In conclusion, a single administration of study agent in patients with STEMI was well tolerated and was associated with a blunted acute inflammatory response. Compared with historical controls, the area under the curve of CRP levels was significantly lower 14 days after admission in the study group (75.9 vs. C-reactive protein (CRP) and plasma AAT levels were determined at admission, 72 hours, and 14 days, and patients were followed clinically for 12 weeks for the occurrence of new onset heart failure, recurrent myocardial infarction, or death. Ten patients with acute STEMI were enrolled and received AAT at 60 mg/kg IV within 12 hours of admission. The objective of this prospective open-label, single-arm treatment study was to determine the safety and tolerability of human plasma-derived AAT and its effects on the acute inflammatory response in non-AAT deficient patients with ST-segment elevation myocardial infarction (STEMI). Administration of human plasma-derived AAT is protective in models of acute myocardial infarction in mice. Yekaterina Opsha, Alison Brophy, in Side Effects of Drugs Annual, 2015 α1-AntitrypsinĪlpha-1 antitrypsin (AAT) has broad anti-inflammatory and immunomodulating properties. Lockett et al., Am J Respir Cell Mol Biol 2013 Tumour necrosis factor-α-converting enzyme (ADAM-17) Janciauskiene et al., Am J Respir Cell Mol Biol 2008 Pixley and Danishefsky, Biochemistry 1983 Serine proteases associated with coagulation Neutrophil elastase, proteinase 3, cathepsin Gĭuranton and Bieth, Am J Respir Cell Mol Biol 2003 Hence, as a broad-spectrum protease inhibitor, A1AT plays more important role in regulating diverse inflammatory responses than inhibitors targeting one specific protease. So far, it appears that A1AT can directly bind cell membrane-associated proteases, like ADAM17, or reduce activity of caspases and metalloproteases indirectly via “serpin” function. How A1AT inhibits nonserine proteases, it is not clear. For example, A1AT inhibits caspases-3 and 8 resulting in antiapoptotic effects and inhibits neutrophil clapain I, with implications to neutrophil migration and functional activities ( Table 6.1). New findings have emerged on the ability of A1AT to inhibit not only serine proteases but also other classes of proteases, like metalloproteases and cysteine-aspartic proteases. The importance of A1AT in maintaining protease–antiprotease homeostasis is supported by a positive correlation between increased elastase levels and severity of emphysema in patients with inherited A1AT deficiency. Remarkably, A1AT does not abolish protease activity but plays a delicate balancing role, allowing enough neutrophil proteases to be present for the host defense, yet at the same time providing an antiprotease screen to prevent host tissue injury. These polymers form spontaneously in the lungs of PiZ patients, where they stimulate recruitment and activation of PMN leading to increased PMN serine proteinase burden, which may promote loss of alveoli in α 1-PI-deficient patients.Ī1AT is well characterized as an inhibitor of neutrophil elastase, cathepsin G, and proteinase 3. Polymers of the Z protein also have proinflammatory properties. The severe lung injury in α 1-PI-deficient individuals may be due to defective confinement of NE-mediated proteolytic activity and to the proinflammatory properties of the PiZ variant protein. PiZ homozygous individuals have an increased risk of developing very severe, early onset panlobular emphysema if they smoke cigarettes. This defective secretion of α 1-PI from hepatocytes in PiZ homozygous individuals results in plasma α 1-PI levels ∼10–15% of normal.
A common deficiency variant of α 1-PI, PiZ, results from a single amino acid substitution ( 342lysine to glutamic acid) causing loop sheet polymerization of Z α 1-PI molecules, which tangle within the endoplasmic reticulum of the hepatocyte forming inclusion bodies. Α 1-PI is a highly polymorphic protein and more than 70 variants have been identified. Owen, in Encyclopedia of Respiratory Medicine, 2006 Pulmonary Emphysema in Patients with α 1-PI Deficiency
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