| Summary: | 碩士 === 國防醫學院 === 海底醫學研究所 === 100 === After the lung transplantation, 15 % patients have severe lung dysfunction due to ischemia-reperfusion injury (IR). The mechanism of lung edema in acute lung injury include： increased permeability and pulmonary vascular resistance, exudated fluid collection, and reduced the alveolar fluid clearance. The mechanism of lung edema clearance is regulated by epithelial sodium channel (ENaC), sodium-potassium ATPase (Na+, K+- ATPase) and the sodium-potassium-chloride cotransporter isoform 1 (NKCC1). The ENaC and the Na+, K+- ATPase play important role in fluid clearance from alveoli, whereas the NKCC1 phosphorylation reduces the AFC and induces severely lung edema. In addition to its effect on AFC, NKCC1 has been shown to increase the vascular permeability in the acute lung injury induced by endotoxemia. However, it remains unknown whether the NKCC1 enhance permeability via inflammatory pathway. This study is aiming to investigate the relationship between NKCC1 and vascular permeability in acute lung injury induced by ischemia-reperfusion using an in situ isolated lung model. Our result showed that IR induced greater lung inflammation, but not lung injury, in the WNK4561A/+ knockin mice, although this group of mice expressed more phosphorylated NKCC1 in the lung as compared with the widetype mice. Perfusion with NKCC1 inhibitor, bumetanide, significantly suppressed the IR-induced activation of IKK-NFκB inflammation pathway in both WNK4561A/+ knockin and widetype mice. Bumetanide also attenuated the high vascular permeability and acute lung injury induced by IR. In summary, our study demonstrated that NKCC1 plays an important role in tissue inflammation and acute lung injury induced by ischemia reperfusion. However, it needs further investigation to clarify whether the insignificant effect of WNK4561A/+ knockin is due to compensatory expression of some protective mechanisms.
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