PhD thesis GMH final version.pdf (3.34 MB)
Download file

The Role of Endogenous Alpha-1 Antitrypsin During Acute Respiratory Distress Syndrome and the Potential for Augmentation Therapy

Download (3.34 MB)
thesis
posted on 23.03.2022, 10:15 authored by Grace HoganGrace Hogan
Acute Respiratory Distress Syndrome (ARDS) is a devastating illness characterised by an acute pulmonary oedema, disruption of the pulmonary alveolocapillary barrier and largescale inflammation. Despite decades of research, a curative therapy for ARDS remains elusive. While supportive strategies have improved survival slightly, a mortality rate of 30-40% persists. Alpha-1 Antitrypsin (AAT) is an endogenous serine protease produced primarily by hepatocytes. Due to the function of AAT as an anti-protease against neutrophil elastase (NE), in addition to its potent anti-inflammatory and bactericidal abilities, AAT has the potential to be a novel treatment option for ARDS. We firstly aimed to investigate the role of endogenous AAT in patients with ARDS and delineate any associations between pulmonary and circulating AAT levels with severity of lung injury and outcomes. Secondly, we wished to examine the immunomodulatory and anti-bacterial actions of AAT on monocyte/macrophages and the underlying mechanism(s) of action at play. Thirdly, we aimed to investigate the therapeutic efficacy of exogenous AAT in a pre-clinical rodent model of pneumonia induced ARDS. Levels of AAT in the bronchoalveolar lavage (BAL) fluid and plasma of patients with ARDS was significantly increased at baseline compared to normal controls. In plasma, AAT increased further at Day 4 before decreasing at Day 14. Elevated baseline and Day 28 plasma AAT levels conferred a survival benefit in ARDS while patients with an underlying deficiency in AAT production experienced a greater severity of lung injury and poorer outcomes. In vitro, AAT significantly attenuated pro-inflammatory interleukin(IL)-6 and tumour necrosis factor alpha (TNF-α) release from macrophages in a microenvironment reminiscent of ARDS. In vivo, intravenous administration of human AAT significantly improved alveolocapillary integrity and modulated inflammatory cytokine release from alveolar macrophages. Taken together, this data underscores the potential use of AAT as a novel pharmacotherapy for ARDS.

Funding

Royal College of Surgeons in Ireland

U.S. Department of Defense

History

First Supervisor

Prof. Gerard Curley

Comments

Submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2021

Published Citation

Hogan, G,. The Role of Endogenous Alpha-1 Antitrypsin During Acute Respiratory Distress Syndrome and the Potential for Augmentation Therapy [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland, 2021

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/11/2021

Programme

  • Doctor of Philosophy (PhD)

Research Area

  • Respiratory Medicine