Journal of applied physiology
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The cecal ligation perforation (CLP) model of sepsis is known to induce severe diaphragm dysfunction, but the cellular mechanisms by which this occurs remain unknown. We hypothesized that CLP induces diaphragm caspase-3 and calpain activation, and that these two enzymes act at the level of the contractile proteins to reduce muscle force generation. Rats (n = 4/group) were subjected to 1) sham surgery plus saline (intraperitoneal); 2) CLP; 3) CLP plus administration of calpain inhibitor peptide III (12 mg/kg ip); or 4) CLP plus administration of a caspase inhibitor, zVAD-fmk (3 mg/kg). ⋯ CLP induces significant reductions in diaphragm contractile protein force-generating capacity. This force reduction is mediated by the combined effects of activated caspase and calpain. Inhibition of these pathways may prevent diaphragm weakness in infected patients.
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The degree to which mechanical ventilation induces ventilator-associated lung injury is dependent on the initial acute lung injury (ALI). Viral-induced ALI is poorly studied, and this study aimed to determine whether ALI induced by a clinically relevant infection is exacerbated by protective mechanical ventilation. Adult female BALB/c mice were inoculated with 10(4.5) plaque-forming units of influenza A/Mem/1/71 in 50 microl of medium or medium alone. ⋯ At the end of the ventilation period, a bronchoalveolar lavage sample was collected to measure inflammatory cells, macrophage inflammatory protein-2, IL-6, TNF-alpha, and protein leak. Influenza infection caused significant increases in inflammatory cells, protein leak, and deterioration in lung mechanics that were not exacerbated by mechanical ventilation, in contrast to previous studies using bacterial and mouse-specific viral infection. This study highlighted the importance of type and severity of lung injury in determining outcome following mechanical ventilation.
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Recent data from our laboratory demonstrated that, when rats are raised in a hypergravity environment, the sensitivity of the vestibulo-cardiovascular reflex decreases. In a hypergravity environment, static input to the vestibular system is increased; however, because of decreased daily activity, phasic input to the vestibular system may decrease. This decrease may induce use-dependent plasticity of the vestibulo-cardiovascular reflex. ⋯ The pressor response was preserved in 3-G rats with GVS (20 +/- 1 mmHg). GVS stimulated Fos expression in the medial vestibular nucleus. These results suggest that GVS stimulated vestibular primary neurons and prevent hypergravity-induced decrease in sensitivity of the vestibulo-cardiovascular reflex.
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We showed recently that IL-4 causes mitochondrial dysfunction in allergic asthma. IL-4 is also known to induce 12/15-lipoxygenase (12/15-LOX), a potent candidate molecule in asthma. Because vitamin E (Vit-E) reduces IL-4 and inhibits 12/15-LOX in vitro, here we tested the hypothesis that Vit-E may be effective in restoring key mitochondrial dysfunctions, thus alleviating asthma features in an experimental allergic murine model. ⋯ Vit-E was administered orally to these mice, and 12/15-LOX expression, key mitochondrial functions, ultrastructural changes of mitochondria in bronchial epithelia, and asthmatic parameters were determined. Vit-E treatment reduced AHR, Th2 response including IL-4, IL-5, IL-13, and OVA-specific IgE, eotaxin, transforming growth factor-beta1, airway inflammation, expression and metabolites of 12/15-LOX in lung cytosol, lipid peroxidation, and nitric oxide metabolites in the lung, restored the activity and expression of the third subunit of cytochrome-c oxidase in lung mitochondria and bronchial epithelia, respectively, reduced the appearance of cytochrome c in lung cytosol, and also restored mitochondrial ultrastructural changes of bronchial epithelia. In summary, these findings show that Vit-E reduces key mitochondrial dysfunctions and alleviates asthmatic features.