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MAG-EPA and 17,18-EpETE target cytoplasmic signalling pathways to reduce short-term airway hyperresponsiveness

  • Signaling and cell physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

This study was aimed to investigate the role of eicosapentaenoic acid monoacylglyceride (MAG-EPA) and 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) on the regulation of contractile reactivity and nuclear protein expression in 72-h-cultured and TNF-α-treated guinea pig tracheal rings. Tension measurements performed on native tissues demonstrated that the cytochrome P-450 epoxygenase (CYP450)-dependent EPA metabolite, 17,18-EpETE, displayed a higher potency than MAG-EPA in inhibiting U-46619-induced tone. Calphostin C (a PKC inhibitor), whether in association or not with MAG-EPA or 17,18-EpETE, had no further effect, while 17,18-EpETE and Y-27632 (a Rho kinase inhibitor) yielded additive effects. Of note, MAG-EPA and 17,18-EpETE pre-treatments normalized the contractile responses to broncho-constrictive agents in 72-h-cultured trachea. The enhanced expression of TNF-α, P-p65-nuclear factor kappaB (NF)-κB, c-fos and c-Jun in 72-h-cultured tissues likely contributed to the hyperresponsiveness. β-Escin-permeabilized preparations demonstrated that 17,18-EpETE abolished Ca2+ hypersensitivity, suggesting a blunting of PKC and/or Rho kinase activation. Lastly, activation of NF-κB and activating protein-1 (AP-1) signalling by exogenous TNF-α markedly increased the contractile response to MCh, through an increase in 17-kDa PKC-potentiated inhibitory protein of PP1 (CPI-17) phosphorylation and IκBα degradation. Dual incubation of 17,18-EpETE with calphostin C or Y-27632 induced cumulative inhibitory effects on MCh responses in TNF-α-incubated tracheal rings. 17,18-EpETE also reduced the detection level of P-p65-NF-κB and AP-1 subunits. The present data provide evidence that MAG-EPA, through its bioactive metabolite, represents a prospective pharmacological target in respiratory diseases.

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Abbreviations

AHR:

Airway hyperresponsiveness

HT:

Hyperreactive trachea

MAG-EPA:

Eicosapentaenoic acid monoacylglyceride

AP-1:

Activating protein-1

PUFA:

Polyunsaturated fatty acid

TNF-α:

Tumour necrosis factor alpha

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Acknowledgments

We wish to thank Dr. Caroline Morin and Dr. Samuel Fortin from SCF Pharma for the gift of MAG-EPA. The authors wish to thank Mr. Pierre Pothier, Ms. Stephanie Corriveau and Elyse Burt for critical review of the manuscript. This work is supported by a CIHR grant MOP-111112 to ER who is a member of the Respiratory Health Network of the FRQS: www.rsr-frqs.ca. We are especially grateful to the members of the animal care facility at the Faculty of Medicine and Health Sciences for their precious collaboration, as well as Mr. Yacine Tabet for logistic support.

Conflict of interest

No conflicts of interest, financial or otherwise, are declared by the authors.

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  1. Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada

    Rayan Khaddaj-Mallat & Éric Rousseau

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  1. Rayan Khaddaj-Mallat
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  2. Éric Rousseau
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Correspondence to Éric Rousseau.

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Khaddaj-Mallat, R., Rousseau, É. MAG-EPA and 17,18-EpETE target cytoplasmic signalling pathways to reduce short-term airway hyperresponsiveness. Pflugers Arch - Eur J Physiol 467, 1591–1605 (2015). https://doi.org/10.1007/s00424-014-1584-1

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