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Abstract
Inflammation and immune response have been implicated in the pathogenesis of cerebral
vasospasm after subarachnoid hemorrhage (SAH). Recently, increased TLR4 expression
has been associated with the development of cerebral vasospasm in a rabbit model of
SAH. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, effective
inhibitors of TLR4 activation, may modulate the vasospasm progression via their anti-inflammation
effects. We investigate whether the blood component oxyhemoglobin (OxyHb) can induce
the expression of Toll-like receptor (TLR) 4 in vascular smooth muscle cells (VSMCs),
and evaluate the modulatory effects of PPARgamma agonist rosiglitazone on OxyHb-induced
inflammation in VSMCs. Cultured VSMCs incubated with or without rosiglitazone were
exposed to OxyHb at 10muM for up to 48h. Expression of TLR4 was assessed by immunocytochemistry
and Western blot analysis. Production of tumor necrosis factor alpha (TNF-alpha) in
conditioned medium were quantified by ELISA. A marked increase of TLR4 production
and TNF-alpha release was observed at 48h after cells were treated with OxyHb. Rosiglitazone
reduced TLR4 immunocytochemistry staining and protein production significantly in
VSMCs. A specific antagonist for PPARgamma, GW9662, could reverse the anti-inflammatory
effects of rosiglitazone. The results demonstrated that OxyHb exposure could induce
TLR4 activation in cultured VSMCs. Rosiglitazone suppressed TLR4 expression and cytokine
release via the activation of PPARgamma and may have a therapeutic potential for the
treatment of vasospasm following SAH.
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