Ratios of activated matrix metalloproteinase‐9 to tissue inhibitor of matrix metalloproteinase‐1 in wound fluids are inversely correlated with healing of pressure ulcers

TLDR

Chronic wounds show elevated inflammatory cytokines and proteinases and reduced growth factor activity compared with acute healing wounds, implying that excessive proteolysis may hinder repair. The study aimed to determine whether MMP and TIMP levels, especially the MMP‑9/TIMP‑1 ratio, predict healing outcomes in chronic pressure ulcers. Researchers quantified MMP‑2, MMP‑9, TIMP‑1, TIMP‑2, and their ratios in fluids and biopsies from 56 patients, sampling at baseline, 10, and 36 days during conventional or cytokine therapy, and correlated these data with healing progress. The MMP‑9/TIMP‑1 ratio decreased as ulcers healed, and lower ratios at day 0 were linked to ≥85 % volume reduction, showing that this ratio predicts healing and supports the proteolysis hypothesis.

Abstract

Previous analyses of fluids collected from chronic, nonhealing wounds found elevated levels of inflammatory cytokines, elevated levels of proteinases, and low levels of growth factor activity compared with fluids collected from acute, healing wounds. This led to the general hypothesis that chronic inflammation in acute wounds produces elevated levels of proteinases that destroy essential growth factors, receptors, and extracellular matrix proteins, which ultimately prevent wounds from healing. To test this hypothesis further, pro- and activated matrix metalloproteinases (MMP-2 and MMP-9), tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and the ratios of MMPs/TIMPs were assayed in fluids and biopsies collected from 56 patients with chronic pressure ulcers. Specimens included ulcers treated for 0, 10, and 36 days with conventional therapy or with exogenous cytokine therapies. Quantitative assay data were correlated with the amount of healing. The average MMP-9/TIMP-1 ratio in fluids from 56 ulcers decreased significantly as the chronic pressure ulcers healed. Furthermore, the average MMP-9/TIMP-1 ratio was significantly lower for fluids collected on day 0 from wounds that ultimately healed well (> or =85% reduction in initial wound volume) compared with wounds that healed poorly (< 50% wound volume reduction). These data show that the ratio of MMP-9/TIMP-1 levels is a predictor of healing in pressure ulcers and they provide additional support for the hypothesis that high levels of MMP activity and low levels of MMP inhibitor impair wound healing in chronic pressure ulcers.