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The incidence of postoperative infection and SSI were significantly reduced by our infection countermeasures, especially by bile leakage management and the use of absorbable sutures.

Our results suggest that pneumoperitoneum increases sympathetic cardiac activity. The choice of general anesthetic did not seem to have a major influence on the change in the cardiac autonomic nervous system after induction of pneumoperitoneum for laparoscopic cholecystectomy.

Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-βENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J-βENaC-Tg mice. Treatments of C57/BL6J-βENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-βENaC-Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-βENaC-Tg mice, consistent with the characteristics of human COPD/CF.

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Airway mucus hyperproduction and fluid imbalance are important hallmarks of cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians. Dysregulated expression and/or function of airway ion transporters, including cystic fibrosis transmembrane conductance regulator (CFTR) and epithelial sodium channel (ENaC), have been implicated as causes of CF-associated mucus hypersecretory phenotype. However, the contributory roles of other substances and transporters in the regulation of CF airway pathogenesis remain unelucidated. Here, we identified a novel connection between CFTR/ENaC expression and the intracellular Zn2 + concentration in the regulation of MUC5AC, a major secreted mucin that is highly expressed in CF airway. CFTR-defective and ENaC-hyperactive airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the zinc importer ZIP2/SLC39A2 (ΔC-ZIP2), which lacks the C-terminal domain. Importantly, ΔC-ZIP2 levels correlated inversely with wild-type ZIP2 and intracellular Zn2 + levels. Moreover, the splice switch to ΔC-ZIP2 as well as decreased expression of other ZIPs caused zinc deficiency, which is sufficient for induction of MUC5AC; while ΔC-ZIP2 expression per se induced ENaC expression and function. Thus, our findings demonstrate that the novel splicing switch contributes to CF lung pathology via the novel interplay of CFTR, ENaC, and ZIP2 transporters.

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