Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.4.3.13 (lysyl oxidase)
 1,248 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Scarring of superficial tissues and chronic fibroses of major organs present major medical problems ranging from disfigurement to progressive disability and death. Growing understanding of the cellular and molecular events, which are common to these intractable disorders, now provides a favourable basis for the development of effective drug therapies. Much attention is focussed on the roles of the many cytokines and growth factors, which contribute to the fibrogenic process. The transforming growth factor (TGF)-beta 1 and 2 isoforms are among the most significant of these and approaches to control their activity include blocking the activation of latent TGF-beta, preventing the ligand-receptor interactions and the inhibition of down-stream signal transduction. Concerns regarding possible risks of the long-term suppression of TGF-beta function point to connective tissue growth factor (CTGF) as a possible alternative target. CTGF is induced by and appears to mediate at least some of the fibrogenic actions of TGF-beta, although not its important antimitogenic activity on epithelial cells. The fibrogenic effects of endothelins and angiotensin II have aroused considerable interest in the anti-fibrotic potential of antihypertensive agents designed primarily to limit the vasoconstrictive activities of these peptides. Polypeptides including interferons alpha and gamma, relaxin, TGF-beta 3 and hepatocyte growth factor, all show an ability to limit fibrogenesis in either clinical or experimental situations. Finally, inhibitors of the enzymes required for the post-translational processing of collagens, including prolyl 4-hydroxylase, C-proteinase and lysyl oxidase provide a more direct means of reducing the deposition of fibrillar collagens into the extracellular matrix although the potentially adverse effects of sustained manipulation of collagen metabolism remain to be investigated.
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PMID:Therapeutic approaches to organ fibrosis. 907 43

Fibrosis after solid organ transplantation is considered an irreversible process and remains the major cause of graft dysfunction and death with limited therapies. This remodeling is characterized by aberrant accumulation of contractile myofibroblasts that deposit excessive extracellular matrix (ECM) and increase tissue stiffness. Studies demonstrate, however, that a stiff ECM itself promotes fibroblast-to-myofibroblast differentiation, stimulating further ECM production. This creates a positive feedback loop that perpetuates fibrosis. We hypothesized that simultaneously targeting myofibroblast contractility with relaxin and ECM stiffness with lysyl oxidase inhibitors could break the feedback loop, reversing established fibrosis. To test this, we used the orthotopic tracheal transplantation (OTT) mouse model, which develops robust fibrotic airway remodeling. Mice with established fibrosis were treated with saline, mono-, or combination therapies. Although monotherapies had no effect, combining these agents decreased collagen deposition and promoted re-epithelialization of remodeled airways. Relaxin inhibited myofibroblast differentiation and contraction in a matrix-stiffness-dependent manner through prostaglandin E2 (PGE2 ). Furthermore, the effect of combination therapy was lost in PGE2 receptor knockout and PGE2 -inhibited OTT mice. This study revealed the important synergistic roles of cellular contractility and tissue stiffness in the maintenance of fibrotic tissue and suggests a new therapeutic principle for fibrosis.
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PMID:Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis. 2780 15