Abstract
Among several protease inhibitors (PI) in the body, α1-antitrypsin (α1AT) and α2-macroglobulin (α2MG) are supposed to be the major with regard to their plasma concentration and activities. Though these PI are able to inhibit several proteases in the body such as plasmin or trypsin in vitro, their physiological function in serum are unknown. Furthermore, it is not clear why there is an increase of these proteins in certain physiological and pathological conditions. Recently proteolytic enzymes such as thrombin or neutral proteases derived from polymorphonuclear leukocytes has been demonstrated on the surface of lymphocytes and also shown to be capable of inducing mitogenesis in lymphocytes. Further, the presence of α1AT or α2MG have been demonstrated on lymphocytes.
The present study was performed firstly to know the fate of these PI in the body which were raised by inflammation or tumor bearing. Secondary, the possible mechanism that the control of proteolytic activity may be involved in the regulation of lymphocyte blastogenesis was studied. As a results, imrnunoregulatory effect of α2MG has been proposed.
Upon turpentine injection serum α1AT rapidly increased to the maximum, which being 1.7 times that of normal control, within 24hr in rats. α2MG increased to maximum value of about 400mg/dl between 24 and 72 hr after turpentine injection. This maximum value is calculated to be about 100 times that of normal control.
Radiolabeled α1AT and α2MG were administered intravenously into the rats bearing inflammatory granuloma or sarcoma and their distributi0ns into various tissues were examined as a function of time. Considerable amount of α1AT remained in blood for 24hr, while very few amount of α2MG and its degradation products were found in the circulation at 6hr after administration. It may be presumed from this result that intravenously administered α2MG was rapidly degraded and disappeared from circulation. α1AT accumulated to a higher extent and persisted longer in the tumor or inflammatory tissues than in any other normal tissues during 72 hr period. Similar results were obtained in the case of α2MG though the level of the protein in the tissues were much lower than those of α1AT.
Among normal tissues examined, the highest distribution of α1AT was found in lung, followed by kidney, muscle, spleen and liver in that order. Considering the anatomical characteristics of the lung that this organ is directly open to outside environment being exposed to the toxic agents and that severe tissue destructions are seen in patients with α1AT deficiency, the accumulation of al AT in lung may be expected to prevent the tissue damage. The distribution of α2MG into normal tissues were far low compared to α1AT and little differences were observed among each tissue. These results suggest that α1AT and α2MG may play some roles in the site of inflammation or tumor tissues to regulate inflammatory processes or tumor proliferation. α1AT would preferably act in the tissue while α2MG in the circulation.
The influence of PI on the immune reaction system was examined in vitro using lymphocytes culture. Con A or PHA induced lymphocyte blastogenesis was inhibited by addition of α2MG in the culture medium. This inhibition was not observed when the concentration of α2MG in culture was physiological level, while remarkable inhibition was occurred when the protein concentration increased up to the serum level in rats with inflammation.
