Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept...

Area of Science:

• Transplantation immunology
• Fibrosis research
• Tissue engineering

Background:

• Fibrosis post-solid organ transplantation is a major cause of graft failure and mortality.
• Established fibrosis involves a positive feedback loop where stiff extracellular matrix (ECM) promotes myofibroblast activity and further ECM deposition.
• Current therapies for established fibrosis are limited.

Purpose of the Study:

• To investigate a novel therapeutic approach for established fibrosis by simultaneously targeting myofibroblast contractility and ECM stiffness.
• To determine if this combination therapy can reverse fibrotic airway remodeling.

Main Methods:

• Utilized the orthotopic tracheal transplantation (OTT) mouse model to induce and study airway fibrosis.
• Administered saline, monotherapies (relaxin or lysyl oxidase inhibitors), or combination therapy to mice with established fibrosis.
• Assessed collagen deposition, re-epithelialization, myofibroblast differentiation, and contraction, including experiments with prostaglandin E2 (PGE2) receptor knockout mice.

Main Results:

• Monotherapies showed no significant effect on established fibrosis.
• Combination therapy significantly decreased collagen deposition and promoted airway re-epithelialization.
• Relaxin's inhibitory effect on myofibroblasts was dependent on matrix stiffness and mediated through prostaglandin E2 (PGE2).
• The therapeutic benefit of combination therapy was abolished in the absence or inhibition of PGE2 signaling.

Conclusions:

• Simultaneously targeting myofibroblast contractility and ECM stiffness offers a promising therapeutic strategy to reverse established fibrosis.
• The synergistic effect of combination therapy is dependent on the prostaglandin E2 (PGE2) pathway.
• This study presents a new therapeutic principle for managing fibrotic diseases.