morphine and Acute-Lung-Injury

Meconium aspiration syndrome (MAS) is a disease closely related to inflammation and oxidative stress. Glycyrrhizic acid (GA) is a triterpenoid isolated from licorice with multiple bioprotective properties. In the present study, impacts of GA against MAS rats, as well as the potential mechanism, will be investigated. MAS model was established on newborn rats, followed by the treatment of 12.5, 25, and 50 mg/kg GA. The wet/dry weight ratio of lung tissues was calculated. The production of IL-6, IL-1β, TNF-α, malonaldehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) was measured using ELISA assay. HE staining was used to evaluate the pathological state of lung tissues and TUNEL assay was used to detect the apoptotic state. The protein expression of Nrf2, Keap1, HO-1, Bcl-2, Bax, and cleaved-Caspase3 was measured by Western blotting assay. The elevated W/D ratio, release of inflammatory factors, lung injury score, and apoptotic index, as well as the activated oxidative stress and suppressed Keap1/Nrf2/HO-1 pathway, in MAS rats were significantly alleviated by GA. After introducing the inhibitor of Nrf2, ML385, the protective property of GA on the pathological state, apoptotic index, and oxidative stress in MAS rats was pronouncedly abolished. Taken together, glycyrrhizin alleviated GAH in rats by suppressing Keap1/Nrf2/HO-1 signaling mediated oxidative stress.

Topics: Acute Lung Injury; Animals; Animals, Newborn; Apoptosis; Glycyrrhizic Acid; Heme Oxygenase-1; Kelch-Like ECH-Associated Protein 1; Lung; Meconium; Meconium Aspiration Syndrome; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Rats; Signal Transduction

Anti-inflammatory drugs are increasingly used for treatment of neonatal meconium aspiration syndrome (MAS), but their adverse effects are poorly known. Therefore, the aim of this study was to evaluate the effects of the antioxidant N-acetylcysteine on cardiovascular parameters in an animal model of MAS. Oxygen-ventilated rabbits were intratracheally instilled 4 mL/kg of meconium suspension (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were given N-acetylcysteine (10 mg/kg, i.v.) or the same volume of saline. Changes in cardiovascular parameters (blood pressure, heart rate, and heart rate variability) were recorded over a 5-min course of solution administration, over 5 min after its end, and then hourly for 5 h. Oxidation markers (thiobarbituric acid-reactive substances (TBARS) and total antioxidant status) and aldosterone, as a non-specific marker of cardiovascular injury, were determined in plasma. Meconium instillation did not evoke any significant cardiovascular changes, but induced oxidative stress and elevated plasma aldosterone. N-acetylcysteine significantly reduced the mentioned markers of injury. However, its administration was associated with short-term increases in blood pressure and in several parameters of heart rate variability. Considering these effects of N-acetylcysteine, its intravenous administration in newborns with MAS should be carefully monitored.

Topics: Acetylcysteine; Acute Lung Injury; Aldosterone; Animals; Anti-Inflammatory Agents; Antioxidants; Blood Pressure; Disease Models, Animal; Heart Rate; Humans; Infant, Newborn; Injections, Intravenous; Intubation, Intratracheal; Lung; Meconium; Meconium Aspiration Syndrome; Oxidative Stress; Rabbits; Respiration, Artificial; Thiobarbituric Acid Reactive Substances

Meconium aspiration in newborns causes lung inflammation and injury, which may lead to meconium aspiration syndrome (MAS). In this study, the effect of the antioxidant N-acetylcysteine on respiratory and inflammatory parameters were studied in a model of MAS. Oxygen-ventilated rabbits were intratracheally given 4 mL/kg of meconium (25 mg/mL) or saline. Thirty minutes later, meconium-instilled animals were administered N-acetylcysteine (10 mg/kg; i.v.), or were left without treatment. The animals were oxygen-ventilated for additional 5 h. Ventilatory pressures, oxygenation, right-to-left pulmonary shunts, and leukocyte count were measured. At the end of experiment, trachea and lung were excised. The left lung was saline-lavaged and a total and differential count of cells in bronchoalveolar lavage fluid (BAL) was determined. Right lung tissue strips were used for detection of lung edema (expressed as wet/dry weight ratio) and peroxidation (expressed by thiobarbituric acid-reactive substances, TBARS). In lung and tracheal strips, airway reactivity to acetylcholine was measured. In addition, TBARS and total antioxidant status were determined in the plasma. Meconium instillation induced polymorphonuclear-derived inflammation and oxidative stress. N-acetylcysteine improved oxygenation, reduced lung edema, decreased polymorphonuclears in BAL fluid, and diminished peroxidation and meconium-induced airway hyperreactivity compared with untreated animals. In conclusion, N-acetylcysteine effectively improved lung functions in an animal model of MAS.

Topics: Acetylcysteine; Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Humans; Infant, Newborn; Injections, Intravenous; Intubation, Intratracheal; Leukocyte Count; Lipid Peroxidation; Lung; Meconium; Meconium Aspiration Syndrome; Oxidative Stress; Pulmonary Edema; Rabbits; Respiration, Artificial; Thiobarbituric Acid Reactive Substances; Trachea

Inflammation, oxidation, lung edema, and other factors participate in surfactant dysfunction in meconium aspiration syndrome (MAS). Therefore, we hypothesized that anti-inflammatory treatment may reverse surfactant dysfunction in the MAS model. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg; Mec) or saline (Sal). Thirty minutes later, meconium-instilled animals were treated by glucocorticoids budesonide (0.25 mg/kg, i.t.) and dexamethasone (0.5 mg/kg, i.v.), or phosphodiesterase inhibitors aminophylline (2 mg/kg, i.v.) and olprinone (0.2 mg/kg, i.v.), or the antioxidant N-acetylcysteine (10 mg/kg, i.v.). Healthy, non-ventilated animals served as controls (Con). At the end of experiments, left lung was lavaged and a differential leukocyte count in sediment was estimated. The supernatant of lavage fluid was adjusted to a concentration of 0.5 mg phospholipids/ml. Surfactant quality was evaluated by capillary surfactometer and expressed by initial pressure and the time of capillary patency. The right lung was used to determine lung edema by wet/dry (W/D) weight ratio. Total antioxidant status (TAS) in blood plasma was evaluated. W/D ratio increased and capillary patency time shortened significantly, whereas the initial pressure increased and TAS decreased insignificantly in Sal vs. Con groups. Meconium instillation potentiated edema formation and neutrophil influx into the lungs, reduced capillary patency and TAS, and decreased the surfactant quality compared with both Sal and Con groups (p > 0.05). Each of the anti-inflammatory agents reduced lung edema and neutrophil influx into the lung and partly reversed surfactant dysfunction in the MAS model, with a superior effect observed after glucocorticoids and the antioxidant N-acetylcysteine.

Topics: Acetylcysteine; Acute Lung Injury; Aminophylline; Animals; Anti-Inflammatory Agents; Antioxidants; Bronchoalveolar Lavage Fluid; Budesonide; Dexamethasone; Disease Models, Animal; Humans; Imidazoles; Infant, Newborn; Leukocyte Count; Lung; Meconium; Meconium Aspiration Syndrome; Neutrophils; Oxidative Stress; Phosphodiesterase Inhibitors; Pulmonary Edema; Pulmonary Surfactants; Pyridones; Rabbits