Investigating the interaction of Cigarette Smoke and Alpha-1 Antitrypsin Deficiency in a mouse model of Chronic Obstructive Pulmonary Disease
- Publication Type:
- Thesis
- Issue Date:
- 2025
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Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterised by chronic inflammation. Although predominantly caused by cigarette smoke (CS), genetic factors such as alpha-1 antitrypsin (A1AT) deficiency also contribute.
This project examined the impact of CS on A1AT deficiency by assessing A1AT gene and protein expression in an experimental model of CS-induced COPD revealing that CS causes fluctuating increases in A1AT protein in the lung, likely as a protective response to CS.
Investigations into the mechanism of A1AT deficiency showed increased inflammation predominantly driven by neutrophils, IL1β and CXCL15 with increased alveolar destruction in A1AT knockout (KO) CS compared to WT CS mice, highlighting exacerbated lung damage in the absence of A1AT. Investigation of the Z A1AT mutation found increased alveolar destruction attributed to Z toxicity.
Conventional DCs accumulated in the lungs of A1AT- KO CS mice suggesting A1AT specific mechanisms may also influence the behaviour of DCs. Further studies showed increased DC migration in A1AT-KO compared to WT mice.
These studies highlight the impact of A1AT, as an antiprotease and modulator of inflammation, specifically neutrophils, conventional DCs and certain cytokines. An improved mouse model of A1AT deficiency and COPD (A1AT-KO CS) was established to test future therapies.
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