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
-
Epimorphin deletion inhibits polyposis in the Apcmin/+ mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion.Am J Physiol Gastrointest Liver Physiol. 2013 Oct 15;305(8):G564-72. doi: 10.1152/ajpgi.00486.2012. Epub 2013 Jul 25. Am J Physiol Gastrointest Liver Physiol. 2013. PMID: 23886856 Free PMC article.
-
The close relationship between heparanase and epithelial mesenchymal transition in gastric signet-ring cell adenocarcinoma.Oncotarget. 2018 Sep 18;9(73):33778-33787. doi: 10.18632/oncotarget.26042. eCollection 2018 Sep 18. Oncotarget. 2018. PMID: 30333909 Free PMC article.
-
Dose-dependent pro- or anti-fibrotic responses of endometriotic stromal cells to interleukin-1β and tumor necrosis factor α.Sci Rep. 2020 Jun 11;10(1):9467. doi: 10.1038/s41598-020-66298-x. Sci Rep. 2020. PMID: 32528066 Free PMC article.
-
Immune antibodies and helminth products drive CXCR2-dependent macrophage-myofibroblast crosstalk to promote intestinal repair.PLoS Pathog. 2015 Mar 25;11(3):e1004778. doi: 10.1371/journal.ppat.1004778. eCollection 2015 Mar. PLoS Pathog. 2015. PMID: 25806513 Free PMC article.
-
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
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