Two distinct bidirectional selective breedings for quantitative traits were initiated from identical genetically heterogeneous mouse populations. The resulting lines are characterized by maximal or minimal acute inflammatory responsiveness (AIR): AIRmax and AIRmin lines, respectively, and by resistance or susceptibility to chemical skin tumorigenesis: Car-R and Car-S lines, respectively. The AIR response to s.c. injection of polyacrylamide microbeads, measured by cell content in the local exudate, was 10 times higher in AIRmax than in AIRmin mice. The response to selection was asymmetrical: the realized heritability was 0.26 in AIRmax and 0.008 in AIRmin, and resulted from the additive effect of 7-11 quantitative trait loci (QTL). Low responsiveness was globally dominant in F1 and 48% of F2 segregant variance was found to be due to genetic factors. These findings are the first demonstration of innate regulation of AIR by germ line genes. Susceptibility to skin tumorigenesis induced by a two-stage initiation (DMBA)-promotion (TPA) protocol was lower in AIRmax mice than in AIRmin mice, a 6-fold difference in tumor induction rate. Intense AIR was found to be associated with resistance, and low AIR with susceptibility to tumorigenesis, in F2 segregants chosen for extreme AIR phenotypes. At least some of the AIR QTLs therefore contain genes controlling tumorigenesis. Tumor phenotypes differed more in Car-R and Car-S than in AIRmax and AIRmin lines, indicating that QTLs unrelated to AIR, contribute to the host response to tumorigenesis. The extreme phenotypes/genotypes of the four selected lines and the known genetic constitution of their foundation population, offer new possibilities to discriminate the genes/mechanisms controlling two important traits: AIR and response to chemical tumorigenesis. Collaborative projects will be favorably considered. The description of tumor resistance genes in AIRmax and Car-R mice may be helpful for epidemiology and therapy of human cancer.
The effects of mepyramine, promethazine, chlorpromazine and lysergic acid diethylamide have been compared on the capillary permeability changes of the skin, produced by histamine, by 5-hydroxytryptamine and by passive cutaneous anaphylaxis in mice. Promethazine, mepyramine and chlorpromazine can inhibit, in decreasing order of activity, the effect of histamine, whilst lysergic acid diethylamide is inactive. Lysergic acid diethylamide and chlorpromazine are equally potent inhibitors of the action of 5-hydroxytryptamine on the peripheral vascular bed, whilst mepyramine is inactive. Promethazine has intermediate activity. Passive cutaneous anaphylaxis is strongly inhibited by chlorpromazine and by promethazine. Mepyramine and lysergic acid diethylamide, each injected alone, affect only weakly the anaphylactic reaction. However, passive cutaneous anaphylaxis is almost completely abolished by the simultaneous injection of the two last antagonists. It is suggested that the anaphylactic reaction in mice is the result of simultaneous release of both mediators, histamine and 5-hydroxytryptamine, each of them strengthening the effect of the other.
It is universally accepted that histamine, whether of endogenous or exogenous origin, is disposed of by the two processes of enzymic destruction and of excretion through the renal tract. There is, however, little information about the way in which exogenous histamine is brought into contact with its specific enzymes. The rapid clearance of histamine from the blood after its intravenous injection (Rose & Browne, 1938) suggests that the uptake of histamine by the tissues may be a method for its immediate disposal from the blood, related to, and as important as, its subsequent metabolic destruction and renal excretion. The details and mechanism.s of this process are still unexplained. The purpose of the present experiments was to investigate this process by means of radioactive histamine, and to examine the fate, distribution and transfer through the tisues of exogenous histamine introduced into the circulation of the living orgamsm. Rose & Browne (1938) suggested that a powerful mechanism existed for the uptake of histamine into the tissues from the circulating blood of the rat, but their results have been criticized on account of the large doses of histamine which they used. Such doses may cause disturbances in the circulation after intravenous injection. In the present experiments, therefore, a relatively small dose of histamine was used for injections so that effects due to circulatory changes could be excluded. METHODSAlbino male rats of the Wistar strain weighing 125-150 g were used in all the experiments. After the intravenous injection of radioactive histamine, blood was removed at intervals of 15, 20 and 40 sec through a fine cannula inserted into the carotid artery, and at intervals from 1 to 240 min
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