Z-alpha1-antitrypsin polymers and small airways disease: a new paradigm in alfa-1 anti-trypsin deficiency-related COPD development?

Abstract

The presence of Alpha1-Antitrypsin (AAT) polymers, known to promote a sustained pro-inflammatory activity, has been previously demonstrated in bronchial biopsies of subjects with Z-AAT deficiency (AATD) suggesting a possible role in the development of COPD through a small airway disease impairment. The study aimed to assess the presence of small airways dysfunction and the potential correlation with the presence of Z-AAT polymers obtained by Exhaled Breath Condensate (EBC) collection in PiZZ subjects, as compared with matched healthy PiMM subjects. We enrolled 19 asymptomatic, never smoker subjects: 9 PiZZ and 10 PiMM as controls, without obstructive ventilatory defect (i.e., normal FEV1/VC% ratio). All subjects underwent complete pulmonary function tests (PFT). EBC was collected in all subjects. ELISA test was applied to search for Z-AAT polymers. The PiZZ subjects showed normal lung volumes and DLCO values. However, in comparison with PiMM subjects, the single breath test N2 wash-out revealed significant differences regarding the phase III slope (1.45±0.35 N2/L vs. 0.96±0.40 N2/L) (p<0.02) in the PiZZ subjects, while the closing volume/vital capacity ratio (14.3±4.5 % vs. 11.3±6.3 %) was not significantly increased. The ELISA test detected the presence of Z-AAT polymers in 44% of PiZZ patients. Asymptomatic, never smoker PiZZ subjects with normal spirometry and lung diffusion capacity showed airways impairment when compared to PiMM subjects. Although Z-AAT polymers were found only in 44% of PiZZ subjects, these findings suggest the possibility that chronic bronchiolitis can develop as a result of the long-term pro-inflammatory activity of Z-AAT polymers in subjects with Z-related AATD.

Early Origins of Chronic Obstructive Pulmonary Disease: Prenatal and Early Life Risk Factors

“…Smoking and occupational exposure to pollutants aggravate the lung damage, leading to COPD development [14]. Moreover, in a Pi*ZZ subject, the presence of alpha1antitrypsin polymers promotes inflammation with consequent impairment in small airways and the long-term development of COPD [15]. AAT deficit is an under-diagnosed condition, but according to a recent study, its prevalence among patients with COPD is 1.29% [95% confidence interval (CI) 0.93-1.74], mainly the Pi*ZZ type (0.92%, 95% CI 0.62-1.31) and less frequently the Pi*SZ type (0.37%, 95% CI 0.19-0.64) [16].…”

Alpha1-antitrypsin deficiency and cardiovascular disease: questions and issues of a debated relation

“…The Z variant causes the synthesis of a defective form of AAT with a marked tendency to generate precipitating polymer aggregates leading to cellular engorgement and subsequent tissue damage. 2,3 In recent decades, research has devoted most of its efforts to finding correlations between AATD and the principal liver and respiratory diseases and in searching for replacement therapies to balance the low serum AAT levels. [4][5][6] However, we cannot ignore that AAT, when released into the bloodstream, carries out its protective and anti-inflammatory action at a systemic level.…”

“…Among these, the Z variant resulting from an aminoacidic substitution GLU342LYS has the most severe clinical consequences, affecting especially its synthesis sites with cirrhosis, emphysema, Chronic Obstructive Pulmonary Disease (COPD) and asthma. The Z variant causes the synthesis of a defective form of AAT with a marked tendency to generate precipitating polymer aggregates leading to cellular engorgement and subsequent tissue damage 2,3 …”