Protective effects of dexmedetomidine-ketamine combination against ventilator-induced lung injury in endotoxemia rats.

BACKGROUND: Pulmonary inflammatory response is crucial in mediating the development of ventilator-induced lung injury (VILI) in animals experiencing endotoxemia. Dexmedetomidine and ketamine are two sedative agents with potent anti-inflammatory capacity. We sought to elucidate the anti-inflammatory effects of dexmedetomidine-ketamine combination against VILI in endotoxemia rats. MATERIALS AND METHODS: Eighty-four adult male rats were allocated to receive normal saline, VILI, VILI plus dexmedetomidine-ketamine combination (D+K), lipopolysaccharide (LPS), LPS plus D+K, LPS plus VILI, or LPS plus VILI plus D+K (designated as the NS, V, V-D+K, LPS, LPS-D+K, LPS/V, and LPS/V-D+K group, respectively; n = 12 in each group). VILI was induced by high-tidal volume ventilation (tidal volume 20 mL/kg; respiratory rate 50 breath/min; FiO(2) 21%). After being mechanically ventilated for 4 h, rats were sacrificed and the levels of pulmonary inflammatory response were evaluated. RESULTS: Histologic findings revealed severe, moderate, and mild inflammation in lung tissues of the LPS/V, LPS, and V groups, respectively, whereas those of the LPS/V-D+K, LPS-D+K, and V-D+K groups revealed moderate, mild, and normal to minimal inflammation, respectively. Moreover, the total cell number and the concentrations of macrophage inflammatory protein-2 and interleukin-1ß in bronchoalveolar lavage fluid as well as the lung water content, leukocyte infiltration, myeloperoxidase activity, and the concentrations of inducible nitric oxide synthase/nitric oxide, and cyclooxygenase 2/prostaglandin E(2) in lung tissues of the LPS/V, LPS, and V groups were significantly higher than those of the LPS/V-D+K, LPS-D+K, and V-D+K groups, respectively. CONCLUSIONS: Dexmedetomidine-ketamine combination could mitigate pulmonary inflammatory response induced by VILI in endotoxemia rats.

Platonin inhibits endotoxin-induced MAPK and AP-1 up-regulation.

BACKGROUND: We previously have shown that platonin, a potent antioxidant, significantly attenuated inflammatory molecules up-regulation in RAW264.7 cells, a murine macrophage-like cell line. Inflammatory molecules expression is under the regulation of activator protein-1 (AP-1), a crucial transcription factor and a heterodimeric protein that composes of proteins from c-Jun and c-Fos families. AP-1 expression is regulated by mitogen-activated protein kinases (MAPKs). We sought to elucidate the effects of platonin on MAPKs and AP-1 up-regulation in activated RAW264.7 cells. MATERIALS AND METHODS: RAW264.7 cells were allocated to receive phosphate buffered saline, lipopolysaccharide (LPS, 100 ng/mL), platonin (100 µM), or platonin plus LPS and designated as the PBS, LPS, platonin, or LPS + platonin group, respectively. After harvesting, expression of the investigated molecules was evaluated. RESULTS: The cytosolic protein concentrations of MAPKs, including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK, of the LPS group were significantly higher than those of the PBS and platonin groups. The nuclear protein concentrations of AP-1, including c-Jun and c-Fos, and the AP-1-DNA binding activity of the LPS group were also significantly higher than those of the PBS and platonin groups. In contrast, the concentrations of ERK, JNK, and p38 MAPK of the LPS + platonin group were significantly lower than those of the LPS group. Moreover, the concentrations of c-Jun and c-Fos and the AP-1-DNA binding activity of the LPS + platonin group were significantly lower than those of the LPS group. CONCLUSIONS: Platonin significantly attenuated MAPKs and AP-1 upregulation in activated RAW264.7 cells.

Multiple models of porcine teschovirus pathogenesis in endemically infected pigs.

Porcine teschoviruses (PTVs) belong to the genus Teschovirus within the family Picornaviridae. PTVs are universal contaminants in pig herds in endemic and multi-infection status. To further the understanding of PTV pathogenesis in endemically infected pigs, a set of samples was studied by real time reverse transcription PCR (qRT-PCR) to quantitate viral loads in tissues and by in situ hybridization (ISH) to locate PTV signals in target cells, both targeting the 5'-NTR. cRNA of PTV-1 and PTV-7, in vitro transcribed from cloned fragments of 5'-NTR of 2 viruses, was used to construct standard curves and to run parallel in qRT-PCR, which had detection limits of 10(1) copies/per reaction, with a linearity in between 10(1) and 10(7) copies/per reaction and correlation coefficients of 0.997-0.9988. The qRT-PCR specifically amplified RNA from PTV-1 to -11, while excluding those of Sapelovirus, PEV-9 and PEV-10. Inguinal lymph node (LN) had the highest viral load of all (assuming 100%), followed by ileac LN (89-91%), tonsil (66-68%), ileum (59-60%), spleen (38-40%), and kidney (30-31%), with the least in brain (22.9%) of the inguinal LN. The 22.9% load in brain was higher than that anticipated from a simple fecal-oral-viremia operative model. The results suggested in addition that intranasal infection and retrograding axonal infection from the tonsils were equally operative and significant. ISH revealed PTV signals in a wider variety of tissue cell types than before. PTV signals were noted most impressively in neurons of the cerebral cortex and hippocampus and in the dark zone of the germinal center and adjacent paracortex of regional LN. Multiple operative models indicated that PTVs seemed to have no difficulty invading the brain. The key to whether encephalitis would ensue resided in the animal's immune status and topographic differences of neurons' susceptibilities to PTVs. When common co-infected agents are present, as is typical in the field, PTVs may synergize in causing diseases.

Effects of dexmedetomidine on regulating pulmonary inflammation in a rat model of ventilator-induced lung injury.

BACKGROUND: We sought to elucidate the effects of dexmedetomidine, a selective alpha2-adrenergic receptor agonist, on the regulation of pulmonary inflammation in ventilator-induced lung injury (VILI) in a rat model. METHODS: A total of 64 adult male Sprague-Dawley rats were assigned to receive either standard ventilation (tidal volume 10 mL/kg; respiratory rate 50 breaths/minute), high-tidal volume ventilation (HVT: tidal volume 20 mL/kg; respiratory rate 50 breaths/minute), HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour), or HVT plus dexmedetomidine (0.5, 2.5 or 5.0 microg/kg per hour) and yohimbine (the alpha2-adrenergic receptor antagonist) (n = 8 in each group). The doses of dexmedetomidine were chosen to correspond to 1, 5 and 10 times the clinical dose (0.5 microg/kg per hour). After maintaining ventilation for 4 hours, rats were sacrificed and pulmonary inflammatory changes as well as the upregulation of pulmonary inflammatory molecules were evaluated. RESULTS: Histological and arterial blood gas analyses confirmed that HVT induced significant lung injury. HVT also significantly increased the pulmonary concentrations of chemokines (e.g. macrophage inflammatory protein-2), cytokines (e.g. tumor necrosis factor-alpha, interleukin [IL]-1beta, and IL-6), inducible nitric oxide synthase/nitric oxide, cyclooxygenase-2/prostaglandin E2. Dexmedetomidine at the dose of 5.0 microg/kg per hour, but not at 0.5 and 2.5 microg/kg per hour, significantly attenuated the effects of HVT. Moreover, these effects of dexmedetomidine were significantly attenuated by yohimbine. CONCLUSION: Dexmedetomidine at clinically relevant doses had no significant effect in attenuating VILI. In contrast, dexmedetomidine at a dose approximately 10 times higher than the clinical dose significantly attenuated VILI. These effects of dexmedetomidine were mediated, at least in part, by the alpha2-adrenergic receptor.