Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

The last two decades efforts have been made in investigation of genes that encode proteins involved in pathogenesis of emphysema and chronic obstructive pulmonary disease (COPD). So far, SERPINA1 gene which encodes protein alpha-1-antitrypsin (A1AT) is the only defined genetic risk factor associated with early development of emphysema. The A1AT is dominant protein of 1 electrophoretic fraction of serum proteins, whose main physiological role is to inhibit neutrophil elastase (NE) in the lower respiratory tract, and protect pulmonary connective tissue from NE released from triggered neutrophiles. Neutrophil elastase is serine protease that degrades elastin of the alveolar walls as well other structural proteins of a variety of tissues. Hereditary alpha-1-antitrypsin deficiency (A1ATD) is associated with retention of mutant A1AT polymers in hepatocytes which leads to decrease of circulating A1AT with less than 15% of normal level in A1ATD homozygotes. Since the integrity of lung alveoli is maintained by proper circulating level of A1AT, severe deficiency of this protein was identified as genetic risk factor for emphysema and COPD. Clinical manifestation of emphysema in patients with A1ATD occurs in 3th decade in smokers and in the 5th decade in non-smokers (Larsson, 1978; Janus et al., 1985) and requires replacement therapy with purified A1AT pooled from donor plasma. Genetic epidemiologic studies show that A1ATD may affect 1 in about 1,500 individuals in Europe (De Serres, 2002). Approximately 3.4 million individuals of all racial subgroups are affected by A1ATD worldwide (De Serres, 2002). Liver disease in early childhood is second clinically significant consequence resulting from retention of mutant A1AT polymers in hepatocytes (Eriksson, 1986; Sveger, 1976). Clinically it is presents as neonatal cholestasis which may progress to juvenile chirosis or slowly progress to the liver disease in adults (Mahadeva and Lomas, 1998). In the early sixties of the last century, Laurell and Eriksson discovered that the absence of the electrophoretic 1-globulin pattern of serum is associated with A1AT deficiency (Laurell and Eriksson, 1963). At the same time was discovered an association between A1ATD and emphysema in relatively young patients in fourth decade of life (Eriksson, 1964; Lieberman,