title: 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.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Davids
authors.forename: Adelaide M
authors.initials: AM
authors.lastname: Carothers
authors.forename: Beatrice C
authors.initials: BC
authors.lastname: Damas
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D017491:Genes, APC / Q000502:physiology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D053668:Syndecan-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; C508242:Sdc1 protein, mouse; D013449:Sulfonamides; D053668:Syndecan-1; D016212:Transforming Growth Factor beta; D051546:Cyclooxygenase 2; D011133:Polysaccharide-Lyases; C083872:heparatinase I; D000068579:Celecoxib