Biomedical subjects
Publications and source records attributed to M Koltai.
Sendai virus given intravenously into CFLP mice produced dose-related suppression of the acute inflammation produced by carrageenan and 5-HT. The inhibition correlated with interferon levels in the blood, suggesting that interferon may account for the virus-induced anti-inflammatory effect.
The dextran-induced anaphylactoid reaction in the rat is susceptible to changes in carbohydrate metabolism. Paw oedema evoked by dextran was studied in norma and streptozotocin diabetic rats whose blood sugar level was determined by the glucose oxidase method. Insulin and tolbutamide increased dextran oedema in normal animals, while butylbiguanide (BBG) did not. The marked inhibition observed in the diabetic state was reversed by insulin and BBG, but not by tolbutamide. The dextran response correlated with the blood sugar level. These results suggest that the weak response to dextran in diabetic rats is due to an impaired peripheral glucose utilization rather than insulin deficiency per se.
The effect of a single dose of the cytotoxic drug cyclophosphamide on the severity of acute myocardial infarction in conscious rats has been studied. One and 4 days after the i.p. injection of 100 mg kg-1 of the drug, the survival rate of rats subjected to coronary ligation was significantly increased. The occurrence of fatal arrhythmias was markedly reduced. The peripheral white blood cell count was profoundly lowered. On the first day after pretreatment, moderate granulocytosis with severe lymphopenia occurred. Four days following the administration of cyclophosphamide, marked granulocytopenia also ensued. In this stage, restoration of white blood cell count by cell suspension prepared from the spleen of normal rats did not significantly affect the cardioprotective effect of cyclophosphamide. The data provide additional evidence that protein synthesis is involved in the early phase of myocardial infarction. The significance of leukocytes in the phenomenon is briefly discussed.
Unconcentrated CSF and 200 times diluted serum samples from 192 patients were examined by agar electrophoresis; their albumin and transferrin content were determined simultaneously by radial immunodiffusion. Using the data on transferrin and albumin concentrations in serum and cerebrospinal fluid, the transferrin/albumin index was calculated in a similar way to the IgG/albumin index. Normally the transferrin/albumin index is 1.68 (n = 77; S.D. = 0.22). If the permeability of the blood-CSF barrier increases, the transferrin/albumin index gradually decreases to 1. If the tau-globulin fraction is increased on the agar pherogram, the transferrin/albumin index will be greater than 2.34 (mean + 3 S.D.).
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The albumin and the IgG were determined in cerebrospinal fluid (CSF) and serum samples from 312 patients by radial immunodiffusion. The correlation between the CSF/serum ratio of IgG and the CSF/serum ratio of albumin was determined by regression analysis in three groups of patients with no signs of IgG synthesis within the central nervous system. The patients were selected on the basis of the state of the blood-CSF barrier, as indicated by the ratio of serum/CSF of albumin. Using the +2 S.D. regression borderlines, the maximal amount of IgG derived from the blood and the minimal amount of IgG synthesized within the central nervous system can be calculated in CSF samples of patients with acute infections and chronic inflammatory diseases.
From a closed colony of randomly-bred Sprague-Dawley CFY rats about 23% failed to respond to intravenous dextran with the characteristic generalized anaphylactoid reaction, but still exhibited an inflammatory response when dextran was given into the foot pad. Brother-sister mating of rats showing the most expressed generalized reaction (reactor rats) yielded good responder offsprings, while the non-reactors had descendants completely unresponsive to systemic dextran. Brother-sister mating of selected non-reactor rats led to a gradual decrease in dextran paw oedema in the subsequent generations, and after the third mating, a complete local non-reactivity developed. In these rats the intradermal injection of dextran failed to increase vascular permeability, while the inflammatory response evoked by histamine, 5-HT, bradykinin, and compound 48/80 remained unchanged as compared to that of the reactor animals. These result show that the anaphylactoid reaction in Sprague-Dawley CFY rats is under genetic control.
The insulin-induced sensitization to generalized and local anaphylactoid reaction evoked by dextran was studied in Sprague-Dawley CFY rats. The generalized reaction was shown to be potentiated by insulin given subcutaneously in a dose-related manner. The minimum effective dose was as low as 0.04 U/kg. When this dose was injected intravenously, a marked but short-lived potentiation was observed. The insulin response could be elicited throughout the whole year. The local oedema induced by subplantar injection of dextran was found to be much less sensitive to insulin. Potentiation was observed during the period from March to October, while in the intermediate months, no such effect could be seen. The seasonal refractory state to insulin was abolished by bilateral adrenalectomy, and daily pretreatment of the rats with insulin for several days. Actinomycin D prevented the restorative effect of insulin pretreatment. Sensitization by a single insulin dose to both systemic and local dextran was suppressed in rats older than 6 months, and the refractoriness was in part reversed by adrenalectomy.
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Insulin, in doses which did not influence the blood sugar level, potentiated the anaphylactic shock in ovalbumin-sensitized CFLP mice and moderately inhibited the carrageenan-induced paw edema. Higher doses were found to produce a dose-dependent inhibition of the inflammatory process at the 2nd hour, and caused less suppression at the 4th hour of the swelling. These results suggest that insulin may play a complex regulatory role in hypersensitivity and inflammatory reactions, and its effect is not necessarily related to hypoglycemia.
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The susceptibility to competitive ganglionic blocking agents such as hexamethonium (C6), tetraethylammonium bromide (TEAB), mecamylamine and d-tubocurarine (d-TC), of the superior cervical ganglion in cats with pancreatectomy and spontaneous diabetes or in animals treated with contrainsular drugs such as cortisone or dihydrochlorothiazide, was found to be decreased as compared to the reactivity of normal controls. The increased tolerance to ganglioplegics was not correlated with the elevation of the blood sugar level, and proved to be resistant to an acute administration of insulin. The results could not be explained by a decrease in the specific cholinesterase activity of the ganglionic tissue due to diabetes. Alteration of the peripheral autonomic synaptic transmission may be an early sign of diabetic neuropathy.
Experiments performed on rats showed that insulin, when applied i.v. or s.c., inhibited the foot edema induced by carrageenin, thermic effect of 45.7 degrees C, compound 48/80 and 5-HT, but moderately increased the paw swelling evoked by kallikrein, a kinin-forming enzyme. The increased vascular permeability elicited by intradermal injection of histamine, 5-HT, bradykinin, PGE1, carrageenin and compound 48/80 was also suppressed. The anti-inflammatory effect was not significantly altered by propranolol and adrenalectomy on the thermal and carrageenin edema, it was variably inhibited on the skin test, and was completely abolished on the paw swelling induced by 5-HT and compound 48/80. Since insulin had little or no effect on the vascular response when given topically together with the vasoactive agents, its complex effect on the acute inflammation appears to be brought about via indirect mechanisms.
The carrageenin-induced foot oedema in rats is considerably decreased by insulin pretreatment, but increased in alloxan diabetes. Maximum inhibition by insulin occurs in the early phase of the oedema reaction and the insulin action is even further increased when it is administered 30 min after carrageenin. Doses of insulin as low as 1 U/kg intravenously produce significant inhibition. Determinations of the components of the kinin system indicate that the kininogenase activity is increased, and both the kininogen and kininase content are in turn decreased in the plasma of insulin-treated animals. When the carrageenin-induced oedema fluid of the paw after insulin is analysed for kininogen and kininase, their levels are significantly decreased when compared with those of oedema fluid without insulin. Histamine content in the oedema fluid is significantly enhanced by insulin. The anti-inflammatory effect of insulin under these conditions therefore appears to involve changes in the kinin system.
Some hypersensitivity reactions and allergic responses are known to be increased by insulin treatment and decreased in diabetes. In contrast, the present experiments showed that paw swelling induced by carrageenin in rats was inhibited by insulin. The anti-inflammatory activity, to some extent, paralleled the dose applied and did not appear to be due to hypoglycaemia. Alloxan diabetes in turn increased the vascular response to carrageenin and abolished the anti-inflammatory effect of insulin. The experiments call attention to the possible significance of insulin in the regulation of the acute non-immune inflammatory process.
During a 4-week period, the electroshock seizure threshold (EST) of R Amsterdam rats was determined. When alloxan induced diabetes, the EST values significantly decreased, while in the alloxan-treated non-diabetic group they remained unchanged. The results suggest that diabetes induces increased excitability in the central nervous system.
The experiments reported here indicate that, when exposed to insulin, viable lymphocytes rapidly released into the incubation medium a factor capable of increasing the dextran-induced anaphylactoid reaction, but having no effect on the inflammatory response evoked by 5-HT. This pro-inflammatory factor was shown to be elaborated by cell suspensions derived from lymph nodes of rats, rabbits, pigs or calves as well as from human tonsils. Thymus cells showed no such activity. The pro-inflammatory factor was termed as anaphylactoid-inflammation-promoting factor (AIPF). Its production depended upon the dose of insulin, and the time of exposure. AIPF was found to have an elution pattern in Sephadex G-100 gels similar to that of BSA (67,000 daltons). The activity was abolished by heat or incubation with DNase or a-chymotrypsin, but was not influenced by RNase. AIPF by itself did not induce increased vascular permeability, and proved to be distinct from the permeability factors present in the lysate of lymph node cells.
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