PMID- 35507773
OWN - NLM
STAT- MEDLINE
DCOM- 20220707
LR  - 20220719
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Linking)
VI  - 67
IP  - 1
DP  - 2022 Jul
TI  - Alpha-1 Antitrypsin Therapy Modifies Neutrophil Adhesion in Patients with 
      Obstructive Lung Disease.
PG  - 76-88
LID - 10.1165/rcmb.2021-0433OC [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated 
      inflammation resulting in emphysema. The cholesterol-rich neutrophil outer plasma 
      membrane plays a central role in adhesion and subsequent transmigration to 
      underlying tissues. This study aimed to investigate mechanisms of increased 
      neutrophil adhesion in AATD and whether alpha-1 antitrypsin (AAT) augmentation 
      therapy abrogates this effect. Plasma and blood neutrophils were donated by 
      healthy controls (n = 20), AATD (n = 30), and AATD patients after AAT 
      augmentation therapy (n = 6). Neutrophil membrane protein expression was 
      investigated using liquid chromatography-tandem mass spectrometry. The effect of 
      once-weekly intravenous AAT augmentation therapy was assessed by calcium 
      fluorometric, mu-calpain, and cell adhesion assays. Decreased neutrophil plasma 
      membrane cholesterol content (P = 0.03), yet increased abundance of integrin alpha-M 
      (fold change 1.91), integrin alpha-L (fold change 3.76), and cytoskeletal adaptor 
      proteins including talin-1 (fold change 4.04) were detected on AATD neutrophil 
      plasma membrane fractions. The described inflammatory induced structural changes 
      were a result of a more than twofold increased cytosolic calcium concentration 
      (P = 0.02), leading to significant calcium-dependent mu-calpain activity (3.5-fold 
      change; P = 0.005), resulting in proteolysis of the membrane cholesterol 
      trafficking protein caveolin-1. Treatment of AAT-deficient individuals with AAT 
      augmentation therapy resulted in increased caveolin-1 and membrane cholesterol 
      content (111.8 +/- 15.5 vs. 64.18 +/- 7.8 mug/2 x 10(7) cells before and after 
      treatment, respectively; P = 0.02), with concurrent decreased neutrophil integrin 
      expression and adhesion. Results demonstrate an auxiliary benefit of AAT 
      augmentation therapy, evident by a decrease in circulating inflammation and 
      controlled neutrophil adhesion.
FAU - McEnery, Tom
AU  - McEnery T
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - White, Michelle M
AU  - White MM
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Gogoi, Debananda
AU  - Gogoi D
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Coleman, Orla
AU  - Coleman O
AD  - National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 
      Dublin 9, Ireland; and.
FAU - Bergin, David
AU  - Bergin D
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Jundi, Bakr
AU  - Jundi B
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Flannery, Ryan
AU  - Flannery R
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
AD  - Colaiste Dhulaigh College of Further Education, Dublin 17, Ireland.
FAU - Alsaif, Fatima Abbas T
AU  - Alsaif FAT
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Landers, Sarah A
AU  - Landers SA
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Casey, Michelle
AU  - Casey M
AUID- ORCID: 0000-0002-2821-6861
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Dunlea, Danielle
AU  - Dunlea D
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Meleady, Paula
AU  - Meleady P
AD  - National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 
      Dublin 9, Ireland; and.
FAU - McElvaney, Noel G
AU  - McElvaney NG
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
FAU - Reeves, Emer P
AU  - Reeves EP
AUID- ORCID: 0000-0002-1922-0447
AD  - Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, 
      Dublin 9, Ireland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Caveolin 1)
RN  - 0 (Integrins)
RN  - 0 (alpha 1-Antitrypsin)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - SY7Q814VUP (Calcium)
SB  - IM
CIN - Am J Respir Cell Mol Biol. 2022 Jul;67(1):6-7. PMID: 35522757
MH  - Calcium/metabolism
MH  - Caveolin 1/metabolism
MH  - Cholesterol/metabolism
MH  - Humans
MH  - Inflammation/metabolism
MH  - Integrins/metabolism
MH  - Neutrophils/metabolism
MH  - *Pulmonary Emphysema/metabolism
MH  - alpha 1-Antitrypsin/metabolism
MH  - *alpha 1-Antitrypsin Deficiency
OTO - NOTNLM
OT  - adhesion
OT  - alpha-1 antitrypsin deficiency
OT  - cell membrane
OT  - cholesterol
OT  - neutrophils
EDAT- 2022/05/05 06:00
MHDA- 2022/07/08 06:00
CRDT- 2022/05/04 15:14
PHST- 2022/05/05 06:00 [pubmed]
PHST- 2022/07/08 06:00 [medline]
PHST- 2022/05/04 15:14 [entrez]
AID - 10.1165/rcmb.2021-0433OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2022 Jul;67(1):76-88. doi: 10.1165/rcmb.2021-0433OC.