Intrapulmonary Delivery of Ricin at High Dosage Triggers a Systemic Inflammatory Response and Glomerular Damage

Abstract

In view of the possibility that ricin may be used as a bioweapon against human populations, we examined the pathological consequences that occur in mice after introduction of ricin into the pulmonary system. Intratracheal instillation of a lethal dose of ricin (20 g/100 g body weight) resulted in a hemorrhagic inflammatory response in multiple organs, accompanied by activation of mitogen-activated protein kinases, increased synthesis of proinflammatory RNA transcripts, and increased levels of circulating cytokines and chemokines. A sublethal dose of instilled ricin (2 g/100 g body weight) induced a similar response in lungs but did not cause detectable damage in other organs. Lungs of mice that recovered from a sublethal dose of ricin displayed evidence of fibrosis and residual damage. A lethal dose of ricin caused accumulation of proinflammatory RNA transcripts and substantial damage to 28S rRNA of multiple organs, including lung, kidney, spleen, liver, and blood, demonstrating that instilled ricin gained access to the circulation. The kidneys of mice instilled with a lethal dose of ricin showed accumulation of fibrin/fibrinogen in glomerular capillaries, increased numbers of glomerular leukocytes, and impairment of kidney function. A sublethal dose of ricin failed to induce damage to 28S rRNA in kidney or other extrapulmonary organs.

RiVax, a recombinant ricin subunit vaccine, protects mice against ricin delivered by gavage or aerosol

“…With regard to the toxicity of aerosolized ricin, it is not entirely clear how death is caused, though it is likely to be related to a large extent to damage in the lung [ 3 ]. However another recent study using doses of 20 μg/100 g of intratracheally delivered ricin (two times their determined LD 50 and which they found to be consistently lethal) showed that ricin gained access to the blood and caused inflammatory responses in multiple organ sites [ 27 ]. This may explain, at least in part, why our i.m.…”

Lethal Ricin Intoxication in Two Adult Dogs: Toxicologic and Histopathologic Findings

“…9,22 In both dogs in the current study, several renal changes could be detected, but the presence of fibrin thrombi could not be demonstrated in the glomerular capillary loops, perhaps because of species differences, the possibility that the rodents were sacrificed after advanced toxicosis occurred, or both. 9,22,23 Another explanation for the absence of fibrin deposits could be fibrinolysis.…”

“…1 Clearly, similar lesions can be seen in different species, but some of them are only described in laboratory models. 9,22,23 In experimental model studies with rats and mice, the major lesion associated with a lethal dose of ricin was impairment of renal function with a typical histopathologic lesion called ''glomerular thrombotic microangiopathy.'' This ricin-induced lesion has been proposed as a model for hemolytic uremia syndrome.…”

Recent advances in the development of vaccines against ricin

“…Yet we also know that much of the syndrome associated with exposure to RT and other toxins is due to an acute inflammatory response. 2,[20][21][22] It is not yet known how antibodies, which are themselves proinflammatory, block the proinflammatory activity of the toxin, rather than enhancing it. We can partially address this question by comparing inflammatory responses in immunized macaques with those observed in the controls.…”