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Review
. 2017 Oct 3;9(10):311.
doi: 10.3390/toxins9100311.

Treatments for Pulmonary Ricin Intoxication: Current Aspects and Future Prospects

Yoav Gal  1 , Ohad Mazor  2 , Reut Falach  3 , Anita Sapoznikov  4 , Chanoch Kronman  5 , Tamar Sabo  6
Affiliations
Review

Treatments for Pulmonary Ricin Intoxication: Current Aspects and Future Prospects

Yoav Gal et al. Toxins (Basel). .

Abstract

Ricin, a plant-derived toxin originating from the seeds of Ricinus communis (castor beans), is one of the most lethal toxins known, particularly if inhaled. Ricin is considered a potential biological threat agent due to its high availability and ease of production. The clinical manifestation of pulmonary ricin intoxication in animal models is closely related to acute respiratory distress syndrome (ARDS), which involves pulmonary proinflammatory cytokine upregulation, massive neutrophil infiltration and severe edema. Currently, the only post-exposure measure that is effective against pulmonary ricinosis at clinically relevant time-points following intoxication in pre-clinical studies is passive immunization with anti-ricin neutralizing antibodies. The efficacy of this antitoxin treatment depends on antibody affinity and the time of treatment initiation within a limited therapeutic time window. Small-molecule compounds that interfere directly with the toxin or inhibit its intracellular trafficking may also be beneficial against ricinosis. Another approach relies on the co-administration of antitoxin antibodies with immunomodulatory drugs, thereby neutralizing the toxin while attenuating lung injury. Immunomodulators and other pharmacological-based treatment options should be tailored according to the particular pathogenesis pathways of pulmonary ricinosis. This review focuses on the current treatment options for pulmonary ricin intoxication using anti-ricin antibodies, disease-modifying countermeasures, anti-ricin small molecules and their various combinations.

Keywords: anti-ricin small molecules; antitoxins; countermeasures; disease-modifying agents; pulmonary intoxication; ricin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Ricin-induced activation of cell signaling pathways and downstream formation of damage mediators. (1) The ribotoxic stress response characterized by MAP3K (PKR and ZAK) activation of MAPK (p38 and JNK) signaling; (2) The nuclear factor kappa B pathway, which is activated upon IкK-induced IкB phosphorylation and degradation; (3) NALP3 inflammasome-mediated IL-1β activation; (4) Apoptotic cell death attributed to pro-apoptotic caspase activation; (5) Proinflammatory cytokines and damage mediators released upon activation of the various signal transduction pathways activated by ricin.
Figure 2
Figure 2
Cellular targets for anti-ricin small molecule compound-based treatment. (1) Receptor mimicry; (2) Blockers of endocytosis; (3–5) Retrograde trafficking blockers; (6) Active-site inhibitors. TGN: trans-Golgi network; ER: endoplasmic reticulum.
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