Gastrointestinal acute radiation syndrome in Göttingen minipigs (Sus scrofa domestica)

Abstract

In the absence of supportive care, exposing Göttingen minipigs to γ-radiation doses of less than 2 Gy achieves lethality due to hematopoietic acute radiation syndrome. Doses of 2 to 5 Gy are associated with an accelerated hematopoietic syndrome, characterized by villus blunting and fusion, the beginning of sepsis, and a mild transient reduction in plasma citrulline concentration. We exposed male Göttingen minipigs (age, 5 mo; weight, 9 to 11 kg) to γ-radiation doses of 5 to 12 Gy (total body; (60)Co, 0.6 Gy/min) to test whether these animals exhibit classic gastrointestinal acute radiation syndrome (GI-ARS). After exposure, the minipigs were monitored for 10 d by using clinical signs, CBC counts, and parameters associated with the development of the gastrointestinal syndrome. Göttingen minipigs exposed to γ radiation of 5 to 12 Gy demonstrate a dose-dependent occurrence of all parameters classically associated with acute GI-ARS. These results suggest that Göttingen minipigs may be a suitable model for studying GI-ARS after total body irradiation, but the use of supportive care to extend survival beyond 10 d is recommended. This study is the first step toward determining the feasibility of using Göttingen minipigs in testing the efficacy of candidate drugs for the treatment of GI-ARS after total body irradiation.

Figure 1.

Patterns of mean blood counts in minipigs irradiated with 5 to 12 Gy. (A) WBC. (B) Platelets. (C) Neutrophils. (D) RBC.

Figure 2.

Histology of jejunum of minipigs irradiated with ⁶⁰Co γ-radiation. (A) Jejunum, 5 Gy: mild intestinal villus blunting and fusion with essentially normal crypts. (B) Jejunum, 9 Gy: moderate intestinal villus blunting and fusion with moderate crypt loss. (C) Jejunum, 11 Gy: marked intestinal villus blunting and fusion with marked crypt loss. (D) Jejunum, 12 Gy: severe loss of intestinal villi and crypts with necrosis and abundant intralesional bacteria. Magnification, 20×.

Figure 3.

Mean citrulline concentration in plasma of minipigs given 5 to 12 Gy ⁶⁰Co γ-radiation and relationship between dose and crypt score at necropsy. (A) Dose- and time-dependent decline in plasma citrulline levels. After doses of 10 Gy or more, citrulline concentrations were significantly (P < 0.05) decreased as early as 2 d after irradiation and did not show signs of recovery within 7 d after irradiation (P < 0.01). (B) Crypt score at necropsy, which describes severity of crypt loss, was positively correlated (P < 0.0001) with dose of radiation.

Figure 4.

Dose-dependent loss of citrulline over time and relationship between plasma citrulline concentration and crypt score at necropsy in minipigs after irradiation. Top panels show the relationship between radiation dose and citrulline levels on days 2 (left), 3 (center), and 7 (right) after irradiation. Bottom panels show the relationship between crypt score at necropsy and plasma citrulline level on days 2 (left), 3 (center), and 7 (right) after irradiation.