Differential effect of resuscitation on Toll-like receptors in a model of hemorrhagic shock without a septic challenge

Huazhen Chen, Elena Koustova, Christian Shults, Elizabeth A. Sailhamer, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

It has been shown that the inflammatory response and cellular damage after hemorrhagic shock are influenced by resuscitation strategies. Toll-like receptors (TLRs) play an important role in signal transduction in inflammatory conditions. However, alterations in TLR expression following hemorrhagic shock and resuscitation have not been well documented. This study was conducted to measure the impact of different resuscitation strategies on TLR expression and downstream signaling in key organs. Methods: Sprague Dawley rats (n = 38) were subjected to a severe volume-controlled hemorrhage protocol. After 75 min of shock, they were resuscitated over 45 min as follows: (1) lactated Ringer's (LR, 81 ml/kg), (2) ketone Ringer's (KR, 81 ml/kg), (3) 7.5% hypertonic saline (HTS, 9.7 ml/kg), (4) 6% hetastarch (HEX, 27 ml/kg), (5) pyruvate Ringer's (PR, 81 ml/kg). Sham hemorrhage (NH) and no resuscitation (NR) groups served as controls. The KR and PR solutions were identical to LR except for equimolar substitution of racemic lactate with beta hydroxybutyrate and sodium pyruvate, respectively. At the end of resuscitation, the expression of TLRs (types 1-10), and cytokines (IL-10, IL-1β and TNF-α) were measured in the lung and spleen using RT-PCR. Levels of phosphorylated and total IkB-α and NF-κB were detected by Western blotting. The systemic and lung protein levels of TNF-α were measured using ELISA and immunohistochemistry. Results: Expression of TLRs in the lung was affected more than in the spleen by hemorrhagic shock and resuscitation. In the lung, hemorrhage increased TLR-2, -3 and -6 (but not TLR-4) mRNA expression, with an up-regulation of the ratio of phosphor-NF-κBp65 and total NF-κBp65, NF-κBp65 activation, and enhanced systemic and tissue TNF-α protein levels. Post-resuscitation, TLR mRNA profile and subsequent downstream proteins in the lung and spleen were affected by the choice of resuscitation strategy. Conclusions: Hemorrhagic shock activates TLR signaling in lung, but not the spleen, probably through an up-regulation of TLR gene expression, and activation of NF-κB pathway. Resuscitation modulates this response in a fluid- and tissue-specific fashion.

Original languageEnglish (US)
Pages (from-to)526-537
Number of pages12
JournalResuscitation
Volume74
Issue number3
DOIs
StatePublished - Sep 2007
Externally publishedYes

Keywords

  • Cytokines
  • Hemorrhagic shock
  • Inflammatory response
  • Lung
  • NF-κB
  • Resuscitation strategies
  • Ringer's solutions
  • Spleen
  • TLR
  • TNF-α

ASJC Scopus subject areas

  • Emergency Medicine
  • Emergency
  • Cardiology and Cardiovascular Medicine

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