![]() Since both processes are a feature of the lungs of patients with both centrilobular and the panlobular emphysema, more typical of AAT deficient subjects ( 19), the link to AAT and its deficiency seems more tenuous. In particular the former class of enzymes has been implicated in airflow obstruction due to damage of the small airways ( 18) and the latter in the development of emphysema. Meanwhile other classes of enzymes such as the metalloproteinases ( 16) and the cysteine proteinase cathepsin B ( 17) have been implicated as causative in the development of COPD. Thus the simple pathway of release of serine proteinases by neutrophils in the lung leading to lung damage when AAT was quantitatively or functionally deficient failed to solve the pathophysiological processes that lead to the development and progression of COPD and emphysema. However subsequent studies failed to confirm these observations showing no difference in AAT function in smokers ( 12- 14) and indeed no significant evidence of oxidised methionine in the lung ( 15). Nevertheless this observation failed to explain why only a proportion of smokers developed COPD as it reflects (at best) a simple chemical interaction that should affect all. These studies formed the basis of an entrenched concept to explain a tip in the proteinase/anti proteinase balance in the lung and other inflamed sites like the gingival cleft ( 11). Indeed two early studies of AAT in lavage fluid from smokers confirmed a reduction in function ( 9, 10). A third alternative proposed was that the active site methionine was oxidised by cigarette smoke producing a localised functional deficiency. However an alternative in subjects with normal AAT levels was that an overwhelming and excessive release of the cognate enzyme overcame the normal inhibitory protection, providing two mechanisms of disruption to the proteinase/proteinase balance required for health ( 8). In AAT deficiency this occurred because of a lack of tissue protection by the inhibitor. The concept was simple, in that serine proteinases were the mediators of the tissue damage in emphysema. These observations led to the proteinase/antiproteinase theory of the development of emphysema. Alternatively active site mutation replacing the methionine with valine can lead to an oxidant resistant form of elastase inhibitor ( 4).Īs these studies were underway purification of purified elastase from the neutrophil ( 6) and subsequently one of the other neutrophilic serine proteinases, proteinase 3 ( 7) were shown to produce emphysema like lesions in animal models. Interestingly a natural variant in which the active site methionine is replaced by arginine converts AAT into an inhibitor of thrombin resulting in a spontaneous bleeding diathesis when an acute phase response increases the concentration ( 5). This critical methionine residue can be readily oxidised leading to major reduction in its ability to inhibit proteinases like elastase ( 4). In the native protein this is methionine and leads to it being most active against human neutrophil elastase (NE) ( 4). ![]() Molecular studies indicated that AAT was not only an inhibitor of serine proteinases but that its inhibitory function and specificity was limited to an inhibitory loop and a critical amino acid at position 342 near the carboxy terminus. These two independent observations led to the assumption that an enzyme or enzymes, normally controlled by AAT, was responsible for a tissue breakdown process in the lung that resulted in destruction of alveolar integrity resulting in emphysematous change. These observations were described at the same time as an animal model of emphysema induced by the plant proteinase papain ( 3). Subsequent family studies confirmed the association with chronic lung disease and the hereditary nature of the α1 protein deficiency. Clinical assessment showed that three of the patients identified with this abnormality had severe, early onset of pulmonary emphysema ( 2), a condition that generally presents in late middle life. ![]() Its’ importance emerged following the description of five blood samples in which the α1 protein band was weak to absent on paper electrophoresis. Accepted for publication Apr 17, 2015.Īlpha-1-antitrypsin (AAT) was first identified as an inhibitor of the proteinase trypsin (and hence its early name) in the 1950’s ( 1). Keywords: Alpha-1-antitrypsin (AAT) inflammation immunity
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |