LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

Pouwels, SD; Hesse, L; Wu, X; Allam, VSRR; van Oldeniel, D; Bhiekharie, LJ; Phipps, S; Oliver, BG; Gosens, R; Sukkar, MB; Heijink, IH

LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

Pouwels, SD Hesse, L Wu, X Allam, VSRR van Oldeniel, D Bhiekharie, LJ Phipps, S Oliver, BG Gosens, R Sukkar, MB Heijink, IH

Permalink

Publisher:: American Physiological Society
Publication Type:: Journal Article
Citation:: American Journal of Physiology: Lung Cellular and Molecular Physiology, 2021, 321, (4), pp. L641-L652
Issue Date:: 2021-10

Closed Access

	Filename	Description	Size
	ajplung.00138.2021.pdf		3.48 MB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Pouwels, SD
dc.contributor.author	Hesse, L
dc.contributor.author	Wu, X
dc.contributor.author	Allam, VSRR
dc.contributor.author	van Oldeniel, D
dc.contributor.author	Bhiekharie, LJ
dc.contributor.author	Phipps, S
dc.contributor.author	Oliver, BG
dc.contributor.author	Gosens, R
dc.contributor.author	Sukkar, MB
dc.contributor.author	Heijink, IH
dc.date.accessioned	2022-01-04T03:09:58Z
dc.date.available	2022-01-04T03:09:58Z
dc.date.issued	2021-10
dc.identifier.citation	American Journal of Physiology: Lung Cellular and Molecular Physiology, 2021, 321, (4), pp. L641-L652
dc.identifier.issn	1040-0605
dc.identifier.issn	1522-1504
dc.identifier.uri	http://hdl.handle.net/10453/152646
dc.description.abstract	The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Physiological Society
dc.relation.ispartof	American Journal of Physiology: Lung Cellular and Molecular Physiology
dc.relation.isbasedon	10.1152/ajplung.00138.2021
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0606 Physiology, 1116 Medical Physiology
dc.subject.classification	Respiratory System
dc.subject.mesh	A549 Cells
dc.subject.mesh	Alveolar Epithelial Cells
dc.subject.mesh	Animals
dc.subject.mesh	Antimicrobial Cationic Peptides
dc.subject.mesh	Benzamides
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	HMGB1 Protein
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Organoids
dc.subject.mesh	Pancreatic Elastase
dc.subject.mesh	Pulmonary Alveoli
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Receptor for Advanced Glycation End Products
dc.subject.mesh	Regeneration
dc.subject.mesh	Pulmonary Alveoli
dc.subject.mesh	Organoids
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Benzamides
dc.subject.mesh	Pancreatic Elastase
dc.subject.mesh	Antimicrobial Cationic Peptides
dc.subject.mesh	HMGB1 Protein
dc.subject.mesh	Regeneration
dc.subject.mesh	Alveolar Epithelial Cells
dc.subject.mesh	A549 Cells
dc.subject.mesh	Receptor for Advanced Glycation End Products
dc.subject.mesh	A549 Cells
dc.subject.mesh	Alveolar Epithelial Cells
dc.subject.mesh	Animals
dc.subject.mesh	Antimicrobial Cationic Peptides
dc.subject.mesh	Benzamides
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	HMGB1 Protein
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Organoids
dc.subject.mesh	Pancreatic Elastase
dc.subject.mesh	Pulmonary Alveoli
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive
dc.subject.mesh	Receptor for Advanced Glycation End Products
dc.subject.mesh	Regeneration
dc.title	LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.
dc.type	Journal Article
utslib.citation.volume	321
utslib.location.activity	United States
utslib.for	0606 Physiology
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-01-04T03:09:56Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	321
utslib.citation.issue	4

Abstract:

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/152646