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Chronic Salmonella Infection Induced Intestinal Fibrosis
Published on: September 22, 2019
Chronic cyclooxygenase-2 inhibition promotes myofibroblast-associated intestinal fibrosis
Jennifer S Davids1, Adelaide M Carothers, Beatrice C Damas
1Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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.
Insights
Long-term use of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, leads to drug-resistant intestinal tumors. This resistance is linked to altered transforming growth factor-beta (TGF-beta) signaling and increased tissue fibrosis.
Area of Science:
- Gastroenterology
- Oncology
- Immunology
Background:
- Anti-inflammatory drugs, including selective cyclooxygenase-2 (COX-2) inhibitors like celecoxib, can prevent intestinal tumor formation by inhibiting inflammatory signaling.
- Previous studies showed celecoxib induces rapid tumor regression in Min/(+) mice, but long-term treatment results in drug-resistant tumors.
Purpose of the Study:
- To investigate whole-tissue changes in inflammatory signaling, focusing on the stroma and extracellular matrix, in response to chronic celecoxib treatment.
- To understand the mechanisms underlying celecoxib resistance in intestinal tumors.
Main Methods:
- Analysis of tissue stroma and extracellular matrix constituents in Min/(+) mice treated with celecoxib.
- Evaluation of changes in myofibroblast populations, transforming growth factor-beta (TGF-beta) signaling components, and extracellular matrix proteins.
Main Results:
- Celecoxib resistance was associated with altered autocrine TGF-beta signaling.
- Chronic treatment led to an expansion of myofibroblast precursors and myofibroblasts, increasing TGF-beta and COX-2 expression.
- Modifications in membrane constituents (syndecan-1, heparanase-1) promoted TGF-beta signaling.
- Long-term celecoxib treatment induced intestinal tissue fibrosis, evidenced by increased collagen, fibronectin, and laminin.
Conclusions:
- Chronic COX-2 inhibition alters TGF-beta signaling in the intestinal mucosa.
- These alterations create conditions that promote chronic inflammation and contribute to drug resistance in intestinal tumors.
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