Neutrophils as a source of factors that increase the length of the inflammatory phase of wound healing in patients with type 2 diabetes mellitus

Abstract

Oxidative stress and neutrophil activation leading to an increase in myeloperoxidase (MPO), elastase and neutrophil extracellular trap (NET) levels in blood are considered as pathogenic mechanisms responsible for the development of extremity damage in people with type 2 diabetes mellitus (T2DM). The aim of this study was to analyze the relationship between factors, associated with neutrophil activation, and the length of the initial phase of wound healing (the inflammatory phase) in T2DM patients. Patients were divided retrospectively into three groups depending on the damage extent: group 1 (wound on toe) < group 2 (wound on foot) < group 3 (wound on lower leg). Compared to the control group (healthy volunteers), T2DM patients at admission to hospital had significantly (p<0.05) increased levels of blood glucose and glycated hemoglobin (groups 1-3), ESR (groups 1 and 3), blood neutrophil count (groups 2 and 3), plasma MPO concentration (groups 1-3) and blood NET concentration (group 3) and decreased levels of plasma thiols (groups 1-3) and erythrocyte glutathione peroxidase activity (groups 2 and 3). The length of hospital stay after surgical procedures corresponded to the length of the inflammatory phase of the wound healing process and correlated with the number of blood neutrophils in patients before surgery (r=0.72, p<0.05). Leukocytic intoxication index depended on wound area (r=0.59, p<0.05), and it was significantly higher for groups 2 and 3 compared to the control group and group 1. The neutrophil count before surgery in T2DM patients with damage in the lower extremities correlated with the length of the inflammatory phase of wound healing. The correlation found can be attributed to an increase in extracellular MPO and NETs, which, in its turn, results from the activation and degranulation of neutrophils and netosis. Thus, the duration of the inflammatory phase of wound healing depends on specific aspects of systemic inflammation increasing oxidative/halogenative stress and intoxication.

Innate Immunity in Diabetic Wound Healing: Focus on the Mastermind Hidden in Chronic Inflammatory

“…The Ongoing Recruitment and Activation of Neutrophils (Polymorphonuclear leukocytes, PMNs). and the Feedback Loop of Oxidative Stress Aggravate the Damage in Diabetic wound PMNs phagocytize, neutralize, and remove microorganisms, cell debris, and other substances through phagocytosis, degranulation, generation of high concentrations of ROS, and Neutrophil extracellular traps (NETs) (Fox et al, 2010;Mikhalchik et al, 2018;Papayannopoulos, 2018). It can also regulate the phenotype of macrophages and the expression of cytokines to mediate the innate immune response, secrete a variety of inflammatory mediators, and an enzyme to regulate the activity of inflammatory cells and the inflammatory response (Daley et al, 2005).…”

Ουδετερόφιλο Και Μεταβολικό-Ενεργειακό Περιβάλλον

“…Βέβαια, πειραματικά αλλά και κλινικά ευρήματα καταδεικνύουν ότι ο διαβήτης τύπου 2 χαρακτηρίζεται από μία κατά κάποιο τρόπο απορυθμισμένη ΝΕΤωση (impaired NET formation), στα πλαίσια της οποίας σχηματίζονται NETs με ασταθή δομή (unstable NET scaffold)(78,83). Μάλιστα, διάφορες μελέτες της τελευταίας πενταετίας υποστηρίζουν πως η υπέρμετρη και συγχρόνως «ελαττωματική» ΝΕΤωση στον T2D ευθύνεται, τουλάχιστον εν μέρει, για την επιρρέπεια σε βακτηριακές λοιμώξεις και τη διαταραχή του μηχανισμού επούλωσης τραύματος που συχνά χαρακτηρίζουν τους διαβητικούς ασθενείς(76,78,83,84). Παρ' όλα αυτά, ο μηχανισμός της ΝΕΤωσης και το πρωτεϊνικό φορτίο των NETs στον T2D, αλλά και η εμπλοκή τους στην παθογένεια του σακχαρώδους διαβήτη τύπου 2 δεν έχουν μελετηθεί εκτενώς, με αποτέλεσμα πολλά ερωτήματα να παραμένουν ακόμη αναπάντητα.…”