Abstract
Neutrophils are important for wound repair, but their persistence can impair the healing process. Neutrophils express matrix metalloproteinases including MMP-9 and its regulator neutrophil gelatinase associated lipocalin (NGAL). Whether wounding affects neutrophil MMP-9 and NGAL in diabetic animals is not known. Skin wound tissue MMP-9 and NGAL was examined by qRT-PCR and immunohistochemistry in control, diabetic and insulin treated diabetic rats. The temporal expression of MMP-9 and NGAL mRNA, MMP-9 activity and the NGAL/MMP-9 complex was also investigated in an implant model and their circulating neutrophils. The cellular localisation of MMP-9 and NGAL was confirmed by immunofluorescence and the ability of glucose to regulate these factors was examined in isolated neutrophils. In skin wound tissue compared with control, diabetes increased neutrophil infiltration, NGAL mRNA and MMP-9 protein (P<0.05). Diabetes significantly increased implant neutrophil NGAL and MMP-9 protein as well as NGAL mRNA, wound fluid NGAL/MMP-9 complex and MMP-9 activity (all <0.05). Circulating neutrophil MMP-9 and NGAL was also increased in these diabetic animals (P<0.05). These changes were prevented by insulin treatment. Ex vivo, high glucose (25mM) increased neutrophil NGAL and MMP-9 (both by 2 fold, P<0.05). NGAL and MMP-9 are increased in wound and circulating neutrophils in diabetic rodents. These changes and the association between higher NGAL and increased wound fluid MMP-9 activity suggest that increased neutrophil NGAL may contribute to increased MMP-9 in poorly healing diabetic wounds. Whether targeting neutrophil NGAL or MMP-9 can improve diabetic wound healing remains to be investigated.
Highlights
Delayed healing of wounds is a poorly understood complication that affects 15–30% of all persons with diabetes [1, 2]
In diabetic animals when compared with control, Total MMP-9 (TMMP-9) was significantly elevated at day 6 (P
In all animals the neutrophil gelatinase associated lipocalin (NGAL)/matrix metalloproteinases (MMPs)-9 complex was highest at day 6 and in diabetic animals was significantly higher than control at days 6 and 12 (Fig 2F)
Summary
Delayed healing of wounds is a poorly understood complication that affects 15–30% of all persons with diabetes [1, 2]. It is associated with much morbidity and the escalating number of people with diabetes in an ageing population will increasingly add to the economic and PLOS ONE | DOI:10.1371/journal.pone.0170951. NGAL, MMP-9 and delayed wound healing in diabetes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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