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.

Preactivated and Disaggregated Shape-Changed Platelets Protected Against Acute Respiratory Distress Syndrome Complicated by Sepsis Through Inflammation Suppression

“…The preparation of lung specimens for morphometric analyses was according to the description of our previous study (30,32). Briefly, the left lung was inflated at a constant airway pressure of 15-20 mmHg and fixed with OCT (Tissue-Tek, Sakura, Netherlands) for immunohistochemical staining, while the right lung was cut into pieces that were either fixed in 4% paraformaldehyde/0.1% glutaradehyde PBS solution before being embedded in paraffin blocks for hematoxylin and eosin (H & E) staining or stored at -80° C for protein and mRNA analyses.…”

“…Additionally, previous studies have revealed that ALI/ARDS not only elicits a severe inflammatory reaction, but it also enhances the generation of oxidative stress and reactive oxygen species (ROS) (5, [16][17][18][19] that further damage the lung parenchyma, The ARDS experimental model has been reported to be successfully created when pure oxygen (i.e., 100% O 2 ) was continuously administered to the rat for 48 h in our recent report (30). Additionally, to mimic the clinical setting of ARDS complicated by sepsis, LPS (1.5 mg/kg i.p for each rat) was administered to groups 3 and 4 at 24 h later after ARDS induction.…”

Enhanced protection against renal ischemia–reperfusion injury with combined melatonin and exendin-4 in a rodent model

“…19,30 Similarly, the dosage of exendin-4 administration was based on our recent reports with minimal modifications. 25,27 Examination of circulating levels of creatinine and blood urea nitrogen (BUN), and collection of 24 h urine for the ratio of urine protein to creatinine at 72 h after acute kidney IR injury Blood samples were collected from all animals in each group for measuring the changes in serum creatinine and BUN levels at 72 h after IR procedure.…”

“…27,30,31 The Oxyblot Oxidized Protein Detection Kit was purchased from Chemicon, Billerica, MA, USA (S7150). DNPH derivatization was carried out on 6 mg of protein for 15 min according to the manufacturer's instructions.…”

Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview

“…The protection mechanism was related with antioxidative damage (Liu et al, 2014). The level of oxidative stress-related markers of mitochondrial apoptosis (Bax, cleaved caspase-3, and PARP, cytochrome c release into the cytosol) decreased in the presence of melatonin in acute respiratory distress syndrome (Sun et al, 2015). Melatonin abolished destructive demyelination effects induced by the drug cuprizone in the corpus callosum, by decreasing oxidative stress and by restoring mitochondrial respiratory enzyme activity and fusion and fission processes (Kashani et al, 2014).…”