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

• Published in: International journal of molecular sciences 2024-04, Vol.25 (8), p.4535
• Main Authors: Horseman, Timothy, Rittase, W Bradley, Slaven, John E, Bradfield, Dmitry T, Frank, Andrew M, Anderson, Joseph A, Hays, Evelyn C, Ott, Andrew C, Thomas, Anjali E, Huppmann, Alison R, Lee, Sang-Ho, Burmeister, David M, Day, Regina M
• Format: Article
• Language: English
• Subjects: acute radiation syndrome; Acute Radiation Syndrome - drug therapy; Analysis; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Blood; Bone marrow; Captopril; Captopril - pharmacology; Cytokines; Disease Models, Animal; Enzymes; Ferroptosis; Ferroptosis - drug effects; gastrointestinal injury; Gastrointestinal Microbiome - drug effects; Gene expression; Genes; H-ARS; Hemorrhage; Inflammation; Inflammation - pathology; Injuries; Intestines - drug effects; Intestines - microbiology; Intestines - pathology; Intestines - radiation effects; Lipid peroxidation; Lipids; Male; Metabolites; microbiome; minipigs; Mortality; Proteins; Radiation; Radiotherapy; RNA; Swine; Swine, Miniature; Trends; Whole-Body Irradiation - adverse effects
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25084535

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 ( Co 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 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 , , , and , and the inflammasome component . Captopril suppressed radiation-induced and . 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.