In humans, acute pancreatitis (AP) has previously been shown to be associated with a decrease in plasma levels of α2-macroglobulin (a2M), the magnitude of which is related to the severity of the disease. This decrease in α2M has been attributed to consumption of this broad-spectrum protease inhibitor by activated proteases released inappropriately from injured acinar cells and by the subsequent rapid clearance of the α2M-protease complexes by cells of the reticuloendothelial system. With respect to several different clinical parameters, the opossum model of AP has previously been found to resemble closely the human disease. The current study demonstrates that opossums have a structural and functional homologue of α2M (α2Mop). α2Mop behaves identically to human α2M on SDS and native PAGE, including a mobility shift from a "slow" to a "fast" electrophoretic form on native PAGE following brief treatment of opossum plasma with trypsin. α2Mo was purified to near homogeneity (96 %), and this purified protein was shown to inhibit trypsin by an entrapment mechanism like that of human a2M. Within the same animals (n=5), α2M was found to decrease 53-77 % on Days 2 and 4 following induction of AP by ligationof the pancreatic duct. As in humans, disappearance of the "slow" form of α2Mop was not accompanied by a buildup of the "fast" electrophoretic form, indicating rapid clearance of α2Mop-protease complexes from the circulation in the opossum. Western blot results, obtained using anti-human a2M, were consistent with these conclusions. This pancreatitis-associated decrease in plasma α2Mop levels was accompanied by a decrease in trypsin-inhibitory capacity of the opossum plasma. AP in the opossum had little or no effect on the total plasma protein concentration. These results establish another clinical parameter of human AP which is reproduced in opossums and recommend the use of this opossum model to evaluate purified α2M as a potential therapy for AP.
|Original language||English (US)|
|Issue number||11 PART II|
|State||Published - 2000|