Nonsteroidal anti-inflammatory-induced inhibition of signal transducer and activator of transcription 6 (STAT-6) phosphorylation in aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin desensitization provides long-term clinical benefits. The exact mechanisms of aspirin desensitization are not clearly understood. OBJECTIVE: We sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on T-cell activation of the IL-4 pathway in aspirin-sensitive patients with asthma and control subjects. METHODS: A total of 11 aspirin-sensitive patients with asthma, 10 aspirin-tolerant patients with asthma, and 10 controls without asthma were studied. PBMCs were stimulated with an anti-CD3 antibody and IL-4 or IL-12, with and without the presence of NSAIDs. The expression of phosphorylated signal transducers and activators of transcription 6 (pSTAT6), phosphorylated signal transducers and activators of transcription 4, and IL-4 was detected in CD4 T cells by flow cytometry. RESULTS: Stimulation with a combination of anti-CD3 and IL-4 induced pSTAT6 in CD4 T cells from all subjects. The induction of pSTAT6 was significantly higher in aspirin-sensitive patients with asthma than in controls subjects. The increase in pSTAT6 was inhibited in a dose-dependent manner by aspirin and indomethacin and minimally by sodium salicylate. This inhibition was strongest in aspirin-sensitive patients. Two-group comparisons showed significant differences in pSTAT6 inhibition by all concentrations of indomethacin and aspirin: between aspirin-sensitive and aspirin-tolerant groups and between aspirin-sensitive and control groups. No differences were found between aspirin-tolerant and control groups at all 3 concentrations. The inhibition of pSTAT6 was associated with reduced IL-4 expression. CONCLUSIONS: NSAIDs inhibited signal transducers and activators of transcription 6 signaling in CD4 T cells. This inhibition was significantly higher in aspirin-sensitive patients than in aspirin-tolerant subjects and was associated with reduced expression of IL-4. These findings have implications for clinical benefits of aspirin desensitization in aspirin-sensitive patients with asthma.

Mechanisms of Benefit with Aspirin Therapy in Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by severe persistent asthma, hyperplastic eosinophilic sinusitis with nasal polyps, and an intolerance to aspirin and other NSAIDs that preferentially inhibit COX-1. For more than 30 years, aspirin desensitization has proven to be of significant long-term benefit in carefully selected patients with AERD. Despite this, the exact mechanisms behind the therapeutic effects of aspirin desensitization remain poorly understood. In this article, we review the current understanding of the mechanisms of aspirin desensitization and discuss future areas of investigation.

Quantifying the effect of resin type and sterilization method on the degradation of ultrahigh molecular weight polyethylene after 4 years of real-time shelf aging.

Alternative sterilization methods including ethylene oxide, gas plasma, and gamma-radiation in an inert environment were implemented in the late 1990s, to limit oxidative degradation of ultrahigh molecular weight polyethylene (PE). There was also a simultaneous transition to PE resins that did not contain calcium stearate. Shelf storage duration of PE inserts following gamma-irradiation in air has been correlated to poor clinical performance and increased wear. This study aimed to determine how sterilization method and resin type influenced degradation of PE after 4 years of real-time shelf aging. It was hypothesized that gamma-irradiation and stearate containing resins would incur significantly more degradation than nonradiated, stearate-free resins. Gamma-irradiated PE samples in air and nitrogen had a significantly increased density and oxidation index, compared to nonirradiated PE after 4 years of shelf aging. Alternative sterilization methods such as ethylene oxide and gas plasma appeared to have significantly less oxidation regardless of PE resin type. A partial correlation demonstrated that density and oxidation index were not correlated (r(2) = 0.079) when examining the influence of sterilization method. The data supported that after 4 years of real-time shelf aging, the type of sterilization method had a larger influence on PE degradation than resin type.

Mechanisms of aspirin desensitization.

Aspirin-exacerbated respiratory disease is a clinical syndrome characterized by severe, persistent asthma, hyperplastic eosinophilic sinusitis with nasal polyps, and reactions to aspirin and other nonsteroidal antiinflammatory drugs that preferentially inhibit cyclooxygenase 1. The mechanisms behind the therapeutic effects of aspirin desensitization remain poorly understood. Recent studies suggest that the clinical benefits may occur through direct inhibition of tyrosine kinases and the signal transducer and activator of transcription 6 signaling pathway, which results in inhibition of interleukin 4 production. In this article, the current understanding of the mechanisms of aspirin desensitization is reviewed and future areas of investigation are discussed.