Long-Term Pulmonary Damage in Surviving Antitoxin-Treated Mice following a Lethal Ricin Intoxication

Abstract

Ricin, a highly potent plant-derived toxin, is considered a potential bioterrorism weapon due to its pronounced toxicity, high availability, and ease of preparation. Acute damage following pulmonary ricinosis is characterized by local cytokine storm, massive neutrophil infiltration, and edema formation, resulting in respiratory insufficiency and death. A designated equine polyclonal antibody-based (antitoxin) treatment was developed in our laboratory and proved efficacious in alleviating lung injury and increasing survival rates. Although short-term pathogenesis was thoroughly characterized in antitoxin-treated mice, the long-term damage in surviving mice was never determined. In this study, long-term consequences of ricin intoxication were evaluated 30 days post-exposure in mice that survived antitoxin treatment. Significant pulmonary sequelae were demonstrated in surviving antitoxin-treated mice, as reflected by prominent histopathological changes, moderate fibrosis, increased lung hyperpermeability, and decreased lung compliance. The presented data highlight, for the first time to our knowledge, the possibility of long-term damage development in mice that survived lethal-dose pulmonary exposure to ricin due to antitoxin treatment.

Short- and long-term outcomes of pulmonary exposure to a sublethal dose of ricin in mice

“…The damage to the lung that we observed during the early time points post-sublethal exposure, included marked interstitial pneumonia, neutrophil infiltration, pro-inflammatory cytokine response, alveolar macrophage and alveolar epithelia type II cell death and edema. These observations stand in line with previous studies, where a lethal dose was used by intranasal instillation 8 , 9 , 28 , 29 , 35 , 36 , which also corresponded with other studies in rodents following inhalation exposure 34 , 42 , 43 . Altogether, our findings further substantiate intranasal instillation as a solid alternative respiratory exposure route for ricin intoxication in mice.…”

“…Recently, a new study evaluated the long-term pulmonary damage (30 days post-exposure) in surviving anti-ricin antibody-treated mice following a lethal ricin intoxication. This study showed evidence of lung fibrosis, hyperpermeability and decreased lung compliance 35 . In majority of these studies that aimed to understand the outcomes of sublethal exposure to ricin, the efforts were focused on the short-time period post exposure, the acute phase of the disease with merely evaluation of the long-term toxicity of ricin.…”

“…demonstrated that mice surviving lethal ricin intoxication following anti-ricin antibody treatment exhibited an impaired pulmonary compliance. However, when ciprofloxacin was co-administered with the anti-ricin antibody treatment, lung function in these mice was restored 35 . Based on these findings, we suggest that ciprofloxacin or doxycycline treatment of mice exposed to sublethal doses of ricin may reduce pro-inflammatory cytokine response, lower markers of oxidative stress, mitigate hyperpermeability of the lungs 28 and improve pulmonary compliance 35 .…”