Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis

Abstract

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. However, studies demonstrate 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, thereby, reversing established fibrosis. To test this, we used the orthotopic tracheal transplanted (OTT) mouse model, which develops robust fibrotic airway remodeling. Mice with established fibrosis were treated with saline, mono-, or combination therapies. While 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 reveals the important synergistic roles of cellular contractility and tissue stiffness in the maintenance of fibrotic tissue and suggests a new therapeutic principle for fibrosis.

Transcriptomic changes during TGF-β-mediated differentiation of airway fibroblasts to myofibroblasts

“…Myofibroblasts are known to contribute to the contractile behaviour of the airways via their expression of molecules that directly interact with and impact on the ECM and the cytoskeletal network 53 . We found that focal adhesion molecule ITGB1 was upregulated in myofibroblasts as expected 54–56 .…”

Crohn's disease associated strictures

“…Many drugs developed for treatment of pulmonary fibrosis may be potential candidates for the treatment of intestinal fibrosis. Pirfenidone (a growth factor inhibitor), SD‐208 (a TGF‐βR1 signaling blocker), Nintedanib (a kinase inhibitor that acts on vascular endothelial fibroblast growth factor receptors), Integrin αvβ6 (activates latent TGFβ) inhibitor, Simtuzumab (a monoclonal antibody to LOXL2) in combination with Relaxin (an inhibitor of myofibroblast contraction), rapamycin and its analogs, sirolimus and everolimus (through their immunosuppressive and anti‐fibrotic action), serotonin (inducer of myofibroblast activation) receptor inhibitors, and Rho kinase (activator of mesenchymal cells) inhibitor have shown some success in the treatment of pulmonary fibrosis in humans and in experimental intestinal fibrosis in animal models. The real clinical effectiveness of these agents in IBD remains to be defined in human trials.…”

Matrix Mechanics as Regulatory Factors and Therapeutic Targets in Hepatic Fibrosis

“…Therefore, disruption of the α-SMA by siRNA knockdown affects the contraction of myofibroblasts, thus reducing the assembly of fibronectin matrix into fibrillary ECM. In addition, a recent study in airway fibrosis has also found that by simultaneously utilizing relaxin and LOX inhibitors to target myofibroblastic contractility and matrix stiffness, respectively, showed that the deposition of collagen could be significantly reduced and the re-epithelialization of remodeled airways could be promoted 98.…”