Enhancement of inflammation and histamine formation by actinomycin D

Abstract

. An inflammation model developed in other laboratories was used in this study. Mice given endotoxin intranasally develop lung inflammation which progresses in intensity for several days. Lung weight is a satisfactory measure of inflammation. . In lungs of mice treated intranasally with endotoxin, histidine decarboxylase was activated within 6 hr, before lung weight had increased substantially. Enzyme activity was near maximal at 24 hr but had dropped by 48 hr, at which time inflammation was increasing. The data are consistent with an early role for histamine in mediating inflammation, but not with an essential role in the later stages. . When actinomycin D, an inhibitor of RNA synthesis, was mixed with endotoxin solution and given to mice intranasally, both lung inflammation and histidine decarboxylase activation were markedly enhanced at 24 and 48 hr, relative to effects produced by endotoxin alone. . Evidence is presented that intranasal instillation of endotoxin into mice increases histamine formation in lung in vivo. . We previously found protein synthesis inhibitors, the only drugs shown capable of blocking histidine decarboxylase activation, to be powerful anti‐inflammatory agents. Now we have found that actinomycin D, the only drug shown capable of enhancing histidine decarboxylase activation, to be strongly pro‐inflammatory. These observations support a causative role for histamine in slowly‐developing inflammation, and also provide a rigorous test for the participation of other mediator candidates.

Effect of glucocorticoids on histamine metabolism in mice

“…Since virtually nothing is known of the mechanism of histidine decarboxylase activation, no further comments on the inhibitory effect of corticoids on this process are warranted. However, in so far as histamine is involved in inflammation (Schayer & Reilly, 1968;Reilly & Schayer, 1969) in adjuvant action (Schayer, 1970) and in reticulo-endothelial function (Schayer, 1964) the opposite effects of glucocorticoids may be, in part, due to suppression of increased local histamine formation. …”