title: Knockdown of myeloid differentiation protein-2 reduces acute lung injury following orthotopic autologous liver transplantation in a rat model.
abstract: BACKGROUND
  Acute lung injury (ALI) is a serious complication that commonly occurs during orthotopic liver transplantation (OLT). Toll-like receptor 2/4 (TLR2/4) are the main membrane receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-κB) signal pathway. We previously showed that TLR2/4 expression on monocytes and serum cytokine levels were increased in patients with ALI induced by OLT. Myeloid differentiation protein-2 (MD-2) expresses the functional domains that combines TLRs and play a key regulatory role in TLRs activation. Therefore, we hypothesized that blocking MD-2 would inhibit the TLR2/4-mediated inflammatory response and lessen ALI induced by liver transplantation.
  
  
  METHODS
  Thirty-two Sprague Dawley (SD) rats were randomly divided into four groups. One group received a sham operation (Group S), and the other three groups underwent orthotopic autologous liver transplantation (OALT) 48 h after intratracheal administration of saline (Model group; Group M), non-targeting siRNA (negative siRNA control group; Group NC) or siRNA against MD-2 (intervention group; Group RNAi). Lung pathology, lung water content, PaO2, and expression levels of MD-2, TLR2/4, NF-κB, TNF-α, IL-1β and IL-6 were assessed 8 h after OALT.
  
  
  RESULTS
  In Groups M and NC, OALT produced marked lung pathology with decreased PaO2 levels and increased MD-2, TLR2/4 gene and protein expression levels. Furthermore, the nuclear translocation of the NF-κB P65 subunit, was increased, as were lung concentrations of TNF-α, IL-1β and IL-6. The pathology of ALI and the severity of the above biochemical changes induced by OALT were significantly reduced in the group treated with MD-2 siRNA.
  
  
  CONCLUSIONS
  MD-2 gene knock-down attenuated the increase in TLR2/4 activation and reduced ALI after OALT.
authors: Department of Anesthesiology, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China. chixinjin@yahoo.com.cn
authors: Xinjin
authors: X
authors: Chi
authors: Ailan
authors: A
authors: Zhang
authors: Gangjian
authors: G
authors: Luo
authors: Hua
authors: H
authors: Xia
authors: Guosong
authors: G
authors: Zhu
authors: Ziqing
authors: Z
authors: Hei
authors: Xiangfu
authors: X
authors: Liu
authors: Jianqi
authors: J
authors: Wei
authors: Zhengyuan
authors: Z
authors: Xia
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D015633:Extravascular Lung Water / Q000378:metabolism; D015870:Gene Expression; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007378:Interleukins / Q000096:biosynthesis; D016031:Liver Transplantation / Q000009:adverse effects*; D008168:Lung / Q000473:pathology; D051218:Lymphocyte Antigen 96 / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007378:Interleukins; C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha