title: Systemic combined melatonin-mitochondria treatment improves acute respiratory distress syndrome in the rat.
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.
authors.affiliation: Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.forename: Fan-Yen
authors.initials: FY
authors.lastname: Lee
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
authors.forename: Hsin-Ju
authors.initials: HJ
authors.lastname: Chiang
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Sung
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Steve
authors.initials: S
authors.lastname: Leu
authors.forename: Ying-Chung
authors.initials: YC
authors.lastname: Wu
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Lu
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chen
authors.forename: Sheng-Ying
authors.initials: SY
authors.lastname: Chung
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Su
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000818:Animals; D015153:Blotting, Western; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*
chemical_list: D008550:Melatonin
keywords: 100% oxygen inhalation; acute respiratory distress syndrome; inflammation; melatonin; mitochondria; oxidative stress