Downregulation of Lung Toll-Like Receptor 4 Could Effectively Attenuate Liver Transplantation-Induced Pulmonary Damage at the Early Stage of Reperfusion.
Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-α and IL-β level were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-α and IL-β, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats' survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Xinjin
X
Chi
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Weifeng
W
Yao
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Ailan
A
Zhang
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Mian
M
Ge
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Jun
J
Cai
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Shaoli
S
Zhou
Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
Zhengyuan
Z
Xia
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Gangjian
G
Luo
Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China.
Ziqing
Z
Hei
D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha