The distribution of [125I]ricin in mice following aerosol inhalation exposure

Ja, Doebler; Nd, Wiltshire; Tw, Mayer; Je, Estep; Rb, Moeller; Rk, Traub; Ca, Broomfield; Ca, Calamaio; Wl, Thompson; Pitt, M. Louise M.

doi:10.1016/0300-483x(94)02978-4

Cited by 35 publications

(21 citation statements)

References 17 publications

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“…These data are consistent with previous reports on the histopathological effects of aerosolized ricin in animal systems. 20,21,[31][32][33] In addition, we have demonstrated that instilled ricin caused widespread nuclear localization of phosphorylated ERK, p38 MAPK, and JNK, but only phosphorylated p38 MAPK was evident in control lungs. These results are consistent with data obtained by immunoblotting, which demonstrated that ricin induced a large increase in phosphorylated JNK and ERK, but not p38 MAPK (Figure 3a).…”

Section: Discussionmentioning

confidence: 66%

“…20 Previous studies using inhaled 125 I-ricin in mice revealed that only a small fraction of the radioactivity reaching the lungs was transferred to extrapulmonary sites. 21 In these experiments, the authors conjectured that the 125 I-ricin was degraded within the lung and that most of the radioactivity that appeared in the circulation was probably in the form of free 125 I. In the present study, we have instilled lethal and sublethal doses of ricin into the tracheae of mice and have examined a number of responses in pulmonary and extrapulmonary tissues including activation of MAP kinase family members, elevation of transcripts that encode inflammatory proteins, the presence of circulating inflammatory cytokines, and apoptotic responses.…”

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confidence: 99%

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

Wong

Korcheva

Jacoby

et al. 2007

The American Journal of Pathology

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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.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

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

Wong

Korcheva

Jacoby

et al. 2007

The American Journal of Pathology

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“…For example, in rodents and nonhuman primates, the 50% lethal dose (LD 50 ) of ricin by injection is approximately 5 g/kg, while the LD 50 of ricin by inhalation is estimated to be as low as 3 g/kg (8). The respiratory mucosa is especially sensitive to ricin, as even trace amounts of toxin are known to elicit widespread necrosis in the airways and alveoli, peribronchovascular edema, mixed inflammatory cell infiltrates, and massive pulmonary alveolar flooding (9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

Chimeric Plantibody Passively Protects Mice against Aerosolized Ricin Challenge

Sully

Whaley

Bohorova

et al. 2014

Clin. Vaccine Immunol.

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e Recent incidents in the United States and abroad have heightened concerns about the use of ricin toxin as a bioterrorism agent. In this study, we produced, using a robust plant-based platform, four chimeric toxin-neutralizing monoclonal antibodies that were then evaluated for the ability to passively protect mice from a lethal-dose ricin challenge. The most effective antibody, c-PB10, was further evaluated in mice as a therapeutic following ricin exposure by injection and inhalation. Ricin toxin is a member of the medically important A-B family of plant and bacterial ribosome-inactivating proteins (RIPs) (1). In its mature form, ricin is a 65-kDa heterodimeric glycoprotein that is a natural constituent of the seeds of the castor plant (Ricinus communis). The 267-amino-acid A subunit (RTA) of ricin is an RNA N-glycosidase that depurinates a conserved adenosine residue within the so-called sarcin-ricin loop (SRL) of eukaryotic 28S rRNA, which is required for activation of the elongation factor EF-Tu (2, 3). RTA is linked via a single disulfide bond to ricin's B subunit (RTB), a 262-amino-acid lectin that is specific for glycoproteins and glycolipids terminating in galactose and Nacetylgalactosamine (Gal/GalNAc). In addition to its role in attachment, RTB also mediates the retrograde transport of ricin to the trans-Golgi network (TGN) and endoplasmic reticulum (ER), where RTA is ultimately delivered across the ER membrane and into the cytoplasm (4, 5). The extraordinary capacity of RTA to inactivate ribosomes (k cat , 1,500/min) makes ricin one of the most potent known RIPs (6, 7). For example, in rodents and nonhuman primates, the 50% lethal dose (LD 50 ) of ricin by injection is approximately 5 g/kg, while the LD 50 of ricin by inhalation is estimated to be as low as 3 g/kg (8). The respiratory mucosa is especially sensitive to ricin, as even trace amounts of toxin are known to elicit widespread necrosis in the airways and alveoli, peribronchovascular edema, mixed inflammatory cell infiltrates, and massive pulmonary alveolar flooding (9-15).The U.S. Departments of Defense (DOD) and Health and Human Services (HHS) have ongoing initiatives to develop antibody-based products capable of providing passive protection against systemic and mucosal ricin exposure (16,17). In addition to protective efficacy, issues related to platform technology, scalability, and speed of manufacturing will ultimately dictate which product(s) will be pursued for advanced development and are consistent with the unique needs for biodefense. In this regard, the Nicotiana benthamiana-based rapid antibody-manufacturing platform (RAMP) provides the potential for extremely fast and high-yield monoclonal antibody (MAb) production that has already proven to be applicable to biodefense (18-21). The technology entails mass infiltration of mature Nicotiana plants with an Agrobacterium tumefaciens suspension carrying T-DNA encoding viral replicons and results in high MAb recovery from original DNA constructs within days (22). The Nicotiana-based RAMP...

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“…Thus, ricin may be missed in some clinicopathologic samples. 6,18 The difference in times of death after exposure of these 2 dogs to ricin could be related to different initial exposure levels rather than differences in metabolism, distribution, or excretion of the toxin. The main advantage of ricinine biomonitoring stems from the small size of the molecule (164 g/mol), which can easily be extracted and quantitated.…”

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confidence: 99%

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

Roels

Coopman²,

Vanhaelen³

et al. 2010

J VET Diagn Invest

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Abstract. Two adult dogs with the same owner were intoxicated by ingestion of fertilizer composed of residual plant material of the castor bean plant (Ricinus communis L.). Both dogs died within 2 and 3 days, respectively, after the first signs of vomiting and abundant hemorrhagic diarrhea. Toxicologic and histopathologic examinations were performed on different organs. Histopathologic examination of the kidneys revealed tubular degeneration and necrosis and membranous glomerulonephritis. Additionally, myocardial degeneration with localized inflammation, lymphoid necrosis, and depletion in the spleen and mesenteric lymph nodes and hemorrhagic ulcerative gastroenteritis were found. The 2 cases could be used to elucidate the lethal dose of ricin and the histopathologic lesions in dogs.

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The distribution of [125I]ricin in mice following aerosol inhalation exposure

Cited by 35 publications

References 17 publications

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

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

Chimeric Plantibody Passively Protects Mice against Aerosolized Ricin Challenge

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

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