PMID- 34405719 OWN - NLM STAT- MEDLINE DCOM- 20211110 LR - 20221207 IS - 1522-1504 (Electronic) IS - 1040-0605 (Linking) VI - 321 IP - 4 DP - 2021 Oct 1 TI - LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE. PG - L641-L652 LID - 10.1152/ajplung.00138.2021 [doi] AB - 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. FAU - Pouwels, Simon D AU - Pouwels SD AUID- ORCID: 0000-0001-7345-8061 AD - Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Hesse, Laura AU - Hesse L AD - Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Wu, Xinhui AU - Wu X AD - Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands. FAU - Allam, Venkata Sita Rama Raju AU - Allam VSRR AD - Graduate School of Health, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia. FAU - van Oldeniel, Daan AU - van Oldeniel D AD - Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Bhiekharie, Linsey J AU - Bhiekharie LJ AD - Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. FAU - Phipps, Simon AU - Phipps S AD - QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. FAU - Oliver, Brian G AU - Oliver BG AUID- ORCID: 0000-0002-7122-9262 AD - Graduate School of Health, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia. FAU - Gosens, Reinoud AU - Gosens R AUID- ORCID: 0000-0002-5595-152X AD - Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Groningen, The Netherlands. FAU - Sukkar, Maria B AU - Sukkar MB AD - Graduate School of Health, Faculty of Health, University of Technology Sydney, Ultimo, New South Wales, Australia. FAU - Heijink, Irene H AU - Heijink IH AUID- ORCID: 0000-0002-1260-8932 AD - Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. AD - Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210818 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Ager protein, mouse) RN - 0 (Antimicrobial Cationic Peptides) RN - 0 (Benzamides) RN - 0 (FPS-ZM1) RN - 0 (HMGB1 Protein) RN - 0 (HMGB1 protein, mouse) RN - 0 (Receptor for Advanced Glycation End Products) RN - EC 3.4.21.36 (Pancreatic Elastase) RN - 0 (Cathelicidins) SB - IM MH - A549 Cells MH - Alveolar Epithelial Cells/*pathology MH - Animals MH - Antimicrobial Cationic Peptides/*metabolism MH - Benzamides/pharmacology MH - Cell Line, Tumor MH - Disease Models, Animal MH - HMGB1 Protein/*metabolism MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Organoids/drug effects MH - Pancreatic Elastase/toxicity MH - Pulmonary Alveoli/*injuries MH - Pulmonary Disease, Chronic Obstructive/pathology MH - Receptor for Advanced Glycation End Products/antagonists & inhibitors/*metabolism MH - Regeneration/physiology MH - Cathelicidins OTO - NOTNLM OT - COPD OT - RAGE OT - emphysema OT - organoids OT - precision cut lung slices EDAT- 2021/08/19 06:00 MHDA- 2021/11/11 06:00 CRDT- 2021/08/18 08:44 PHST- 2021/08/19 06:00 [pubmed] PHST- 2021/11/11 06:00 [medline] PHST- 2021/08/18 08:44 [entrez] AID - 10.1152/ajplung.00138.2021 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2021 Oct 1;321(4):L641-L652. doi: 10.1152/ajplung.00138.2021. Epub 2021 Aug 18.