Effect of dual SEH/COX-2 inhibition on allergen-induced airway inflammation

Mythili Dileepan, Stephanie Rastle-Simpson, Yana Greenberg, Dayanjan S. Wijesinghe, Naren Gajenthra Kumar, Jun Yang, Sung Hee Hwang, Bruce D. Hammock, P. Sriramarao, Savita P. Rao

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Arachidonic acid metabolites resulting from the cyclooxygenase (COX), lipoxygenase, and cytochrome P450 oxidase enzymatic pathways play pro- and anti-inflammatory roles in allergic airway inflammation (AAI) and asthma. Expression of COX-2 and soluble epoxide hydrolase (sEH) are elevated in allergic airways and their enzymatic products (e.g., prostaglandins and diols of epoxyeicosatrienoic acids, respectively) have been shown to participate in the pathogenesis of AAI. Here, we evaluated the outcome of inhibiting the COX-2 and sEH enzymatic pathways with a novel dual inhibitor, PTUPB, in A. alternata-induced AAI. Allergen-challenged mice were administered with 10 or 30 mg/ kg of PTUPB, celecoxib (selective COX-2 inhibitor), t-TUCB (selective sEH inhibitor) or vehicle daily by gavage and evaluated for various features of AAI. PTUPB and t-TUCB at 30 mg/kg, but not celecoxib, inhibited eosinophilic infiltration and significantly increased levels of anti-inflammatory EETs in the lung tissue of allergen-challenged mice. t-TUCB significantly inhibited allergen-induced IL-4 and IL-13, while a less pronounced reduction was noted with PTUPB and celecoxib. Additionally, t-TUCB markedly inhibited eotaxin-2, an eosinophil-specific chemokine, which was only marginally reduced by PTUPB and remained elevated in celecoxib-treated mice. PTUPB or t-TUCB administration reversed allergen-induced reduction in levels of various lipid mediators in the lungs, with only a minimal effect noted with celecoxib. Despite the anti-inflammatory effects, PTUPB or t-TUCB did not reduce allergen-induced airway hyperresponsiveness (AHR). However, development of structural changes in the allergic airways, such as mucus hypersecretion and smooth muscle hypertrophy, was significantly inhibited by both inhibitors. Celecoxib, on the other hand, inhibited only airway smooth muscle hypertrophy, but not mucus hypersecretion. In conclusion, dual inhibition of COX-2 and sEH offers no additional advantage relative to sEH inhibition alone in attenuating various features associated with A. alternata-induced AAI, while COX-2 inhibition exerts only moderate or no effect on several of these features. Dual sEH/COX-2 inhibition may be useful in treating conditions where eosinophilic inflammation co-exists with pain-associated inflammation.

Original languageEnglish (US)
Article number1118
JournalFrontiers in Pharmacology
Issue numberSEP
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by the University of Minnesota College of Veterinary Medicine (to PS) and in part by NIEHS (River Award R35ES030443 to BDH) and NIH (HD087198 to DW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
Copyright © 2019 Dileepan, Rastle-Simpson, Greenberg, Wijesinghe, Kumar, Yang, Hwang, Hammock, Sriramarao and Rao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


  • Allergic airway inflammation
  • COX-2
  • Eosinophilia
  • Pharmacological inhibition
  • Soluble epoxide hydrolase


Dive into the research topics of 'Effect of dual SEH/COX-2 inhibition on allergen-induced airway inflammation'. Together they form a unique fingerprint.

Cite this