Repair and Regeneration of Peripheral Nerve Fibrosis

Twenty million Americans suffer from peripheral nerve injury (PNI) and is undoubtedly one of the major unmet medical needs. Approximately $150 billion is spent annually in the United States for Nerve Injuries. Moreover, 50,000 cases of PNI repairs are performed annually in the United States with even less than 42% experiencing satisfactory sensory recovery. Despite extensive medical research, there aren’t any approved small molecule antifibrotic treatment pertaining to nerve injuries. Peripheral nerve fibrosis (PNF) associated with chronic inflammation, perineural adhesions and scarring are often reported in patients with nerve injury. Surgical interventions including external neurolysis is the common available option. Unfortunately, postsurgical adhesions and fibrosis, often lead to aberrated wound healing and impairment of nerve functions. Though, various treatment strategies have been tried including use
of grafts, biomaterials, no treatment modality seems to be promising as of now.
The aim of this study was to investigate the effects of L-Alanine-L-Glutamine (L-Ala-L-Gln) and Pirfenidone (PFD) on hypoxic and TGF-ß1 stimulated fibroblasts and their ability to induce anti-fibrotic phenotype. Rat perineurial derived fibroblasts were exposed to hypoxic conditions or externally activated by TGF-ß1 and expression of hypoxic and pro-fibrotic markers were assessed following treatment with L-Ala-L-Gln (0-100mM) or with PFD (0-0.25 mg/ml). PFD was found to act through targeted downregulation of the TGF-ß pathway and significantly reduced pro-fibrotic and celladhesion inducing factors at the protein and RNA level. In rat perineurial derived fibroblasts, L-Ala-L-Gln and PFD modulated several pro-fibrotic factors and associated
pathways to induce an anti-fibrotic phenotype. In conclusion, our results showed that L-Ala-L-Gln and PFD suppressed fibrotic phenotype and might prove to be effective anti-fibrotic agents for neural fibrosis. These promising results will lead to identification of a non-invasive biomarker for the assessment of neural fibrosis. These results can easily be translated into the clinical settings and we expect our discoveries to assist
clinicians to identify a novel therapeutic strategy for neural fibrosis and support invasive surgical applications.