A model for the investigation of factors influencing haemorrhagic necrosis mediated by tumour necrosis factor in tissue sites primed with mycobacterial antigen preparations

Abstract

SUMMARYMycobacterial lesions and skin sites challenged with soluble mycobacterial antigen are very sensitive to the necrotizing effect of tumour necrosis factor (TNE). We have used a model that permits separate quantitative assessment of swelling and haemorrhage to show that when these reactions are elicited in mice that have not been deliberately immunized, pretreatment of the mice with lipopolysaccharide (LPS), or with a MoAb to CR3 which blocks emigration of myeloid cells into the tissues, will block both the swelling and the haemorrhage. On the other hand, treatment with an inhibitor of plateletactivating factor (PAE), or with misoprostol (a synthetic prostaglandin El analogue), or with cobra venom factor (CVE) which depletes complement, preferentially blocks the haemorrhagic component, while leaving the swelling relatively unaltered. As swelling occurs before the haemorrhage is seen, it is possible that these factors act at a late stage in the cascade of events leading to the tissue damage. However, LPS and CVF were able to inhibit swelling and haemorrhage in the massive reactions elicited in pre-immunized animals, whereas the PAE inhibitor had no detectable effect.

Intragranulomatous necrosis in lungs of mice infected by aerosol with Mycobacterium tuberculosis is related to bacterial load rather than to any one cytokine or T cell type

“…For a long time, IN has been linked to DTH (considered as an independent form of cellular immunity), essentially as a mechanism to destroy macrophages that are poorly activated by cellular-mediated immunity and thus harbor living bacilli [1,2] or as a cytotoxic activity mostly mediated by CD8 þ cells [20]. Another perspective was given by suggesting that the origin of IN was a local type of Shwartzman reaction [5] and that TNF plays a key role in the development of IN based on the evidence obtained using an experimental model of skin lesions in foot pads [4], which also showed that a Th2 environment would favor such a necrosis [21].…”

“…In this case, infected granulomas were considered to be ''prepared'' sites because of the presence of M. tuberculosis. The release of tumor necrosis factor (TNF) from macrophages activated and triggered in the lesion may cause tissue damage [4,5].…”