Identification of New Potential Therapies for Colitis Amelioration Using an Appendicitis-Appendectomy Model.
Inflamm Bowel Dis
; 25(3): 436-444, 2019 02 21.
Article
en En
| MEDLINE
| ID: mdl-30329049
ABSTRACT
The appendix contains copious lymphoid tissue and is constantly exposed to gut flora. Appendicitis followed by appendectomy (AA), when done at a young age, prevents or significantly ameliorates inflammatory bowel diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis. Our unique murine AA model is the only existing experimental model of AA. Herein, the appendiceal pathology closely resembles the pathological features of human appendicitis. Our AA model protects against experimental colitis in an age-, bacteria- and antigen-dependent manner. Appendicitis-appendectomy performed in the most proximal colon curbs T helper 17 (Th17) cell activity, diminishes autophagy, modulates interferon activity-associated molecules, and suppresses endothelin vasoactivity-mediated immunopathology in the most distal colon. These changes induced by AA contribute to limiting colitis pathology. Manipulating and modulating various aspects of these pathways, pathophysiology, and molecular interactions will assist the development of novel therapeutic options to manage IBD. Competitive inhibition of the Th17 cell recruitment factor CCL20 or the chemokine CCL17 with antibodies, combinatorial peptides, or small molecules may limit colitic pathology. The chemokines CCL5 and CXCL11 could be investigated as potential therapies. Inhibition of the autophagy-associated molecules VPS15, LAMP2, LC3A, XBP1, or ULK1 may decrease colitic pathology. Curtailing endothelin-activity may decrease colitic impact. The antiproliferative, immunomodulatory molecules IFIT1, IFIT2, IFIT3, and IFI44 may have direct therapeutic value in ameliorating colitis. The molecules IRF4, IRF8, IRF2BP1, IFRD1, and IFRD2 are potentially good target molecules to competitively inhibit towards curbing colitis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Apendicectomía
/
Apendicitis
/
Colitis
/
Quimiocinas
/
Modelos Animales de Enfermedad
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Inflamm Bowel Dis
Asunto de la revista:
GASTROENTEROLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Australia