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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Evaluation of Urothelial Stretch-Induced Cyclooxygenase-2 Expression in Novel Human Cell Culture and Porcine in Vivo Ureteral Obstruction Models

Travis J. Jerde, William S. Mellon, Dale E. Bjorling and Stephen Y. Nakada
Journal of Pharmacology and Experimental Therapeutics June 2006, 317 (3) 965-972; DOI: https://doi.org/10.1124/jpet.105.099184
Travis J. Jerde
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William S. Mellon
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Dale E. Bjorling
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Stephen Y. Nakada
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Abstract

Obstruction and stretch induce cyclooxygenase (COX)-2 expression and prostanoid synthesis in urinary tissues, causing pain, inflammation, hypercontractility, and cell proliferation. Our objective was to characterize acute COX-2 induction during in vivo ureteral obstruction, establish a cell culture model of urothelial stretch-induced COX-2 expression, and evaluate whether mechanotransduction could alter transcriptional and post-transcriptional regulation of COX-2. We performed laparoscopic unilateral ureteral ligation in pigs and allowed progression for 1, 2, 6, 24, or 48 h. We evaluated COX-2 expression with reverse transcriptase (RT)-polymerase chain reaction (PCR) and immunoblotting. We cultured primary human urothelial cells on stretch plates, applied stretch for up to 48 h, and measured COX-2 expression by RT-PCR and immunoblotting, transcription with run-on assays, and mRNA stability with actinomycin mRNA decay assays. In vivo ureteral obstruction induced COX-2 expression 4-fold within 6 h, maintaining induction for 24 h. In cell culture, stretch induced COX-2 steady-state mRNA and protein within the first 3 h of stretch, maintaining this induction for over 6 h. Three hours of stretch doubled COX-2 transcription relative to unstretched controls and increased COX-2 mRNA half-life 3-fold. This is the first report to characterize in vivo temporal stretch-induced COX-2 expression in the urothelium and establish a primary urothelial cell culture model for the study of stretch-induced COX-2 mechanisms. This is also the first report to identify alterations in steady-state COX-2 mRNA having components of both transcriptional and post-transcriptional regulation of stretch-regulated COX-2. Future elucidation of COX-2 signaling may identify novel therapeutic targets for treating stretch and distension of urinary tissues.

Footnotes

  • This work was supported by the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases Award R21DK066060-02.

  • doi:10.1124/jpet.105.099184.

  • ABBREVIATIONS: COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; RT, reverse transcriptase; dNTP, deoxyribonucleotide triphosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; sb, starting base; PBS, phosphate-buffered saline; TIA-1, T-cell intracytoplasmic antigen-1.

    • Received December 8, 2005.
    • Accepted February 27, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Evaluation of Urothelial Stretch-Induced Cyclooxygenase-2 Expression in Novel Human Cell Culture and Porcine in Vivo Ureteral Obstruction Models

Travis J. Jerde, William S. Mellon, Dale E. Bjorling and Stephen Y. Nakada
Journal of Pharmacology and Experimental Therapeutics June 1, 2006, 317 (3) 965-972; DOI: https://doi.org/10.1124/jpet.105.099184

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Evaluation of Urothelial Stretch-Induced Cyclooxygenase-2 Expression in Novel Human Cell Culture and Porcine in Vivo Ureteral Obstruction Models

Travis J. Jerde, William S. Mellon, Dale E. Bjorling and Stephen Y. Nakada
Journal of Pharmacology and Experimental Therapeutics June 1, 2006, 317 (3) 965-972; DOI: https://doi.org/10.1124/jpet.105.099184
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