[PDF][PDF] alpha 1-Antitrypsin: molecular pathology, leukocytes, and tissue damage.

RW Carrell - The Journal of clinical investigation, 1986 - Am Soc Clin Investig
RW Carrell
The Journal of clinical investigation, 1986Am Soc Clin Investig
Introduction: a,-antitrypsin and the serpins The maintenance of health requires a balance
between thedefensive and offensive systems ofthe body. One such balance that is now just
becoming understood at the molecular level is the one between the enzymes that break
downprotein and the an-tiproteases that act as their inhibitors. Of particular importance is the
group of closely related enzymes, the serine proteases, which are responsible for triggering
the inflammatory cascades of the plasma such as coagulation, kinin release, fibrinolysis, and …
Introduction: a,-antitrypsin and the serpins The maintenance of health requires a balance between thedefensive and offensive systems ofthe body. One such balance that is now just becoming understood at the molecular level is the one between the enzymes that break downprotein and the an-tiproteases that act as their inhibitors. Of particular importance is the group of closely related enzymes, the serine proteases, which are responsible for triggering the inflammatory cascades of the plasma such as coagulation, kinin release, fibrinolysis, and complement activation. The triggering by these enzymes of the plasma cascades is controlled by an appropriately specialized group of plasma protease inhibitors, eg, antithrombin, antiplasmin, and the first component ofcomplement (C1)'inhibitor. These serine protease inhibitors are now known to belong to the same proteinfamily-the serpins-and consequently to share a common molecular structure andmechanism, Table I (1-6). The archetype ofthe serpin family is a,-antitrypsin, the inhibitor present at highest concentration in human plasma. Although named a,-antitrypsin, its physiologic target is leukocyte elastase rather than trypsin (7), and for this reason, it is alter-natively called a,-proteinase inhibitor; in this review, the his-torical name will be retained and sometimes abbreviated to an-titrypsin.
Interest has focused on a,-antitrypsin because ofthe frequent occurrence of its genetic deficiency in Europeans and the asso-ciation of its homozygous deficiency with the development of premature emphysema (8) and progressive liver disease (9). In-vestigation of the molecular basis of this association (10) has stimulated research into the general pathogenesis ofemphysema. More recently, the structural studies of a,-antitrypsin have pro-vided an insight into the function of the other plasma serpins and their vulnerability in the shock syndromes (11).
The Journal of Clinical Investigation