Knockdown of myeloid differentiation protein-2 reduces acute lung injury following orthotopic autologous liver transplantation in a rat model

Xinjin Chi, Ailan Zhang, Gangjian Luo, Hua Xia, Guosong Zhu, Ziqing Hei, Xiangfu Liu, Jianqi Wei, Zhengyuan Xia

Research output: Contribution to journalArticlepeer-review

Abstract

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. Method: 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. Conclusion: MD-2 gene knock-down attenuated the increase in TLR2/4 activation and reduced ALI after OALT.

Original languageEnglish (US)
Pages (from-to)380-387
Number of pages8
JournalPulmonary Pharmacology and Therapeutics
Volume26
Issue number3
DOIs
StatePublished - Jun 2013

Keywords

  • Acute lung injury (ALI)
  • Liver transplantation
  • Myeloid differentiation protein-2 (MD-2)
  • RNA interference (RNAi)

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Biochemistry, medical
  • Pharmacology (medical)

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