RESUMO
A reparative approach of disrupted epithelium in obstructive airway diseases, namely asthma and chronic obstructive pulmonary disease (COPD), may afford protection and long-lasting results compared to conventional therapies, e.g., corticosteroids or immunosuppressant drugs. Here, we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. It may include and surpass single-inhibitors of stress and secondary growth factor pathway signaling, i.e., the new medicinal chemistry in lung diseases. Enhanced polyamine biosynthesis has been charged with aggravating prognosis by competing for L-arginine at detriment of nitric oxide (NO) synthesis with bronchoconstrictive effects. Although excess spermine, a higher polyamine, is harmful to airways physiology, spermidine can pivot the cell homeostasis during stress conditions by the activation of TCPTP. In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. Moreover, a further beneficial effect of spermidine may derive from its ability to promote autophagy, possibly in a TCPTP-dependent way. Since doses of spermidine in the micromolar range are sufficient to activate TCPTP, low amounts of spermidine administered in sustained release modality may provide an optimal pharmacologic profile for the treatment of obstructive airway diseases.
RESUMO
AIM: To test the growth-promoting activity of the polyamine spermidine bound to various polymeric compounds in supramolecular complexes. METHODS: A thiazolyl blue cell viability assay was used to determine the growth-promoting potency of spermidine-supramolecular complexes in a human skin fibroblast cell line exposed to spermidine and different spermidine-supramolecular complexes that were obtained by combining spermidine and polyanionic polymers or cyclodextrin. Reconstituted human vaginal epithelium was exposed to a specific spermidine-supramolecular complex, i.e., spermidine-hyaluronan (HA) 50, and cell proliferation was determined by Ki-67 immunohistochemical detection. Transepithelial electrical resistance and histological analysis were also performed on reconstituted human vaginal epithelium to assess tissue integrity. RESULTS: The effect of spermidine and spermidine-supramolecular complexes was first tested in skin fibroblasts. Spermidine displayed a reverse dose-related mode of activity with mmol/L growth inhibition, whereas 30% stimulation over basal levels was detected at µmol/L and nmol/L levels. Novel spermidine-supramolecular complexes that formed between spermidine and polyanionic polymers, such as HA, alginate, and polymaleate, were then tested at variable spermidine concentrations and a fixed polymer level (0.1% w/v). Spermidine-supramolecular complexes stimulated the cell growth rate throughout the entire concentration range with maximal potency (up to 80%) at sub-µmol/L levels. Similar results were obtained with spermidine-(α-cyclodextrin), another type of spermidine-supramolecular complex. Moreover, the increased expression of Ki-67 in the reconstituted human vaginal epithelium exposed to spermidine-HA 50 showed that the mode of action behind the spermidine-supramolecular complexes was increased cell proliferation. Functional and morphological assessments of reconstituted human vaginal epithelium integrity did not show significant alterations after exposure to spermidine-HA, thus supporting its safety. CONCLUSION: Spermidine found in spermidine-supramolecular complexes displayed potentiated regenerative effects. Safety data on reconstituted human vaginal epithelium suggested that assessing spermidine-supramolecular complex efficacy in atrophic disorders is justified.