA (p22phox) in human asthma and murine house dust mite (HDM)-induced allergic airway inflammation.

RESULTS: Increased expression and localisation of p22-PHOX was observed in biopsies of asthmatic patients. HDM treated wild-type mice possessed elevated p22phox expression, corresponded with elevated superoxide production. p22phox knockout (KO) mice did not induce superoxide and were protected against HDM-induced goblet cell hyperplasia and mucus production and HDM-induced airway-hyperreactivity (AHR). IL-13 induced tracheal hyperreactivity and Signal transducer and activator of transcription (STAT)6 phosphorylation was attenuated in the absence of p22phox or catalase pretreatment.

INNOVATION: Our study identifies increased expression of p22phox in lungs of asthmatic patients and in experimental model. The induced AHR and mucus hypersecretion is result of an increased ROS from the p22phox dependent NADPH oxidase, which in turn activates STAT6 for the pathological feature of Asthma.

CONCLUSIONS: Together with the increased p22phox expression in lungs of asthmatic patients, these findings demonstrate a crucial role of p22phox dependent NADPH oxidase for the development of mucus hypersecretion and AHR in HDM-induced model of asthma. This suggests inhibition of functional NADPH oxidase by selective interference of p22phox might hold promising therapeutic strategy for the management of asthma.

Text
Nagaraj et al_Antioxid Redox Signal_2017May16_PMID_28510479_final revision - Accepted Manuscript
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More information

Accepted/In Press date: 15 May 2017
e-pub ahead of print date: 26 June 2017
Published date: 20 December 2017
Keywords: Journal Article
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 408278
URI: https://eprints.soton.ac.uk/id/eprint/408278
ISSN: 1523-0864
PURE UUID: a01317e5-e5e9-4e46-ab8a-27c50eb7ad11
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

Catalogue record

Date deposited: 19 May 2017 04:02
Last modified: 10 Dec 2019 06:01

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