Joaquin Cagliani1, Weng-Lang Yang2, Max Brenner3, Ping Wang4. 1. Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York; Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York. 2. Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York; Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York. 3. Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York; Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York. 4. Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, New York; Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York. Electronic address: pwang@northwell.edu.
Abstract
BACKGROUND: Hemorrhagic shock (HS) caused by rapid loss of a large amount of blood is the leading cause of early death after severe injury. When cells are damaged during HS, many intracellular components including DNA are released into the circulation and function as endogenous damage-associated molecular patterns (DAMPs) that can trigger excessive inflammatory response and subsequently multiple organ dysfunction. We hypothesized that the administration of deoxyribonuclease I (DNase I) could reduce cell-free DNA and attenuate tissue damage in HS. METHODS: Eight-week-old male C57BL/6 mice underwent HS by controlled bleeding from the femoral artery for 90 min, followed by resuscitation with Ringer's lactate solution (vehicle) or DNase I (10 mg/kg BW). RESULTS: At 20 h after HS, serum levels of cell-free DNA were increased by 7.6-fold in the vehicle-treated HS mice compared with sham, while DNase I reduced its levels by 47% compared with the vehicle group. Serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) and proinflammatory cytokine interleukin 6 were significantly reduced in the DNase I-treated mice. In the lungs, messenger RNA levels of proinflammatory cytokines (interleukin 6 and interleukin 1 β), chemoattractant macrophage inflammatory protein - 2, and myeloperoxidase activity were significantly decreased in HS mice after DNase I. Finally, DNase I significantly improved the 10-day survival rate in HS mice. CONCLUSIONS: Administration of DNase I attenuates tissue damage and systemic and lung inflammation, leading to improvement of survival in HS mice. Thus, DNase I may potentially serve as an adjunct therapy for managing patients with HS.
BACKGROUND:Hemorrhagic shock (HS) caused by rapid loss of a large amount of blood is the leading cause of early death after severe injury. When cells are damaged during HS, many intracellular components including DNA are released into the circulation and function as endogenous damage-associated molecular patterns (DAMPs) that can trigger excessive inflammatory response and subsequently multiple organ dysfunction. We hypothesized that the administration of deoxyribonuclease I (DNase I) could reduce cell-free DNA and attenuate tissue damage in HS. METHODS: Eight-week-old male C57BL/6 mice underwent HS by controlled bleeding from the femoral artery for 90 min, followed by resuscitation with Ringer's lactate solution (vehicle) or DNase I (10 mg/kg BW). RESULTS: At 20 h after HS, serum levels of cell-free DNA were increased by 7.6-fold in the vehicle-treated HSmice compared with sham, while DNase I reduced its levels by 47% compared with the vehicle group. Serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) and proinflammatory cytokine interleukin 6 were significantly reduced in the DNase I-treated mice. In the lungs, messenger RNA levels of proinflammatory cytokines (interleukin 6 and interleukin 1 β), chemoattractant macrophage inflammatory protein - 2, and myeloperoxidase activity were significantly decreased in HSmice after DNase I. Finally, DNase I significantly improved the 10-day survival rate in HSmice. CONCLUSIONS: Administration of DNase I attenuates tissue damage and systemic and lung inflammation, leading to improvement of survival in HSmice. Thus, DNase I may potentially serve as an adjunct therapy for managing patients with HS.
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