Decline of lung function in hereditary alpha-1 antitrypsin deficiency (AATD) progresses over time even following smoking cessation or in never smokers, or upon AAT augmentation. This is likely due to accumulation of misfolded, severe disease-causing variants of AAT within the cells’ endoplasmic reticulum, resulting in inflammatory stress, as previously shown in immune and liver cells.
Inflammation increases hallmarks of ageing such as foreshortened telomeres, evident in AATD; this can induce cellular senescence. Senescent cells are persistent and produce inflammatory mediators. Cell death is also a potential consequence of excess inflammation and can disrupt lung homeostasis and promote further inflammation. This study aims to characterise the outcomes for cells in the lungs of people with AATD across these scenarios – senescence or cell death – and to investigate therapies to specifically address this.
Working with the National Centre for Expertise in AATD at Beaumont Hospital Dublin, people with AATD and their non-deficient counterparts, with and without lung disease, will undergo bronchoalveolar lavage to retrieve lung immune cells and brushing to obtain lung tissue cells and these will be examined by cutting edge spectral cytometry for senescence and cell death, building on our preliminary findings. We will also analyse AATD heterozygous individuals to assess the consequences of lesser production of misfolded AAT.
We will confirm the importance of this paradigm by treating patient cells ex vivo with senescence targeting therapeutics to mitigate inflammation and consequent cell death. We will further explore these approaches in a murine model of AATD.
These targeted interventions will specifically address the disease process to slow lung function decline in AATD, leading the way for improved quality of life for an estimated 3.4 million people suffering from AATD worldwide by identifying therapeutic targets in a context where specific therapeutics are lacking.