PMID- 36068572 OWN - NLM STAT- MEDLINE DCOM- 20220908 LR - 20231213 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 23 IP - 1 DP - 2022 Sep 6 TI - Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency. PG - 232 LID - 10.1186/s12931-022-02161-z [doi] LID - 232 AB - BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder most commonly secondary to a single mutation in the SERPINA1 gene (PI*Z) that causes misfolding and accumulation of alpha-1 antitrypsin (AAT) in hepatocytes and mononuclear phagocytes which reduces plasma AAT and creates a toxic gain of function. This toxic gain of function promotes a pro-inflammatory phenotype in macrophages that contributes to lung inflammation and early-onset COPD, especially in individuals who smoke cigarettes. The aim of this study is to determine the role of cigarette exposed AATD macrophages and bronchial epithelial cells in AATD-mediated lung inflammation. METHODS: Peripheral blood mononuclear cells from AATD and healthy individuals were differentiated into alveolar-like macrophages and exposed to air or cigarette smoke while in culture. Macrophage endoplasmic reticulum stress was quantified and secreted cytokines were measured using qPCR and cytokine ELISAs. To determine whether there is "cross talk" between epithelial cells and macrophages, macrophages were exposed to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and their inflammatory response was determined. RESULTS: AATD macrophages spontaneously produce several-fold more pro-inflammatory cytokines as compared to normal macrophages. AATD macrophages have an enhanced inflammatory response when exposed to cigarette smoke-induced extracellular vesicles (EVs) released from airway epithelial cells. Cigarette smoke-induced EVs induce expression of GM-CSF and IL-8 in AATD macrophages but have no effect on normal macrophages. Release of AAT polymers, potent neutrophil chemo attractants, were also increased from AATD macrophages after exposure to cigarette smoke-induced EVs. CONCLUSIONS: The expression of mutated AAT confers an inflammatory phenotype in AATD macrophages which disposes them to an exaggerated inflammatory response to cigarette smoke-induced EVs, and thus could contribute to progressive lung inflammation and damage in AATD individuals. CI - (c) 2022. The Author(s). FAU - Khodayari, Nazli AU - Khodayari N AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. Nazli.khodayari@medicine.ufl.edu. FAU - Oshins, Regina AU - Oshins R AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. FAU - Mehrad, Borna AU - Mehrad B AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. FAU - Lascano, Jorge E AU - Lascano JE AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. FAU - Qiang, Xiao AU - Qiang X AD - MilliporeSigma, Burlington, MO, USA. FAU - West, Jesse R AU - West JR AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. FAU - Holliday, L Shannon AU - Holliday LS AD - Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, FL, USA. FAU - Lee, Jungnam AU - Lee J AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. FAU - Wiesemann, Gayle AU - Wiesemann G AD - College of Medicine, University of Florida, Gainesville, FL, USA. FAU - Eydgahi, Soroush AU - Eydgahi S AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. FAU - Brantly, Mark AU - Brantly M AD - Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, 1600 SW Archer Rd Rm M453A, Gainesville, FL, 32610, USA. LA - eng GR - R01 AI135128/AI/NIAID NIH HHS/United States GR - U01 EB024501/EB/NIBIB NIH HHS/United States GR - F007320/Alpha-1 Foundation/ PT - Journal Article DEP - 20220906 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Cytokines) RN - 0 (alpha 1-Antitrypsin) SB - IM EIN - Respir Res. 2023 Nov 4;24(1):266. PMID: 37925417 MH - *Cigarette Smoking/adverse effects MH - Cytokines/metabolism MH - Epithelial Cells/metabolism MH - *Extracellular Vesicles/metabolism MH - Leukocytes, Mononuclear/metabolism MH - Macrophage Activation MH - *Pneumonia/metabolism MH - *Pulmonary Disease, Chronic Obstructive/metabolism MH - Nicotiana MH - alpha 1-Antitrypsin/genetics/metabolism MH - *alpha 1-Antitrypsin Deficiency/genetics PMC - PMC9446525 OTO - NOTNLM OT - Alpha-1 antitrypsin OT - Cigarette smoke OT - Extracellular vesicles OT - Lung disease OT - Macrophages COIS- The authors have no conflict of interest. EDAT- 2022/09/07 06:00 MHDA- 2022/09/09 06:00 PMCR- 2022/09/06 CRDT- 2022/09/06 23:39 PHST- 2022/03/03 00:00 [received] PHST- 2022/08/27 00:00 [accepted] PHST- 2022/09/06 23:39 [entrez] PHST- 2022/09/07 06:00 [pubmed] PHST- 2022/09/09 06:00 [medline] PHST- 2022/09/06 00:00 [pmc-release] AID - 10.1186/s12931-022-02161-z [pii] AID - 2161 [pii] AID - 10.1186/s12931-022-02161-z [doi] PST - epublish SO - Respir Res. 2022 Sep 6;23(1):232. doi: 10.1186/s12931-022-02161-z.