Jung Wook Hwang1, Min Ji Lee2, Tae Nyoung Chung3, Han A Reum Lee3, Jung Ho Lee3, Seo Yoon Choi3, Ye Jin Park3, Chul Hee Kim3, Isom Jin1, Seong Hoon Kim1, Hyo-Bum Kwak4, Jun-Won Heo4, Kwangmin Na5, Sangchun Choi6, Yong-Soo Choi7, Kyuseok Kim8. 1. Department of Biotechnology, CHA University, Gyeonggi-Do, South Korea. 2. Department of Emergency Medicine, CHA Bundang Medical Center CHA University, Gyeonggi-Do, South Korea. 3. Department of Emergency Medicine, CHA University School of Medicine, Gyeonggi-Do, South Korea. 4. Department of Biomedical Science, Program in Biomedical Science and Engineering, Inha University, Incheon, South Korea. 5. Paean Biotechnology Inc., Seoul, South Korea. 6. Department of Emergency Medicine, Ajou University School of Medicine, Suwon, South Korea. 7. Department of Biotechnology, CHA University, Gyeonggi-Do, South Korea. yschoi@cha.ac.kr. 8. Department of Emergency Medicine, CHA University School of Medicine, Gyeonggi-Do, South Korea. dremkks@cha.ac.kr.
Abstract
BACKGROUND: Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis. METHODS: We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens. RESULTS: Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study. CONCLUSIONS: In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.
BACKGROUND:Sepsis has a high mortality rate, but no specific drug has been proven effective, prompting the development of new drugs. Immunologically, sepsis can involve hyperinflammation, immune paralysis, or both, which might pose challenges during drug development. Recently, mitochondrial transplantation has emerged as a treatment modality for various diseases involving mitochondrial dysfunction, but it has never been tested for sepsis. METHODS: We isolated mitochondria from L6 muscle cells and umbilical cord mesenchymal stem cells and tested the quality of the isolated mitochondria. We conducted both in vivo and in vitro sepsis studies. We investigated the effects of intravenous mitochondrial transplantation on cecal slurry model in rats in terms of survival rate, bacterial clearance rate, and the immune response. Furthermore, we observed the effects of mitochondrial transplantation on the immune reaction regarding both hyperinflammation and immune paralysis. To do this, we studied early- and late-phase cytokine production in spleens from cecal slurry model in rats. We also used a lipopolysaccharide (LPS)-stimulated human PBMC monocyte model to confirm the immunological effects of mitochondrial transplantation. Apoptosis and the intrinsic apoptotic pathway were investigated in septic spleens. RESULTS: Mitochondrial transplantation improved survival and bacterial clearance. It also mitigated mitochondrial dysfunction and apoptosis in septic spleens and attenuated both hyperinflammation and immune paralysis in the spleens of cecal slurry model in rats. This effect was confirmed with an LPS-stimulated human PBMC study. CONCLUSIONS: In rat polymicrobial cecal slurry model, the outcome is improved by mitochondrial transplantation, which might have an immunomodulatory effect.
Authors: Mervyn Singer; Clifford S Deutschman; Christopher Warren Seymour; Manu Shankar-Hari; Djillali Annane; Michael Bauer; Rinaldo Bellomo; Gordon R Bernard; Jean-Daniel Chiche; Craig M Coopersmith; Richard S Hotchkiss; Mitchell M Levy; John C Marshall; Greg S Martin; Steven M Opal; Gordon D Rubenfeld; Tom van der Poll; Jean-Louis Vincent; Derek C Angus Journal: JAMA Date: 2016-02-23 Impact factor: 56.272
Authors: James D McCully; Douglas B Cowan; Christina A Pacak; Ioannis K Toumpoulis; Haripriya Dayalan; Sidney Levitsky Journal: Am J Physiol Heart Circ Physiol Date: 2008-10-31 Impact factor: 4.733
Authors: Min Ji Lee; Jinkun Bae; Jung Ho Lee; Ye Jin Park; Han A Reum Lee; Sehwan Mun; Yun-Seok Kim; Chang June Yune; Tae Nyoung Chung; Kyuseok Kim Journal: Int J Mol Sci Date: 2022-06-13 Impact factor: 6.208
Authors: Ye Jin Park; Min Ji Lee; Jinkun Bae; Jung Ho Lee; Han A Reum Lee; Sehwan Mun; Yun-Seok Kim; Chang June Yune; Tae Nyoung Chung; Kyuseok Kim Journal: Life (Basel) Date: 2022-03-14