Lung microhaemorrhage drives oxidative/inflammatory damage in α1-antitrypsin deficiency
| Autor: | Cesare Saltini, Naweed Mohammad, Yan Xin, Rodolfo Alvarado, Andrew J. Ghio, Craig G. Moneypenny, Alberto Riva, Dongtao Fu, Tammy Flagg, Giovanni F.A. Saltini, Ivan Arisi, Kristianna M. Fredenburg, Yang Zhang, Jorge E. Lascano, Mark Brantly |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | ERJ Open Research, Vol 9, Iss 3 (2023) |
| Druh dokumentu: | article |
| ISSN: | 2312-0541 23120541 |
| DOI: | 10.1183/23120541.00662-2022 |
| Popis: | Background Animal models using intratracheal instillation show that elastase, unopposed by α1-antitrypsin (AAT), causes alveolar damage and haemorrhage associated with emphysematous changes. The aim of the present study was to characterise any relationship between alveolar haemorrhage and human AAT deficiency (AATD) using bronchoalveolar lavage (BAL) and lung explant samples from AATD subjects. Methods BAL samples (17 patients, 15 controls) were evaluated for free haem (iron protoporphyrin IX) and total iron concentrations. Alveolar macrophage activation patterns were assessed using RNA sequencing and validated in vitro using haem-stimulated, monocyte-derived macrophages. Lung explants (seven patients, four controls) were assessed for iron sequestration protein expression patterns using Prussian blue stain and ferritin immunohistochemistry, as well as ferritin iron imaging and elemental analysis by transmission electron microscopy. Tissue oxidative damage was assessed using 8-hydroxy-2′-deoxyguanosine immunohistochemistry. Results BAL collected from AATD patients showed significantly elevated free haem and total iron concentrations. Alveolar and interstitial macrophages in AATD explants showed elevated iron and ferritin accumulation in large lysosomes packed by iron oxide cores with degraded ferritin protein cages. BAL macrophage RNA sequencing showed innate pro-inflammatory activation, replicated in vitro by haemin exposure, which also triggered reactive oxygen species generation. AATD explants showed massive oxidative DNA damage in both lung epithelial cells and macrophages. Conclusions BAL and tissue markers of alveolar haemorrhage, together with molecular and cellular evidence of macrophage innate pro-inflammatory activation and oxidative damage, are consistent with free haem stimulation. Overall, this initial study provides evidence for a pathogenetic role of elastase-induced alveolar haemorrhage in AATD emphysema. |
| Databáze: | Directory of Open Access Journals |
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