What are the practical, ethical, and pathobiological considerations in the use of minipigs as an animal model in drug discovery for acute radiation syndrome and delayed effects of acute radiation exposure?

Kenchegowda, Doreswamy; Seed, Thomas M.; Singh, Vijay K.

doi:10.1080/17460441.2020.1811671

Cited by 2 publications

(1 citation statement)

References 22 publications

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“…Because of the ethical issues for the testing and development of radiation countermeasures, the US Food and Drug Administration Animal Rule requires a demonstration of countermeasure efficacy in two animal models, one of which must be a non-rodent [77]. Recent studies suggest that, because of anatomical and physiological similarities, swine recapitulate many of the characteristics of H-ARS in humans [78]. Our laboratory has repeatedly demonstrated the efficacy of captopril as a mitigator of H-ARS in mice and Göttingen minipigs [34,35,40].…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome

Horseman,

Rittase,

Slaven

et al. 2024

IJMS

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Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril’s effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42–0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome

Horseman,

Rittase,

Slaven

et al. 2024

IJMS

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Effects of captopril against radiation injuries in the Göttingen minipig model of hematopoietic-acute radiation syndrome

et al. 2021

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Our laboratory has demonstrated that captopril, an angiotensin converting enzyme inhibitor, mitigates hematopoietic injury following total body irradiation in mice. Improved survival in mice is correlated with improved recovery of mature blood cells and bone marrow, reduction of radiation-induced inflammation, and suppression of radiation coagulopathy. Here we investigated the effects of captopril treatment against radiation injuries in the Göttingen mini pig model of Hematopoietic-Acute Radiation Syndrome (H-ARS). Minipigs were given captopril orally (0.96 mg/kg) twice daily for 12 days following total body irradiation (60Co 1.79 Gy, 0.42–0.48 Gy/min). Blood was drawn over a time course following irradiation, and tissue samples were collected at euthanasia (32–35 days post-irradiation). We observed improved survival with captopril treatment, with survival rates of 62.5% in vehicle treated and 87.5% in captopril treated group. Additionally, captopril significantly improved recovery of peripheral blood mononuclear cells, and a trend toward improvement in recovery of red blood cells and platelets. Captopril significantly reduced radiation-induced expression of cytokines erythropoietin and granulocyte-macrophage colony-stimulating factor and suppressed radiation-induced acute-phase inflammatory response cytokine serum amyloid protein A. Using quantitative-RT-PCR to monitor bone marrow recovery, we observed significant suppression of radiation-induced expression of redox stress genes and improved hematopoietic cytokine expression. Our findings suggest that captopril activities in the Göttingen minipig model of hematopoietic-acute radiation syndrome reflect findings in the murine model.

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What are the practical, ethical, and pathobiological considerations in the use of minipigs as an animal model in drug discovery for acute radiation syndrome and delayed effects of acute radiation exposure?

Cited by 2 publications

References 22 publications

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome

Ferroptosis, Inflammation, and Microbiome Alterations in the Intestine in the Göttingen Minipig Model of Hematopoietic-Acute Radiation Syndrome

Effects of captopril against radiation injuries in the Göttingen minipig model of hematopoietic-acute radiation syndrome

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