Improvement of ventilation-induced lung injury in a rodent model by inhibition of inhibitory κB kinase.
BACKGROUND
Inhibition of nuclear factor κB (NF-κB) activation is a well-know strategy to ameliorate ventilation-induced lung injury (VILI). Inhibitory κB kinase (IKK) plays a key role in the regulation of NF-κB activation. In this study, we determined whether inhibition of IKK by an IKK inhibitor exerts lung protection in a rat model of VILI.


METHODS
Anesthetized and mechanically ventilated Sprague-Dawley rats were randomly assigned to a standard (tidal volume, 8 mL/kg) or high-tidal volume (tidal volume, 25 mL/kg) ventilation group. An IKK inhibitor (IKK 16) or vehicle was administrated 1 hour before the induction of VILI. All groups were ventilated and observed for 5 hours.


RESULTS
High-pressure ventilation caused activation of NF-κB, increased pulmonary inflammatory mediator levels, lung edema, and impairment of gas exchange. The IKK inhibitor treatment significantly reduced these changes and increased interleukin 10 levels, heme oxygenase 1 activity, protein kinase B (Akt) phosphorylation levels, and nuclear amounts of nuclear factor E2-related factor 2 protein.


CONCLUSIONS
IKK may be a therapeutic target for VILI. An IKK inhibitor, IKK 16, can dampen VILI in rats. The beneficial effect of the IKK 16 may be mediated through the inhibition of NF-κB pathway and up-regulation of nuclear factor E2-related factor 2-regulated heme oxygenase 1 through the activation of the phosphatidylinositol 3 kinase/Akt.
From the Department of Cardiothoracic Surgery (Y.-S.S., Y.-F.Y.), the Second Xiangya Hospital of Central South University, Changsha, Hunan; Department of Cardiothoracic Surgery (Y.-S.S., Q.-B.M.), Subei People's Hospital of Jiangsu Province, Yangzhou, Jiangsu; Department of Surgery (W.T.), Yangzhou East Hospital, Yangzhou, Jiangsu; and Department of Cardiothoracic Surgery (Y.-B.Z.), Hangzhou First People's Hospital, Hangzhou, Zhejiang, China.
Yu-Sheng
YS
Shu
Wei
W
Tao
Qian-Bing
QB
Miao
Ya-Bing
YB
Zhu
Yi-Feng
YF
Yang
D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D016328:NF-kappa B; D051550:I-kappa B Kinase