Transforming growth factor β1 inhibition protects from noise-induced hearing loss

Abstract

Excessive exposure to noise damages the principal cochlear structures leading to hearing impairment. Inflammatory and immune responses are central mechanisms in cochlear defensive response to noise but, if unregulated, they contribute to inner ear damage and hearing loss. Transforming growth factor β (TGF-β) is a key regulator of both responses and high levels of this factor have been associated with cochlear injury in hearing loss animal models. To evaluate the potential of targeting TGF-β as a therapeutic strategy for preventing or ameliorating noise-induced hearing loss (NIHL), we studied the auditory function, cochlear morphology, gene expression and oxidative stress markers in mice exposed to noise and treated with TGF-β1 peptidic inhibitors P17 and P144, just before or immediately after noise insult. Our results indicate that systemic administration of both peptides significantly improved both the evolution of hearing thresholds and the degenerative changes induced by noise-exposure in lateral wall structures. Moreover, treatments ameliorated the inflammatory state and redox balance. These therapeutic effects were dose-dependent and more effective if the TGF-β1 inhibitors were administered prior to inducing the injury. In conclusion, inhibition of TGF-β1 actions with antagonistic peptides represents a new, promising therapeutic strategy for the prevention and repair of noise-induced cochlear damage.

MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse

“…Auditory brainstem responses (ABRs) were registered in 4-, 8-, and 12-week-old mice (n ¼ 5 per genotype and age group), essentially as reported by Cediel et al (2006) 19 with the modifications reported by Murillo-Cuesta et al (2015). 20 In brief, ABR recordings were obtained under anesthesia with ketamine (75 mg/ kg, Imalgene, Merial) and xylacine (5 mg/kg, Rompun, Bayer). Click (0.1 ms, 30 pps rate) and tone-burst stimuli (8,16,20,28, and 40 kHz, 5 ms, 50 pps rate) were generated with SigGenRP software (Tucker-Davis Technologies).…”

TGF β‐1 and WNT Signaling Pathways Collaboration Associated with Cochlear Implantation Trauma‐Induced Fibrosis

“…Fibrocytes, macrophages, and spiral ganglion cells of the damaged area release chemokines, inflammatory cytokines, such as interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, and growth factors, for example, TGF‐β1 which is remarkably important for its modulatory role in inflammation. High levels of TGF‐β1 are associated with a form of wound healing comprised of inflammation; angiogenesis; migration and proliferation of fibroblasts, and connective tissue remodeling result in scar formation (Murillo‐Cuesta et al, ). Excessive deposition of collagen along with extracellular matrix around the cochlear implant (CI) electrode not only affects apical cochlear structures important for low‐frequency residual hearing but also increases impedance and affects CI performance (Bas et al, ).…”

TGF‐β antagonist attenuates fibrosis but not luminal narrowing in experimental tracheal stenosis

“…We used a peptide antagonist of TGF‐β that has demonstrated its ability to reduce fibrosis across different species by interfering the binding of TGF‐β to its receptors in vivo. p17 has shown potent antifibrotic effects by interfering TGFβ1 and β2 activity in a variety of animal models, either by systemic or local application . Although local application by direct surgical implantation of collagen sponges containing p17 is not a feasible strategy to treat human stenosis, it guaranteed inhibitor availability in this proof of concept study.…”

“…Therefore, TGF‐β represents a potential therapeutic target in different fibrotic conditions. TGF‐β antagonistic antibodies or peptides have shown antifibrotic activity in a variety of experimental models of fibrosis …”