HPE Alpha 1 Antitrypsin Deficiency | Page 8

anti-NE capacity. 33 Further studies have shown that AAT is exquisitely sensitive to inactivation by products of cigarette smoke, which render AAT unable to inhibit NE. 34 A combination of low levels of AAT, increased neutrophilic inflammation and cigarette smoking is the ‘perfect storm’, which results in the accelerated emphysema seen in AATD individuals who smoke. Effects in the liver and elsewhere In most cases of AATD, the deficiency results not from a failure of AAT production but from a retention of AAT in the liver, with subsequent systemic and local deficiencies, particularly in the lung. The Z mutant of AAT (ZAAT) is retained within the ER of hepatocytes as polymers. Misfolding of mutant forms of AAT within the ER of AAT- producing cells can lead to inflammatory effects that contribute significantly to the liver disease associated with this condition. 35 In order to cope with the increased load of misfolded protein within the ER, cellular disposal mechanisms (ERAD pathway, autophagy) are activated. When misfolded proteins accumulate within the ER, the cell undergoes ‘ER stress’, which is characterised by a number of intracellular responses including the unfolded protein response, ER overload response, and apoptosis. 36,37 Translational attenuation (premature termination of the translation process) occurs as an immediate response, reducing the load of host protein synthesis in the ER and preventing further accumulation of unfolded proteins. 38 Little is known about the underlying mechanism but it is thought to involve increased calcium leak from a distended ER. 39 In AATD it is not clear whether increased autophagy causes mitochondrial damage or whether the mitochondria are directly damaged by ZAAT accumulation in the ER. In any event, apoptotic pathways are triggered in AATD cells. 40 Some studies have postulated a specific role for activation of caspase-4, an ER-specific caspase 41 in AATD patients whereas others have shown that while caspase-4 is activated, it is not essential for ZAAT-induced apoptosis. These studies suggested a central role for P-I-3 kinase and Bad with the potential for the bile acid tauroursodeoxycholic acid to target this pathway and promote cell survival in ZAAT-expessing cells. 40 Other pro-apoptotic pathways in AATD include the unopposed action of TNF-a. 42 Inhibitors of apoptosis are upregulated in References 1 Bergin DA et al. Alpha-1 antitrypsin: a potent anti- inflammatory and potential novel therapeutic agent. Arch Immunol Ther Exp (Warsz) 2012;60(2):81–97. 2 Beatty K, Bieth J, Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1- antichymotrypsin. 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