Chronic cyclooxygenase-2 inhibition promotes myofibroblast-associated intestinal fibrosis
- PMID: 20179298
- PMCID: PMC2833233
- DOI: 10.1158/1940-6207.CAPR-09-0146
Chronic cyclooxygenase-2 inhibition promotes myofibroblast-associated intestinal fibrosis
Abstract
Anti-inflammatory drugs prevent intestinal tumor formation, an activity related to their ability to inhibit inflammatory pathway signaling in the target tissue. We previously showed that treatment of Min/(+) mice with the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib induced rapid tumor regression; however, drug-resistant tumors appeared with long-term treatment. In this study, we investigated whole-tissue changes in inflammatory signaling by studying constituents of the tissue stroma and extracellular matrix. We found that celecoxib resistance was associated with changes in factors regulating autocrine transforming growth factor-beta (TGFbeta) signaling. Chronic drug treatment expanded the population of bone marrow-derived CD34(+) vimentin(+) alphaSMA(-) myofibroblast precursors and alphaSMA(+) vimentin(+) F4/80(-) myofibroblasts in the lamina propria and submucosa, providing a source of increased TGFbeta and COX-2 expression. Membrane constituents regulating TGFbeta availability, including syndecan-1 and heparanase-1, were also modified by chronic treatment in a manner promoting increased TGFbeta signaling. Finally, long-term celecoxib treatment induced tissue fibrosis, as indicated by increased expression of collagen, fibronectin, and laminin in the basement membrane. We conclude that chronic COX-2 inhibition alters TGFbeta signaling in the intestinal mucosa, producing conditions consistent with chronic inflammation.
Figures





Similar articles
-
Persistent cyclooxygenase-2 inhibition downregulates NF-{kappa}B, resulting in chronic intestinal inflammation in the min/+ mouse model of colon tumorigenesis.Cancer Res. 2010 Jun 1;70(11):4433-42. doi: 10.1158/0008-5472.CAN-09-4289. Epub 2010 May 18. Cancer Res. 2010. PMID: 20484034 Free PMC article.
-
Antifibrotic and fibrolytic properties of celecoxib in liver damage induced by carbon tetrachloride in the rat.Liver Int. 2010 Aug;30(7):969-78. doi: 10.1111/j.1478-3231.2010.02256.x. Epub 2010 May 26. Liver Int. 2010. PMID: 20524983
-
Imatinib-resistant K562 cells are more sensitive to celecoxib, a selective COX-2 inhibitor: role of COX-2 and MDR-1.Leuk Res. 2008 Jun;32(6):855-64. doi: 10.1016/j.leukres.2007.11.007. Epub 2008 Feb 20. Leuk Res. 2008. PMID: 18083230
-
Cyclooxygenase-2 inhibitor, celecoxib, inhibits leiomyoma cell proliferation through the nuclear factor κB pathway.Reprod Sci. 2014 Sep;21(9):1187-95. doi: 10.1177/1933719114542010. Epub 2014 Jul 6. Reprod Sci. 2014. PMID: 25001017 Free PMC article.
-
Clinical pharmacology of celecoxib, a COX-2 selective inhibitor.Expert Opin Pharmacother. 2007 Aug;8(11):1719-32. doi: 10.1517/14656566.8.11.1719. Expert Opin Pharmacother. 2007. PMID: 17685888 Review.
Cited by
-
Nadroparin sodium activates Nrf2/HO-1 pathway in acetic acid-induced colitis in rats.Inflammation. 2012 Jun;35(3):1213-21. doi: 10.1007/s10753-012-9431-z. Inflammation. 2012. PMID: 22350949
-
Phenotypic screening of 1,953 FDA-approved drugs reveals 26 hits with potential for repurposing for Peyronie's disease.PLoS One. 2022 Dec 12;17(12):e0277646. doi: 10.1371/journal.pone.0277646. eCollection 2022. PLoS One. 2022. PMID: 36508413 Free PMC article.
-
Celecoxib increases EGF signaling in colon tumor associated fibroblasts, modulating EGFR expression and degradation.Oncotarget. 2015 May 20;6(14):12310-25. doi: 10.18632/oncotarget.3678. Oncotarget. 2015. PMID: 25987127 Free PMC article.
-
Multifocal Signal Modulation Therapy by Celecoxib: A Strategy for Managing Castration-Resistant Prostate Cancer.Int J Mol Sci. 2019 Dec 3;20(23):6091. doi: 10.3390/ijms20236091. Int J Mol Sci. 2019. PMID: 31816863 Free PMC article.
-
Controversials of Microscopic Colitis.Front Med (Lausanne). 2021 Oct 12;8:717438. doi: 10.3389/fmed.2021.717438. eCollection 2021. Front Med (Lausanne). 2021. PMID: 34712675 Free PMC article. Review.
References
-
- Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. The American Journal of Surgery. 1989;157:175–9. - PubMed
-
- Steinbach G, Lynch PM, Phillips RKS, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. The New England Journal of Medicine. 2000;342(26):1946–52. - PubMed
-
- Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355(9):885–95. - PubMed
-
- Bertagnolli MM. Chemoprevention of colorectal cancer with cyclooxygenase-2 inhibitors: two steps forward, one step back. Lancet Oncology. 2007;8:439–43. - PubMed
-
- Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352(11):1071–80. - PubMed
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Research Materials