Glycated ɑ1-Antitrypsin Involvement in Impaired Wound Healing: In- Vivo and In-Vitro Models

Impaired wound healing causes considerable morbidity among patients with diabetes. Human ɑ1-antitrypsin (hAAT) directs inflammation in injured tissues toward resolution. Upon glycation, gly-hAAT loses anti-proteolytic activity, but whether it fails to modulate inflammation and to promote wound repair is unknown. Objective : Explore the impact of clinical-grade hAAT on wound repair under hyperglycemic conditions, and the role of gly-hAAT in impaired wound healing pathophysiology. Research Design and Methods : Mice were rendered hyperglycemic and excisional wounding was performed, treated with topical albumin or hAAT every three days from time of wounding. Wound area was followed and samples collected for histology and gene expression analysis. Gly-hAAT was generated from clinical-grade hAAT in laboratory settings. In-vitro, RAW 264.7 macrophage responses were assessed and re-epithelialization was tested using A549 and HaCaT cells in the presence of gly-hAAT, and in the presence of sera from individuals with poor glucose control, both supplemented with clinical-grade hAAT. Results : Topical hAAT accelerated in-vivo and in-vitro wound closure. Vascular maturity appeared earlier in hAAT-rich conditions, and gene expression skewed towards anti-inflammatory IL-1β/IL-1Ra ratio. Gly-hAAT inhibited normoglycemic mouse wound closure and epithelial cell gap closure, both systems rescued by clinical-grade hAAT. Gly-hAAT evoked an inflammatory response in macrophages, and diabetic patient serum inhibited epithelial cell gap closure; both trends were reversed by clinical-grade hAAT. Conclusions : Topical hAAT accelerates wound closure under hyperglycemic conditions, and gly-hAAT is inflammatory and fails to benefit wound repair. Considering its phenomenal safety profile, it is suggested that clinical-grade hAAT is primed for testing in clinical settings.