Fibrostenotic Phenotype of Myofibroblasts in Crohn's Disease is Dependent on Tissue Stiffness and Reversed by LOX Inhibition.
J Crohns Colitis
; 12(7): 849-859, 2018 Jun 28.
Article
em En
| MEDLINE
| ID: mdl-29672662
ABSTRACT
BACKGROUND AND AIMS:
Crohn's disease is a chronic inflammatory disorder of the intestine and often leads to fibrosis, characterized by excess extracellular matrix [ECM] deposition, increased tissue stiffness, and stricture formation. Here we evaluated the contribution of myofibroblast-ECM interactions to the development of intestinal fibrosis in Crohn's disease.METHODS:
Matched primary human myofibroblasts were isolated from stenotic, inflamed and normal-appearing small intestine within the same Crohn's disease patient [n = 10]. Cells were analyzed by gene expression profiling, microscopy and functional assays, including matrix metalloproteinase [MMP] production and ECM contraction.RESULTS:
We demonstrated that myofibroblasts isolated from stenotic intestine differed both in phenotype and function from those isolated from purely inflammatory or normal-appearing intestine of the same patient. Stenotic myofibroblasts displayed increased expression of genes associated with ECM modulation and collagen deposition. Upon culture in a fibrotic environment, normal myofibroblasts increased expression of MMPs to counteract the mechanical force exerted by the matrix. Interestingly, stenotic myofibroblasts showed a paradoxical response with decreased expression of MMP3. In addition, stenotic myofibroblasts expressed increased levels of the collagen crosslinking enzyme lysyl oxidase [LOX] and induced significantly more ECM contraction than both normal and inflamed myofibroblasts. Importantly, LOX inhibition completely restored MMP3 activity in stenotic myofibroblasts grown in a fibrotic environment, and prevented excessive ECM contraction.CONCLUSIONS:
Together these data indicate aberrancies in the myofibroblast-ECM interaction in Crohn's disease, and identify LOX inhibition as a potential anti-fibrotic agent in this condition.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Crohn
/
Matriz Extracelular
/
Miofibroblastos
/
Proteína-Lisina 6-Oxidase
Tipo de estudo:
Etiology_studies
Limite:
Adolescent
/
Adult
/
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article