Naomi-Liza Denning1, Monowar Aziz2, Mahendar Ochani3, Jose M Prince4, Ping Wang5. 1. Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY. 2. Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY. 3. Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY. 4. Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Cohen Children's Medical Center at Hofstra/Northwell Health, New Hyde Park, NY. 5. Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; Elmezzi Graduate School of Molecular Medicine, Manhasset, NY. Electronic address: pwang@northwell.edu.
Abstract
BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.
BACKGROUND:Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS:Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.
Authors: Anthony Stallion; Tzuyung D Kou; Samir Q Latifi; Kelly A Miller; Beverly B Dahms; David L Dudgeon; Alan D Levine Journal: J Pediatr Surg Date: 2005-03 Impact factor: 2.545
Authors: Seung Mok Ryoo; JungBok Lee; Yoon-Seon Lee; Jae Ho Lee; Kyoung Soo Lim; Jin Won Huh; Sang-Bum Hong; Chae-Man Lim; Younsuck Koh; Won Young Kim Journal: Crit Care Med Date: 2018-06 Impact factor: 7.598