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Insulin resistance plays an important role in obesity-associated asthma exacerbations. Using a murine model of allergic airway inflammation, we evaluated the insulin signaling transmission in lungs of obese compared with lean mice. We further evaluated the effects of the polyphenol resveratrol in the pulmonary insulin signaling. In lean mice, insulin stimulation significantly increased phosphorylations of AKT, insulin receptor substrate 1 (IRS-1) and insulin receptor β (IRβ) in lung tissue and isolated bronchi (p < 0.05), which were impaired in obese group. Instead, obese mice displayed increased tyrosine nitrations of AKT, IRβ and IRS-1 (p < 0.05). Two-week therapy of obese mice with resveratrol (100 mg/kg/day) restored insulin-stimulated AKT, IRS-1 and IRβ phosphorylations, and simultaneously blunted the tyrosine nitration of these proteins. Additionally, the c-Jun N-terminal kinase (JNK) and inhibitor of NF-κB Kinase (IκK) phosphorylations were significantly increased in obese group, an effect normalized by resveratrol. In separate experiments, the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (20 mg/kg/day, three weeks) mimicked the protective effects exerted by resveratrol in lungs of obese mice. Lungs of obese mice display nitrosative-associated impairment of insulin signaling, which is reversed by resveratrol. Polyphenols may be putative drugs to attenuate asthma exacerbations in obese individuals.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. We investigate the role of toll-like receptor 4 (TLR4) on voiding dysfunction and inflammation in the cyclophosphamide (CYP)-induced mouse cystitis. Male C57BL/6 [wild-type, (WT)] and/or TLR4 knockout (TLR4) mice were treated with an injection of CYP (300 mg/kg, 24 h) or saline (10 ml/kg). The pharmacological blockade of the TLR4 by resatorvid (10 mg/kg) was also performed 1 h prior CYP-injection in WT mice. Urodynamic profiles were assessed by voiding stain on filter paper and filling cystometry. Contractile responses to carbachol were measured in isolated bladders. In CYP-exposed WT mice, mRNA for TLR4, myeloid differentiation primary response 88, and TIR-domain-containing adapter-inducing interferon-β increased by 45%, 72%, and 38%, respectively ( P < 0.05). In free-moving mice, CYP-exposed mice exhibited a higher number of urinary spots and smaller urinary volumes. Increases of micturition frequency and nonvoiding contractions, concomitant with decreases of intercontraction intervals and capacity, were observed in the filling cystometry of WT mice ( P < 0.05). Carbachol-induced bladder contractions were significantly reduced in the CYP group, which was paralleled by reduced mRNA for M2 and M3 muscarinic receptors. These functional and molecular alterations induced by CYP were prevented in TLR4 and resatorvid-treated mice. Additionally, the increased levels of inflammatory markers induced by CYP exposure, myeloperoxidase activity, interleukin-6, and tumor necrosis factor-alpha were significantly reduced by resatorvid treatment. Our findings reveal a central role for the TLR4 signaling pathway in initiating CYP-induced bladder dysfunction and inflammation and thus emphasize that TLR4 receptor blockade may have clinical value for IC/BPS treatment.

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