Systemic combined melatonin–mitochondria treatment improves acute respiratory distress syndrome in the rat |
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| Authors: | Ying Hsien Kao Hsin Ju Chiang Pei Hsun Sung Tzu Hsien Tsai Yu Chun Lin Steve Leu Ying Chung Wu Hung I Lu Yung Lung Chen Sheng Ying Chung Hon Kan Yip |
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| Institution: | 1. Department of Medical Research, E‐Da Hospital, I‐Shou University, Kaohsiung, Taiwan;2. Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;3. Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;4. Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;5. Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan |
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| Abstract: | Despite high in‐hospital mortality associated with acute respiratory distress syndrome (ARDS), there is no effective therapeutic strategy. We tested the hypothesis that combined melatonin–mitochondria treatment ameliorates 100% oxygen‐induced ARDS in rats. Adult male Sprague‐Dawley rats (n = 40) were equally categorized into normal controls, ARDS, ARDS‐melatonin, ARDS with intravenous liver‐derived mitochondria (1500 μg per rat 6 hr after ARDS induction), and ARDS receiving combined melatonin–mitochondria. The results showed that 22 hr after ARDS induction, oxygen saturation (saO2) was lowest in the ARDS group and highest in normal controls, significantly lower in ARDS‐melatonin and ARDS‐mitochondria than in combined melatonin–mitochondria group, and significantly lower in ARDS‐mitochondria than in ARDS‐melatonin group. Conversely, right ventricular systolic blood pressure and lung weight showed an opposite pattern compared with saO2 among all groups (all P < 0.001). Histological integrity of alveolar sacs showed a pattern identical to saO2, whereas lung crowding score exhibited an opposite pattern (all P < 0.001). Albumin level and inflammatory cells (MPO+, CD40+, CD11b/c+) from bronchoalveolar lavage fluid showed a pattern opposite to saO2 (all P < 0.001). Protein expression of indices of inflammation (MMP‐9, TNF‐α, NF‐κB), oxidative stress (oxidized protein, NO‐1, NOX‐2, NOX‐4), apoptosis (mitochondrial Bax, cleaved caspase‐3, and PARP), fibrosis (Smad3, TGF‐β), mitochondrial damage (cytochrome C), and DNA damage (γ‐H2AX+) exhibited an opposite pattern compared to saO2 in all groups, whereas protein (HO‐1, NQO‐1, GR, GPx) and cellular (HO‐1+) expressions of antioxidants exhibited a progressively increased pattern from normal controls to ARDS combined melatonin–mitochondria group (all P < 0.001). In conclusion, combined melatonin–mitochondrial was superior to either treatment alone in attenuating ARDS in this rat model. |
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| Keywords: | 100% oxygen inhalation acute respiratory distress syndrome inflammation melatonin mitochondria oxidative stress |
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