Abstract
Ricin, a plant-derived exotoxin, inhibits protein synthesis by ribosomal inactivation. Due to its wide availability and ease of preparation, ricin is considered a biothreat, foremost by respiratory exposure. We examined the in vivo interactions between ricin and cells of the lungs in mice intranasally exposed to the toxin and revealed multi-phasic cell-type-dependent binding profiles. While macrophages (MΦs) and dendritic cells (DCs) displayed biphasic binding to ricin, monophasic binding patterns were observed for other cell types; epithelial cells displayed early binding, while B cells and endothelial cells bound toxin late after intoxication. Neutrophils, which were massively recruited to the intoxicated lung, were refractive to toxin binding. Although epithelial cells bound ricin as early as MΦs and DCs, their rates of elimination differed considerably; a reduction in epithelial cell counts occurred late after intoxication and was restricted to alveolar type II cells only. The differential binding and cell-elimination patterns observed may stem from dissimilar accessibility of the toxin to different cells in the lung and may also reflect unequal interactions of the toxin with different cell-surface receptors. The multifaceted interactions observed in this study between ricin and the various cells of the target organ should be considered in the future development of efficient post-exposure countermeasures against ricin intoxication.
Highlights
Ricin is a highly toxic ribosome-inactivating protein (RIP) derived from the seeds of the castor plant, Ricinus communis
Lung alveolar epithelial cells are of two types, respiratory alveolar type I (ATI) and surfactant-secreting alveolar type II (ATII) cells [14], the latter being dispersed between the alveolar type I cells (ATI) cells
We monitored the interactions between ricin and the cells of the lung and delineated the alterations occurring to different pulmonary cell populations following in vivo exposure to the toxin
Summary
Ricin is a highly toxic ribosome-inactivating protein (RIP) derived from the seeds of the castor plant, Ricinus communis. A-chain depurinates a single adenine in the 28S rRNA This deletion prevents the binding of elongation factor 2 to the ribosome and, is directly responsible for both the inhibition of protein translation [6] and the initiation of events leading to inflammatory responses [7,8]. Studies in rodents and nonhuman primates have demonstrated that ricin delivered into the pulmonary system leads to acute lung injury (ALI) and symptoms resembling acute respiratory distress syndrome (ARDS) [1]. We examined the kinetics of ricin binding and internalization to lung cells in vivo and delineated the effects of these interactions on the cellular composition of the lung. The varied binding performances of the different cell types comprising the mouse lung were accompanied by differential alterations in the hematopoietic and parenchymal cell populations. Our data suggest that differential ricin binding and internalization determine the impairment of tissue integrity and function
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