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L-Ala-L-Gln Suppresses Hypoxic Phenotype and Fibrogenic Activity of rat Perineurial Fibroblasts.

BACKGROUND
Twenty million Americans suffer from peripheral nerve injury (PNI) and approximately $150 billion is spent annually in the United States for the treatment of 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. Available therapies control painful symptoms, but do not treat axonal degeneration or neuronal cell death. Peripheral nerve fibrosis (PNF) associated with chronic inflammation, perineural adhesions and scarring are often reported in patients with nerve injury. Unfortunately, post-surgical adhesions and fibrosis often lead to aberrated wound healing and impairment of nerve functions. Various treatment strategies have been attempted, including the use of grafts, biomaterials; however, few appear promising.


OBJECTIVE
L-Alanyl-L-Glutamine (L-Ala-L-Gln) was reported to protect the lung from sepsis induced injury, and to play an immunomodulatory role in stress and fibrosis. The aim of this study was to examine the potential anti-fibrotic effects of L-Ala-L-Gln in an in vitro model of neural fibrosis.


METHODS
Primary fibroblasts isolated from rat sciatic nerve were exposed to chronic (48h) and episodic (2h) hypoxic conditions. Cultures were then treated for 48h with various concentrations of L-Ala-L-Gln (0, 1, 10 and 100mM). The expression of hypoxic and pro-fibrotic markers in the different culture conditions was assessed by immunocytochemistry and western blot analyses. Quantitative phosphor-proteomic profiling was performed to investigate mechanistically the impact of L-Ala-L-Gln on collagen biosynthesis and hypoxia-driven tissue fibrosis in vitro.


RESULTS
In protein expression assays, L-Ala-L-Gln significantly reduced markers related to the cellular response to hypoxia, in particular HIF-1 signaling. L-Ala-L-Gln also significantly reduced expression of pro-fibrotic and cell-adhesion inducing factors. Phospho-proteomic data indicated that L-Ala-L-Gln modulates several pro-fibrotic factors and associated pathways.


CONCLUSION
Altogether, our data demonstrate that L-Ala-L-Gln efficiently suppresses hypoxia-mediated fibrotic processes at different concentrations in rat primary fibroblasts. Thus, L-Ala-L-Gln presents high potential therapeutic value as an antifibrotic pharmaceutical agent for the treatment of neural fibrosis.