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* Department of Surgery, University Health Network, and
Department of Medicine, St. Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada;
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115; and
Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06510
The Toll-like receptor 4 (TLR4) has recently been shown to function
as the major upstream sensor for LPS. In this study, a rodent model of
lung injury following resuscitated hemorrhagic shock was used to
examine the regulation of TLR4 gene and protein expression in vivo and
in vitro. Intratracheal LPS alone induced a rapid reduction in whole
lung TLR4 mRNA, an effect which is also observed in recovered alveolar
macrophages. This effect appeared to be due to a lowering of TLR4 mRNA
stability by 
69%. By contrast, while shock/resuscitation alone had
no effect on TLR4 mRNA levels, it markedly altered the response to LPS.
Specifically, antecedent shock prevented the LPS-induced reduction in
TLR4 mRNA levels. This reversal was explained by the ability of prior
resuscitated shock both to prevent the destabilization of TLR4 mRNA by
LPS and also to augment LPS-stimulated TLR4 gene transcription compared
with LPS alone. Oxidant stress related to shock/resuscitation appeared
to contribute to the regulation of TLR4 mRNA, because supplementation
of the resuscitation fluid with the antioxidant
N-acetylcysteine reversed the ability of
shock/resuscitation to preserve TLR4 mRNA levels following LPS. TLR4
protein levels in whole lung mirrored the changes seen for TLR4 mRNA.
Considered in aggregate, these data suggest that levels of
tlr4 expression are controlled both transcriptionally as
well as posttranscriptionally through altered mRNA stability and that
antecedent shock/resuscitation, a form of global ischemia/reperfusion,
might influence regulation of this gene.
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