Novel swine model of ricin-induced acute respiratory distress syndrome

Abstract

Pulmonary exposure to the plant toxin ricin leads to respiratory insufficiency and death. To date, in-depth study of acute respiratory distress syndrome (ARDS) following pulmonary exposure to toxins is hampered by the lack of an appropriate animal model. To this end, we established 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-treated pigs. Up to 30 h 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 large elevation in respiratory rate with minimal response in tidal volume. This response was followed by decompensation, manifested by a decrease in minute volume and severe hypoxemia, refractory to oxygen treatment. Radiological evaluation revealed evidence of early diffuse bilateral 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. Histological studies revealed lung tissue insults that accumulated over time and led to 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 ARDS. The establishment of this animal model of pulmonary ricinosis should help in the pursuit of efficient medical countermeasures specifically tailored to deal with the respiratory deficiencies stemming from ricin-induced ARDS.

Early disruption of the alveolar-capillary barrier in a ricin-induced ARDS mouse model: neutrophil-dependent and -independent impairment of junction proteins

“…At the clinical level, pulmonary exposure to ricin induces neutrophil influx to the lungs accompanied by a cytokine storm and the generation of a severe edema in the alveoli and pulmonary interstitium, which in turn leads to respiratory failure and death (11,35,44). Recently, we have shown that the clinical manifestations of ricin-induced respiratory damage in swine comply fully with the accepted diagnostic criteria for ARDS (18).…”

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

“…In nonhuman primates (NHPs), inhalation of RT elicits the clinical equivalent of acute respiratory distress syndrome (ARDS), characterized by widespread apoptosis of alveolar macrophages, intraalveolar edema, neutrophilic infiltration, accumulation of proinflammatory cytokines, and fibrinous exudate (3)(4)(5). Similar effects are observed in mice, rats, and swine (6)(7)(8)(9)(10)(11). RT is derived from castor beans (Ricinus communis) and is a 65-kDa heterodimeric glycoprotein consisting of 2 subunits, RTA and RTB, joined via a single disulfide bond.…”

Total Body Irradiation Mitigates Inflammation and Extends the Therapeutic Time Window for Anti-Ricin Antibody Treatment against Pulmonary Ricinosis in Mice

“…In addition to depurination-induced cell death and tissue damage, pulmonary ricin exposure results in a severe localized inflammation, associated with an intrapulmonary cytokine storm, massive neutrophil recruitment, and pulmonary edema, subsequently resulting in respiratory failure and death [ 3 , 11 , 12 ]. The clinical manifestation of ricin-induced respiratory damage in swine complies with the accepted diagnostic criteria for acute respiratory distress syndrome (ARDS) [ 13 ].…”