SELECTIVE NECROSIS OF CARDIAC AND SKELETAL MUSCLE INDUCED EXPERIMENTALLY BY MEANS OF PROTEOLYTIC ENZYME SOLUTIONS GIVEN INTRAVENOUSLY

Focal necrosis of cardiac and skeletal muscle was produced regularly in rabbits by means of a single intravenous or intra-arterial injection of a solution of crude papain. Similar lesions were produced in rats and mice injected with this material. The intravenous injection of solutions of ficin, trypsin, and streptokinase also resulted in comparable lesions of cardiac and skeletal muscle in rabbits. The lesions in the myocardium became apparent within 6 hours after injection of the enzyme; they consisted essentially of focal degeneration and necrosis of the sarcoplasm and myofibrils within a segment of muscle fiber. An inflammatory reaction consisting of a small number of polymorphonuclear leukocytes and considerable numbers of mononuclear cells, and often multi-nucleated giant cells, was present within the lesions. In some instances severely damaged fibers were replaced by fibrous tissue and in others proliferation of muscle cell nuclei and restitution of the fiber appeared to take place. Similar changes of a lesser degree were also observed in skeletal muscle. The findings are discussed in connection with the pathogenesis of the anatomical lesions of rheumatic fever, periarteritis nodosa, and other hypersensitivity states

EXPERIMENTAL ERYTHROBLASTOSIS FETALIS IN RABBITS : I. CHARACTERIZATION OF A PAIR OF ALLELIC BLOOD GROUP FACTORS AND THEIR SPECIFIC IMMUNE ISOANTIBODIES

A pair of blood group factors, designated G and g, was identified in rabbits by serological means. These factors were found to be alleles, and one or the other or both of them were regularly present in the red cells of every one of a large number of mongrel and inbred rabbits. The factors were not demonstrable in other tissue cells or in the body fluids. They were capable of stimulating the formation of specific immune isoantibodies when repeatedly injected into appropriate rabbits. In most instance both agglutinating and coating antibodies to the G or g factors were present in a given antiserum. The coating antibodies-which did not act as true blocking antibodies-were detected by means of an antiglobulin test (Coombs test), or by means of specific cells modified by the action of trypsin. The antibodies were heat-stable and were active over a wide temperature range; and under suitable conditions, they proved to be potent hemolysins and also capable of fixing complement. The characteristics of the antigens and antibodies of the rabbit G-g system bear a striking resemblance to those of the Rh-Hr system of man

EXPERIMENTAL ERYTHROBLASTOSIS FETALIS IN RABBITS : II. THE PASSAGE OF BLOOD GROUP ANTIGENS AND THEIR SPECIFIC ISOANTIBODIES ACROSS THE PLACENTA

Female rabbits became immunized during pregnancy to the rabbit blood group factors G or g in five out of ten instances in which the red cells of the fetuses carried one of the factors absent in the mother. Antibodies so produced were of low titer and disappeared in all cases within 6 weeks after the birth of the litter. Repeated pregnancies did not result in additive increases in titer. Antibodies to the G-g factors, whether produced by the injection of red cells or by pregnancy, crossed the placenta readily from mother to fetus and were found at birth (and prior to nursing) associated with the red cells and in the serum of the fetuses. The rabbit placenta appeared to be equally permeable to the agglutinating and coating antibodies. The implications of these findings and their relation to the pathogenesis of erythroblastosis fetalis are briefly touched upon

THE PATHOGENESIS OF HYPERLIPEMIA INDUCED BY MEANS OF SURFACE-ACTIVE AGENTS : I. INCREASED TOTAL BODY CHOLESTEROL IN MICE GIVEN TRITON WR 1339 PARENTERALLY

Mice rendered hyperlipemic by means of intravenous or subcutaneous injections of triton WR 1339 were found to have an increase in the total amount of cholesterol in their bodies. This observation indicates that the injected surface-active agent affects the metabolism of cholesterol and brings about hyperlipemia by augmenting the synthesis of lipides, or by interfering with their degradation or excretion, or by some combination of these factors. The implications of the findings for the pathogenesis of the hyperlipemia induced by triton are discussed further in the accompanying paper (16)

THE PATHOGENESIS OF HYPERLIPEMIA INDUCED BY MEANS OF SURFACE-ACTIVE AGENTS : II. FAILURE OF EXCHANGE OF CHOLESTEROL BETWEEN THE PLASMA AND THE LIVER IN RABBITS GIVEN TRITON WR 1339

Rabbits subjected to subtotal hepatectomy failed to develop increased serum cholesterol levels following parenteral injection of triton WR 1339, the finding indicating that the liver is essential for the establishment of the hypercholesterolemia induced by surface-active agents. The cholesterol content of the livers of rabbits rendered hyperlipemic by means of triton remained unchanged both during the rapid rise of the serum cholesterol levels and during the return to normal values. By contrast, the cholesterol content of the livers of rabbits fed cholesterol rose progressively over a period of 5 weeks, concommittant with the increase in serum cholesterol levels. The findings provide support for the hypothesis that surface-active agents bring about hyperlipemia by altering the circulating lipoproteins in some manner so that they are retained in the circulating body fluids

THE INFLUENCE OF INTRAVENOUSLY ADMINISTERED SURFACE-ACTIVE AGENTS ON THE DEVELOPMENT OF EXPERIMENTAL ATHEROSCLEROSIS IN RABBITS

A study was made of the relationship of blood lipids to the development of experimental atherosclerosis. Rabbits fed a diet containing cholesterol were found to develop hyperlipemia characterized by a great increase in blood cholesterol and a much lesser increase in blood phospholipids; after several weeks they manifested conspicuous atherosclerosis of the aorta, as has often been observed by others. Comparable rabbits fed the same diets containing added cholesterol were given in addition repeated intravenous injections of the surface-active agents Tween 80 and Triton A20; these animals developed hyperlipemia which was characterized by a great increase in blood cholesterol and an equivalent or even greater increase in phospholipids, and they had much less atherosclerosis than did the control rabbits fed cholesterol alone. In further experiments it was observed that repeated intravenous injections of Tween 80 did not result in resorption of previously induced atherosclerosis in rabbits. The findings are discussed in relation to the pathogenesis of natural and experimental atherosclerosis

INHIBITION OF LIPOPROTEIN LIPASE ACTIVITY FOLLOWING INJECTION OF PITUITARY EXTRACTS INTO RABBITS

Rabbits given a single subcutaneous injection of an alkaline extract of hog, bovine, or human anterior pituitary glands developed marked hyperlipemia within 12 to 24 hours. The injections in some instances were followed by sickening and death of the animal, though no anatomical changes responsible for these consequences could be determined. No such sequelae were observed in animals given much larger injections of comparable extracts made from other tissues. An inhibitor to lipoprotein lipase appeared regularly in the serum of the injected animals in association with the hyperlipemia. The injection of heparin into such animals failed to result in the elaboration of clearing factor, and serum from these animals inhibited in vitro the hydrolysis of lipid emulsions by active lipoprotein lipase obtained from normal rabbits or human beings. The inhibitor was produced only in vitro by the pituitary extracts. It did not antagonize the anticoagulant action of heparin, and is probably a lipoprotein

SELECTIVE INHIBITION BY PREPARATIONS OF STREPTOCOCCAL FILTRATES OF THE OXIDATIVE METABOLISM OF MITOCHONDRIA PROCURED FROM RABBIT MYOCARDIUM

When solutions of streptolysin O were added to Warburg flasks containing, among other constituents, suspensions of mitochondria from the myocardium of rabbits and citrate, fumarate, or alpha-ketoglutarate as the substrate, there followed regularly a sharp reduction, and eventually complete cessation, of oxygen consumption. This phenomenon was not observed when succinate was the substrate in the flasks, the finding pointing to a selective interference with DPN as the underlying change. The agent in the solutions of streptolysin O responsible for this effect was shown to be a streptococcal product, and to be non-dialyzable and heat-labile. It differed from streptolysin O in that it did not appear to require prior activation with cysteine, and its effectiveness was not diminished by treatment with cholesterol or antistreptolysin globulins

SUSTAINED HYPERLIPEMIA INDUCED IN RABBITS BY MEANS OF INTRAVENOUSLY INJECTED SURFACE-ACTIVE AGENTS

The intravenous injection of the surface-active agents Tween 80 and Triton A20 into rabbits fed a normal diet resulted in marked and sustained elevations of the cholesterol, phospholipid, and total lipid content of their blood. The increase in phospholipid in general paralleled that of the blood cholesterol. The implications of the findings are briefly discussed

NEUTRALIZING ANTIBODIES TO STREPTOCOCCAL DIPHOSPHOPYRIDINE NUCLEOTIDASE IN THE SERUM OF EXPERIMENTAL ANIMALS AND HUMAN BEINGS

Specific neutralizing antibodies directed against streptococcal DPNase were induced experimentally in rabbits and guinea pigs by the injection of partially purified preparations of the enzyme. Similar antibodies capable of inhibiting the biological activity of the enzyme were found to occur naturally in the serum of a very high percentage of human beings, and the titer of these antibodies often rose sharply following streptococcal infections. The antibody response to streptococcal DPNase in general paralleled that to streptolysin O, though in some instances antibodies to one increased when those to the other did not