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EET Displays Anti-Inflammatory Effects in TNF-–Stimulated Human Bronchi

Putative Role of CPI-17

¹ Le Bilarium, Department of Physiology and Biophysics, ² Service of Thoracic Surgery, and ³ Department of Pathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada

Correspondence and requests for reprints should be addressed to Eric Rousseau, Ph.D., Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001, 12th Avenue North, Sherbrooke, PQ, J1H 5N4 Canada. E-mail: Eric.Rousseau{at}USherbrooke.ca

The aim of the present study was to investigate the anti-inflammatory effects of 14,15-epoxyeicosatrienoic acid (EET) on reactivity and Ca²⁺ sensitivity in TNF-–stimulated human bronchi. Tension measurements performed on either control, TNF-–, or TNF- + EET–pretreated bronchi revealed that 100 nM 14,15-EET pretreatments significantly reduced the reactivity of TNF-–pretreated tissues to contractile agonists. EET also normalized the relaxing response to isoproterenol in TNF-–treated bronchi. Pretreatment with 100 nM 14,15-EET prevented TNF-–induced IB degradation, as demonstrated by an increase in IB protein levels on Western blot analysis. The anti-inflammatory properties of EET were mediated by the inhibition of IB degradation, suggesting a lower activation of NF-B. The Ca²⁺ sensitivity of TNF-–stimulated bronchi was also evaluated on β-escin–permeabilized preparations. Observed mean responses demonstrated that EET pretreatments abolished Ca²⁺ hypersensitivity developed by TNF-–stimulated bronchial explants. Moreover, 14,15-EET significantly reduced PDBu-induced Ca²⁺ sensitivity in TNF-–stimulated bronchi. Western blot and RT-PCR analyses revealed that CPI-17 protein and transcript levels were increased in TNF-–treated bronchi, as opposed to being decreased in the presence of 14,15-EET. This eicosanoid also reduced U-46619–induced Ca²⁺ sensitivity, which is related to the activation of Rho-kinase pathway. These results were also correlated with an increase in protein staining and transcription level of p116^Rip, a RhoA inhibitory-binding protein. Altogether, these data demonstrate that 14,15-EET is a potent modulator of the hyperreactivity triggered by TNF- in human airway smooth muscle cells.

Key Words: epoxyeicosatrienoic acid • TNF- • human bronchial smooth muscle • CPI-17 • NF-B

CLINICAL RELEVANCE The current research and the results obtained may be highly relevant for human diseases, such as asthma and chronic obstructive pulmonary disease.