Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?

Crossley, Diana; Stockley, Robert A.; Sapey, Elizabeth

doi:10.1007/s40266-019-00684-7

Cited by 6 publications

(2 citation statements)

References 179 publications

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“…Growing evidence suggests that ECM dysregulation is an important hallmark of lung ageing, mostly as a result of proteinase/ anti-proteinase imbalance (Meiners et al, 2015). This is exemplified in AATD, where ECM degradation is a hallmark of the disease (Crossley et al, 2019). ECM degradation is closely associated with proteinases, and although neutrophil serine proteinases are the quintessential proteinase for ECM degradation (Butler et al, 2018), others are implicated.…”

Section: Ecm Dysregulationmentioning

confidence: 99%

Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways

Faniyi

Hughes

Scott

et al. 2022

British J Pharmacology

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Lung diseases disproportionately affect elderly individuals. The lungs form a unique environment: a highly elastic organ with gaseous exchange requiring the closest proximity of inhaled air containing harmful agents and the circulating blood. The lungs are highly susceptible to senescence, with age and ‘inflammageing’ creating a pro‐inflammatory environment with a reduced capacity to deal with challenges. While lung diseases may have disparate causes, the burden of ageing and inflammation provides a common process that can exacerbate seemingly unrelated pathologies. However, these shared pathways may also provide a common route to treatment, with increased interest in drugs that target ageing processes across respiratory diseases. In this review, we will examine the evidence for the increased burden of lung disease in older adults, the structural and functional changes seen with advancing age and assess what our expanding knowledge of inflammation and ageing pathways could mean for the treatment of lung disease. LINKED ARTICLES This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc

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Section: Ecm Dysregulationmentioning

confidence: 99%

Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways

Faniyi

Hughes

Scott

et al. 2022

British J Pharmacology

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“…Alpha 1 Anti-trypsin deficiency (AATD) is a rare, genetic cause of Chronic Obstructive Pulmonary Disease (COPD) with an emphysema dominant phenotype. It affects between 1 in 2000 to 1 in 5000 individuals [ 1 ]. The lung disease associated with AATD is variable but in general, is associated with faster progression and decline in lung physiology compared with non-AATD COPD [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools

Sapey,

Crowley,

Edgar

et al. 2024

Orphanet J Rare Dis

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Background Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD. This study had three aims. To compare CVD risk in never-augmented AATD patients to non-AATD COPD and healthy controls (HC). To assess relationships between CVD risk and lung physiology. To determine if neutrophil proteinase activity was associated with CVD risk in AATD. Cardiovascular risk was assessed by QRISK2® score and aortic stiffness measurements using carotid-femoral (aortic) pulse wave velocity (aPWV). Medical history, computed tomography scans and post-bronchodilator lung function parameters were reviewed. Systemic proteinase 3 activity was measured. Patients were followed for 4 years, to assess CVD development. Results 228 patients with AATD, 50 with non-AATD COPD and 51 healthy controls were recruited. In all COPD and HC participants, QRISK2® and aPWV gave concordant results (with both measures either high or in the normal range). This was not the case in AATD. Once aPWV was adjusted for age and smoking history, aPWV was highest and QRISK2® lowest in AATD patients compared to the COPD or HC participants. Higher aPWV was associated with impairments in lung physiology, the presence of emphysema on CT scan and proteinase 3 activity following adjustment for age, smoking status and traditional CVD risk factors (using QRISK2® scores) in AATD. There were no such relationships with QRISK2® in AATD. AATD patients with confirmed CVD at four-year follow up had a higher aPWV but not QRISK2® at baseline assessment. Conclusion aPWV measured CVD risk is elevated in AATD. This risk is not captured by QRISK2®. There is a relationship between aPWV, lung disease and proteinase-3 activity. Proteinase-driven breakdown of elastin fibres in large arteries and lungs is a putative mechanism and forms a potential therapeutic target for CVD in AATD.

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Living with the enemy: from protein-misfolding pathologies we know, to those we want to know

Emwas

Alghrably

Dhahri

et al. 2021

Ageing Research Reviews

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Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease?

Cited by 6 publications

References 179 publications

Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways

Inflammation, ageing and diseases of the lung: Potential therapeutic strategies from shared biological pathways

Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools

Living with the enemy: from protein-misfolding pathologies we know, to those we want to know

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