LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE
| Autor: | Reinoud Gosens, Laura Hesse, Irene H. Heijink, Daan van Oldeniel, Maria B. Sukkar, Simon D. Pouwels, Venkata Sita Rama Raju Allam, Brian G. Oliver, Xinhui Wu, Linsey J. Bhiekharie, Simon Phipps |
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| Přispěvatelé: | Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC) |
| Rok vydání: | 2021 |
| Předmět: |
endocrine system diseases
Physiology Respiratory System Receptor for Advanced Glycation End Products SUSCEPTIBILITY DISEASE RAGE (receptor) Mice Pulmonary Disease Chronic Obstructive SMOKE-INDUCED EMPHYSEMA HMGB1 Protein Diffuse alveolar damage organoids Mice Knockout Pancreatic Elastase biology respiratory system RAGE Organoids emphysema medicine.anatomical_structure Benzamides cardiovascular system medicine.symptom GLYCATION END-PRODUCTS INDUCED DAMP RELEASE Pulmonary and Respiratory Medicine Inflammation HMGB1 Epithelial Damage INFLAMMATION Cathelicidins Cell Line Tumor Physiology (medical) medicine Animals Humans Regeneration COPD A549 cell Lung RECEPTOR business.industry Regeneration (biology) nutritional and metabolic diseases Cell Biology Mice Inbred C57BL Pulmonary Alveoli Disease Models Animal 0606 Physiology 1116 Medical Physiology A549 Cells Alveolar Epithelial Cells Cancer research biology.protein business human activities Antimicrobial Cationic Peptides precision cut lung slices |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology, 321(4), L641-L652. AMER PHYSIOLOGICAL SOC |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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