Local treatment with protease-inhibitors does not affect the expression of matrix-metalloproteases, but promotes wound healing in diabetic patients

Wound healing in diabetes is impaired and non-healing ulcers are relevant complications. Persistent high levels of matrix-metalloproteases (MMP) are relevant for wound chronification. Therefore the topical use of protease-inhibitors (PI) should influence the healing and promote the transition from a chronic to an acute wound. Methods: We studied 33 patients with diabetic foot lesions (Wagner 2). 15 patients received standard good wound care. 18 Patients were additionally treated with a daily changed PI (Promogran™). At the first visit and at day 4 and 8, two 3mm punch biopsies were taken from the wound center. We analysed samples by ELISA for MMP-1,-2,-8,-9, Tissue Inhibitor of MMP (TIMP-2) and Interleukin 1-β (IL1) levels. We also analysed the mRNA levels of MMP-1,-9,-13,-14, IL1 and TNFα by RT-PCR (TaqMan). Results: We observed an significant reduction of the wound area in the treatment group (16%) when compared with the placebo group (1,6%) already during the short treatment period (p=0.045). Both groups were not different for age, duration of diabetes, HbA1c and initial size of the lesion (mean size treatment: 1237mm 2 vs. placebo: 1132mm 2 ). All these factors had no statistical influence of the MMP expression or wound healing dynamic. Levels of MMP mRNA, IL1 and TNFα were not different between both groups and at the three different time-points. ELISA-levels of MMP in wound tissue were not significant different. IL1 was at day 8 increased in the treatment group (p=0.01). Interestingly, we found a significant reduction of the MMP-9/TIMP-2 ratio in the group exhibiting a more rapid healing course. Conclusions: The local treatment with a PI beneficially affects wound healing. Our data did not show an effect on the absolute expression of MMP and growth factors by local treatment with PI, while the MMP-9/TIMP-2 ratio in wound tissue was decreased. Equally important, we did not find a compensatory increase in the MMP-mRNA expression since wound size was clearly reduced. PI might thus be useful tools for treating chronic diabetic ulcerations.