A study on renal papillary necrosis experimentally produced by the Shwartzman mechanism in rabbits

To produce renal papillary necrosis experimentally by means of the Shwartzman mechanism in rabbits, E. coli endotoxin was injected into the renal pelvis unilaterally through the ureter as a preparative procedure after pretreatment by local administration of alcohol, and the same endotoxin was given again 24 hours later, but intravenously this time via the ear vein, as a provocation. Marked necrosis was produced in the renal papillae, where many intravascular fibrin thrombi were found histologically. Such papillary necrosis was largely prevented by heparin administration, and this lesion was considered to be the univisceral Shwartzman reaction occurring in the renal papillae. The lesion produced in the new experimental system of renal papillary necrosis described here has a good similarity to that of human cases in etiology, pathogenesis and morphology. The present system may therefore be a good model of human renal papillary necrosis, and should be useful for future studies.     

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

Mycobacterial lesions and skin sites challenged with soluble mycobacterial antigen are very sensitive to the necrotizing effect of tumour necrosis factor (TNF). 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 platelet-activating factor (PAF), or with misoprostol (a synthetic prostaglandin E1 analogue), or with cobra venom factor (CVF) 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 PAF inhibitor had no detectable effect.     

Involvement of tumor necrosis factor-α, interleukin-I β, interleukin-8, and interleukin-I receptor antagonist in acute lung injury caused by local Shwartzman reaction

A local Shwartzman reactlon (LSR) was prepared in rabbit lung as a model of acute lung injury. To induce LSR, intratracheal injection of lipopolysaccharide (LPS) 10 μg into the lower lobe of the right lung, followed 24 h later by I.v. injectlon of LPS (10 μg/kg). In the lung with the LSR, myeloperoxidase activity, representing neutrophil accumulation, peaked at 1–2 h and was sustained for 48 h after challenge with i.v. LPS. The lung water content peaked at 12 h, and decreased gradually. Histological findings showed diffuse interstitial widenlng, lntra-alveolar leukocyte infiltration with hemorrhage, and alveolar exudate formation. The production of tumor necrosis factor-α (TNF-α), interleukin-1 β (IL-1β), interleukin 8 (IL-8), and IL-1 receptor antagonist (IL-1Ra) in the lung was analyzed. TNF-α first elevated and peaked at 0.5h (66.±16.7ng/g.lung), subsequently, 11–1β and 11–8 increased and peaked at 2h (17.8 ± 3.4 ng/g. lung and 336.9±49.6ng/g.lung, respectively). IL-1Ra was present even before the challenge, and the production increased to show a dual peak (0.5 h, 1.5±0.2 μg/g.lung; and 2h, 1.6±0.1 μg/g.lung), and a large concentration of IL-1 Ra was sustained for 48 h. lmmunohistochemistry showed that the cellular source of these cytokines was alveolar macrophages and infiltrating neutrophils. Thus, disclosing the kinetics of the generation of cytokines led to a better understanding of thelr roles, namely TNF-α as an initiator, IL-1 and IL-8 as amplitier and effector, and IL-1 Ra as regulator of the intensity of acute inflammation.     

A study on pulmonary hemorrhage experimentally produced by the Shwartzman mechanism in rabbits. Possible relationship to pulmonary hemorrhage in man

The lung was chosen as a target organ of the univisceral Shwartzman reaction in this study. Rabbits were selected as the experimental animal, and E. coli endotoxin was used as the Shwartzman reagent. Preparative procedures were applied through the trachea into the lung in several ways; direct injection of the endotoxin solution and inhalation of the atomized endotoxin solution by natural breathing. The provocation was made by intravenous injection of the same endotoxin 24 hours later. The lung showed severe hemorrhage associated with inflammatory cell infiltration, interstitial fibrosis, macrophage accumulation, etc. The severity and extent of these changes varied, to some extent, between groups as well as between individual animals. The fundamental character was, however, common to all, and the incidence of the lesion in the lung was quite high. The relationship of the present results to idiopathic pulmonary hemorrhage and Goodpasture's syndrome is also discussed from the viewpoint of human pathology.