Pulmonary exposure to the plant toxin ricin, leads to respiratory insufficiency and death. To date, in-depth study of the functional disorders ensuing pulmonary intoxication, a prerequisite for establishing a clinically-relevant therapeutic protocol, is hampered by the lack of an appropriate animal model. To this end, we set up the pig, as a large animal model for the comprehensive study of the multifarious clinical manifestations of pulmonary ricinosis.Here we report for the first time, the monitoring of barometric whole body plethysmography for pulmonary function tests in non-anesthetized ricin-intoxicated pigs. Up to 30 hours post-exposure, as a result of progressing hypoxemia and to prevent carbon dioxide retention, animals exhibited a compensatory response of elevation in Minute Volume, attributed mainly to a robust elevation in respiratory rate with minimal response in tidal volume. This response was followed by decompensation, manifested by a descent in Minute Volume and severe hypoxemia, refractory to oxygen treatment. Radiological evaluation revealed evidence of early diffuse bi-lateral pulmonary infiltrates while hemodynamic parameters remained unchanged, excluding cardiac failure as an explanation for respiratory insufficiency. Ricin-intoxicated pigs suffered from increased lung permeability accompanied by cytokine storming while histological studies revealed lung tissue insults accumulating over time, up to the development of diffuse alveolar damage. Charting the decline in PaO2/FiO2 ratio in a mechanically-ventilated pig, confirmed that ricin-induced respiratory damage complies with the accepted diagnostic criteria for Acute Respiratory Distress Syndrome. The establishment of this animal model of pulmonary ricinosis, should assist us in our pursuit of efficient medical countermeasures, specifically-tailored to deal with the respiratory deficiencies stemming from ricin-induced Acute Respiratory Distress Syndrome.

Ricin, a plant-derived toxin originating from the seeds of Ricinus communis (castor bean plant), is one of the most lethal toxins known. To date, there is no approved post-exposure therapy for ricin exposures. This work demonstrates for the first time the therapeutic efficacy of equine-derived anti-ricin F(ab’)₂ antibodies against lethal pulmonary and systemic ricin exposures in swine. While administration of the antitoxin at 18 h post-exposure protected more than 80% of both intratracheally and intramuscularly ricin-intoxicated swine, treatment at 24 h post-exposure protected 58% of the intramuscular-exposed swine, as opposed to 26% of the intratracheally exposed animals. Quantitation of the anti-ricin neutralizing units in the anti-toxin preparations confirmed that the disparate protection conferred to swine subjected to the two routes of exposure stems from variance between the two models. Furthermore, dose response experiments showed that approximately 3 times lesser amounts of antibody are needed for high-level protection of the intramuscularly compared to the intratracheally intoxicated swine. This study, which demonstrates the high-level post-exposure efficacy of anti-ricin antitoxin at clinically relevant time-points in a large animal model, can serve as the basis for the formulation of post-exposure countermeasures against ricin poisoning in humans.

The ability of mono N-methyl-1,4-diazabicyclo[2.2.2]octane fluoride (Me-DABCOF, 1) to act as a bifunctional reagent that effectively and universally neutralizes both the persistent and extremely toxic blister agent HD and the nerve agent VX in nearly neutral aqueous solution, alumina powder or a hydrogel formulation, is described.

Scherzer P, et al. Anat Cell Biol. 2011 Sep;44(3):176-185. http://dx.doi.org/10.5115/acb.2011.44.3.176

Ricin toxin isolated from the castor bean (Ricinus communis) is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e., intramuscular penetration, have been described recently in various animal models, the preceding mechanism underlying the clinical manifestations of systemic ricin poisoning has not been completely defined. Here, we show that following intramuscular administration, ricin bound preferentially to the vasculature in both mice and swine, leading to coagulopathy and widespread hemorrhages. Increased levels of circulating VEGF and decreased expression of vascular VE-cadherin caused blood vessel impairment, thereby promoting hyperpermeability in various organs. Elevated levels of soluble heparan sulfate, hyaluronic acid and syndecan-1 were measured in blood samples following ricin intoxication, indicating that the vascular glycocalyx of both mice and swine underwent extensive damage. Finally, by using side-stream dark field intravital microscopy imaging, we determined that ricin poisoning leads to microvasculature malfunctioning, as manifested by aberrant blood flow and a significant decrease in the number of diffused microvessels. These findings, which suggest that glycocalyx shedding and microcirculation dysfunction play a major role in the pathology of systemic ricin poisoning, may serve for the formulation of specifically tailored therapies for treating parenteral ricin intoxication.