People with alpha-1 antitrypsin deficiency (AATD) are at substantial risk for chronic obstructive pulmonary disease (COPD), and develop the condition approximately 10 years earlier than matched, AAT-sufficient counterparts. Lung function decline is progressive over time even following smoking cessation or in never smokers. This implies that an intrinsic or age-related process may sustain the inflammation that gives rise to COPD. Inflammation in AATD can result from cellular stress due to accumulation of the severe disease variants of AAT within the endoplasmic reticulum (ER). Inflammation can induce senescence in cells ? a persistent, pro-inflammatory phenotype. As such, we posit that senescence is central to AATD.

To date, we have shown that Z-AAT accumulates in the ER of monocytes and neutrophils from ZZ individuals with resultant ER stress and increased cytokine production. Using spectral cytometry, we are identifying senescent leukocytes in the peripheral circulation and airway, as well as airway epithelial cells, in people with ZZ homozygous AATD, compared with matched MM cohorts with or without COPD and with people with AATD receiving AAT augmentation therapy. We have also quantified the senescence-associated secretory phenotype in the airway by multiplex ELISA.

The relevance of this paradigm will be confirmed by treating cells ex vivo with novel therapeutics that mitigate senescence. This study will open the way for investigation of strategies to mitigate senescence in AATD and, hence, inflammation and lung function decline, using existing senescence-targeting therapies that have shown clinical promise in other conditions.

Funding: Alpha-1 Laurells Training Award (Grifols)