Biotransformation of DYN 1-17 in inflamed nasal tissues: potential immunotherapeutics for chronic rhinosinusitis

• ¹ School of Pharmaceutical Sciences, University of Science Malaysia, Malaysia
• ² School of Biomedical Sciences, The University of Melbourne, Australia
• ³ Faculty of Medicine, The University of Queensland, Australia
• ⁴ School of Pharmacy, University of Queensland, Australia

Background Dynorphin 1-17 (DYN 1-17) has a significant implication in inflammation. Upon release at inflammatory sites, this endogenous neuropeptide is subject to rapid metabolism, yielding an array of smaller fragments. DYN 1-17 and its fragments have been previously demonstrated to regulate diverse inflammatory responses during tissue injury. To date, biotransformation of DYN 1-17 in human disease condition has not yet been reported. This study aimed to explore the biotransformation of DYN 1-17 in nasal biopsies from chronic rhinosinusitis (CRS) patients and the fragmentation patterns were compared with those observed previously in inflamed rat paw tissues. Methods DYN 1-17 (150 M) was incubated with human nasal tissue specimens at 37°C in different matrices (pH 7.4 and pH 5.5) over a range of incubation periods. The resultant fragments were then separated using a C4 column. Detection and characterization of the fragments were performed by mass spectrometry using total ion current mode. The identities of some major fragments identified in the tissue homogenates were confirmed using commercially available peptides, with respect to their retention time and mass spectra. Results Incubation of DYN 1-17 in inflamed nasal biopsies occasioned 22 fragments at pH 5.5 and 14 fragments at pH 7.4. Upon comparison, a similar range of fragments was observed following metabolism of DYN 1-17 in inflamed rat paw and human nasal tissues, suggesting that similar processing enzymes are present in both tissue homogenates. Intriguingly, DYN 3-14 was the most prevalent and stable fragment produced throughout the incubation period, highlighting a rationale for its activity during an inflammatory response. Conclusion Differential biotransformation fragments of DYN 1-17 are produced in different inflamed tissues, suggesting that disease pathophysiology may influence the fragmentation patterns of this peptide. The major hydrolysis fragment, DYN 3-14, possesses important roles in immunoregulation and may be developed into a potential immunotherapeutic for CRS.