Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Abstract

Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dosedependently reduced the IL-1b-induced release of IL-6 and vascular endothelial growth factor, the TNF-a-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-a-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-g (PPARg), these anti-inflammatory effects were not affected by a specific PPARg inhibitor (GW 9662) or by the knockdown of PPARg using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the antiinflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARg or AMPK.

PPAR antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function

“…26 Conversely, in other experiments, BADGE and GW9662 did not antagonize PPARγ signaling nor prevent adipogenesis in vitro and in vivo. [27][28][29][30] In one study, BADGE actually promoted adipogenesis at nanomolar levels, while higher concentrations of BADGE were cytotoxic. 28 We found that low dose BADGE had either no therapeutic effect or even worsened BM failure, whereas high dose BADGE did not add to hematological improvement.…”

Rosiglitazone Did Not Induce Acute Kidney Injury in Normocholesterolemic Rats Despite Reduction in Glomerular Filtration Rate

“…In addition, PPARγ agonists also vasodilate both pre- and postglomerular arterioles that decrease the glomerular capillary pressure (P GC ) [13] allowing the reduction in glomerular hyperfiltration and albumin excretion when used in diabetic patients [3]. However, the use of PPARγ agonists is not restricted to diabetic patients due to its anti-inflammatory action [2,9,10]. Thus, the reduction in P GC may diminish GFR and blood supply to tubular epithelial cells predisposing non-diabetic patients using PPARγ agonists to renal ischemia and AKI.…”

“…Thus, the European Medicines Agency suspended RGL from the European market since September 2010. Despite well documented side effects, many other studies continue to indicate the use of RGL in diabetic and nondiabetic patients due to its anti-inflammatory property [9,10]. …”

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease

“…In vitro, human ASM cytokine secretion and proliferation have been shown to be suppressed by the PPAR␥ agonists RGZ and ciglitazone (CGZ) (10,27,30,34,37). However, only some of these anti-inflammatory and antiremodeling activities were inhibited by the selective PPAR␥ antagonist GW9662, suggesting both PPAR␥-dependent and -independent mechanisms (30, 34).…”