Peroxisome proliferator-activated receptor gamma agonist rosiglitazone attenuates oxyhemoglobin-induced Toll-like receptor 4 expression in vascular smooth muscle cells.

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.

Wu Y ，Zhao XD ，Zhuang Z ，Xue YJ ，Cheng HL ，Yin HX ，Shi JX ... -  《-》

Therapeutic potential of peroxisome proliferator-activated receptor γ agonist rosiglitazone in cerebral vasospasm after a rat experimental subarachnoid hemorrhage model.

The pathogenesis of cerebral vasospasm is closely associated with inflammation and immune response in arterial walls. Recently, the authors proved the key role of Toll-like receptor (TLR)4 in the development of vasospasm in experimental subarachnoid hemorrhage (SAH) model. Because peroxisome proliferator-activated receptor (PPAR) gamma agonists are identified as effective inhibitors of TLR4 activation, we investigated the anti-inflammation properties of PPAR-gamma agonist rosiglitazone in basilar arteries in a rat experimental SAH model and evaluated the effects of rosiglitazone on vasospasm. Inflammatory responses in basilar arteries were assessed by immunohistochemical staining for intercellular molecule (ICAM)-1 and myeloperoxidase (MPO). Expression of TLR4 was determined by western blot analysis. The degree of cerebral vasospasm was evaluated by measuring the mean diameter and cross-sectional area of basilar arteries. Rosiglitazone suppressed the SAH-induced inflammatory responses in basilar arteries by inhibiting the TLR4 signalling. Furthermore, rosiglitazone could attenuate cerebral vasospasm following SAH. Therefore, we suggested that PPAR-gamma agonists may be potential therapeutic agents for cerebral vasospasm.

Wu Y ，Tang K ，Huang RQ ，Zhuang Z ，Cheng HL ，Yin HX ，Shi JX ... -  《-》

Rosiglitazone regulates c-reactive protein-induced inflammatory responses via glucocorticoid receptor-mediated inhibition of p38 mitogen-activated protein kinase-toll-like receptor 4 signal pathway in vascular smooth muscle cells.

Liu N ，Liu JT ，Ji YY ，Lu PP ... -  《-》

PPARγ attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells.

Zhang LL ，Gao CY ，Fang CQ ，Wang YJ ，Gao D ，Yao GE ，Xiang J ，Wang JZ ，Li JC ... -  《-》

Regulation of cigarette smoke-induced toll-like receptor 4 expression by peroxisome proliferator-activated receptor-gamma agonists in bronchial epithelial cells.

This study was designed to determine the effects of peroxisome proliferator-activated receptor-gamma (PPARγ) on airway inflammatory response to cigarette smoke (CS) exposure. For the in vivo experiments, 50 male Wistar rats were randomly assigned to one of four groups and were exposed to CS and pretreatment with a PPARγ agonist, rosiglitazone or a vehicle (saline). PPARγ antagonist bisphenol A diglycidyl ether (BADGE) or saline was administered before rosiglitazone treatment. Leukotriene B4 (LTB4) and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay. PPARγ and toll-like receptor 4 (TLR4) expression levels were assessed by immunohistochemistry and real-time polymerase chain reaction. For the in vitro experiments, human bronchial epithelial cells were stimulated with CS or phosphate buffer saline, pretreated with PPARγ agonist rosiglitazone or 15-deoxy-(Δ12,14)-PG J2 before CS exposure. BADGE was administered prior to the agonist treatment. PPARγ, TLR4 and inhibitor of κB (IκBα) expression levels were assessed by Western bot. CS exposure decreased PPARγ expression, as well as increased IL-8, LTB4 and TLR4 expression levels in bronchial epithelial cells in vivo and in vitro. Moreover, PPARγ ligands counteracted CS-induced airway inflammation by reducing IL-8 and LTB4 expression levels that are associated with TLR4 and nuclear factor-kappa B (NF-κB). CS exposure increased the pro-inflammatory activity of bronchial epithelial cells by affecting PPARγ expression. Moreover, PPARγ may play a significant role as a modulator of the TLR4-dependent inflammatory pathway through NF-κB in bronchial epithelial cells.

Yin Y ，Hou G ，Li ER ，Wang QY ，Kang J ... -  《-》