In vitro evaluation of anti‐fibrotic effects of select cytokines for vocal fold scar treatment

Abstract

Scarring of the vocal fold lamina propria (LP) can cause considerable voice disorders due to reduced pliability in scar tissue, attributed in part to abnormal extracellular matrix (ECM) deposition produced by the fibrotic vocal fold fibroblast (fVFF). Cytokines with anti-fibrotic potential have been investigated to limit abnormal LP ECM, but are limited by the need for repeat injections. Moreover, the potentially significant role played by activated macrophages (AMOs) is usually not considered even though the interaction between AMO and fibrotic fibroblasts is known to regulate scar formation across different tissues. AMO are also regulated by cytokines that are used for LP scar removal, but little is known about AMO behaviors in response to these cytokines within the context of LP scar. In the present study, we evaluated anti-fibrotic effects of hepatocyte growth factor (HGF), interleukin-10 (IL-10) and interleukin-6 (IL-6) in a 3D, in vitro fVFF-AMO co-culture system using poly(ethylene glycol) diacrylate (PEGDA) hydrogels. Data from all cytokines was synthesized into a heat-map that enabled assessment of specific associations between AMO and fVFF phenotypes. Cumulatively, our results indicated that both HGF and IL-10 are potentially anti-fibrotic (reduction in fibrotic markers and enhancement in normal, anti-fibrotic VFF markers), while IL-6 displays more complex, marker specific effects. Possible associations between AMO and fVFF phenotypes were found and may highlight a potential desirable macrophage phenotype. These data support the therapeutic potential of HGF and IL-10 for LP scar treatment, and shed light on future strategies aimed at targeting specific AMO phenotypes. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018.

The Role of Cytokines in Modulating Vocal Fold Fibrosis: A Contemporary Review

“…47 Exogenous HGF administration was thought to have a significant endogenous antifibrotic effect on VF scarring, which has been associated with the improvement of lamina propria biomechanical properties, including reversing undesirable ECM production and promoting endogenous HGF expression in vivo 48,49 (Table II) and in vitro. 50,51 These data support the therapeutic potential of HGF for lamina propria scar treatment. The purpose of preclinical studies is to determine reasonable concentrations, reveal pharmacokinetics, and evaluate the safety of HGF administration.…”

“…This period is regarded as the key period for the remodeling of VF scars 47 . Exogenous HGF administration was thought to have a significant endogenous antifibrotic effect on VF scarring, which has been associated with the improvement of lamina propria biomechanical properties, including reversing undesirable ECM production and promoting endogenous HGF expression in vivo 48,49 (Table 2) and in vitro 50,51 . These data support the therapeutic potential of HGF for lamina propria scar treatment.…”

Pathophysiology of Fibrosis in the Vocal Fold: Current Research, Future Treatment Strategies, and Obstacles to Restoring Vocal Fold Pliability

“…Recently, Chen et al demonstrated that a decrease in pro-inflammatory markers (TNF-α, IL-6) and an increase in anti-inflammatory markers (i.e., IL-10/IL-12) may favor antifibrotic outcomes via reduction in fibrotic proteins and supported the therapeutic potential of HGF and IL-10 for VF scar treatment using in vitro models [109]. These perspectives would bring the light of hope on future strategies targeting specific activated macrophages phenotypes for establishing an anti-inflammatory approach for the VF scar.…”

The Challenges of OSCC Diagnosis: Salivary Cytokines as Potential Biomarkers

“…The antifibrotic effects of several cytokines were evaluated in an in vitro study by Chen et al [ 39 ] as vocal fold scar treatment. Their results showed that IL-6 and IL-10 displayed an antifibrotic and anti-inflammatory action in vitro, providing a possible new solution in cases of vocal fold scarring.…”