Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors
Abstract
To assess the differences in proteolytic activity of acute and chronic wound environments, wound fluids were collected from acute surgical wounds (22 samples) and chronic wounds (25 samples) of various etiologies, including mixed vessel disease ulcers, decubiti and diabetic foot ulcers. Matrix metalloproteinase (MMP) activity measured using the Azocoll assay was significantly elevated by 30 fold in chronic wounds (median 22.8 microg MMP Eq/ml) compared to acute wounds (median 0.76 microg MMP Eq/ml) (p < 0.001). The addition of the matrix metalloproteinase inhibitor Illomostat decreased the matrix metalloproteinase activity by approximately 90% in all samples, confirming that the majority of the activity measured was due to matrix metalloproteinases. Gelatin zymograms indicated predominantly elevated matrix metalloproteinase-9 with smaller elevations of matrix metalloproteinase-2. In addition tissue inhibitor of metalloproteinase-1 levels were analyzed in a small subset of acute and chronic wounds. When tissue inhibitor of metalloproteinase-1 levels were compared to protease levels there was an inverse correlation (p = 0.02, r = - 0.78). In vitro degradation of epidermal growth factor was measured by addition of 125I labelled epidermal growth factor to acute and chronic wound fluid samples. There was significantly higher degradation of epidermal growth factor in chronic wound fluid samples (mean 28.1%) compared to acute samples (mean 0.6%). This also correlated to the epidermal growth factor activity of these wound fluid samples (p < 0. 001, r = 0.64). Additionally, the levels of proteases were assayed in wound fluid collected from 15 venous leg ulcers during a nonhealing and healing phase using a unique model of chronic wound healing in humans. Patients with nonhealing venous leg ulcers were admitted to the hospital for bed rest and wound fluid samples were collected on admission (nonhealing phase) and after 2 weeks (healing phase) when the ulcers had begun to heal as evidenced by a reduction in size (median 12%). These data showed that the elevated levels of matrix metalloproteinase activity decreased significantly as healing occurs in chronic leg ulcers (p < 0.01). This parallels the processes observed in normally healing acute wounds. This data also supports the case for the addition of protease inhibitors in chronic wounds in conjunction with any treatments using growth factors.
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Elevated levels of IL-1β have been found in wounds of diabetic humans and mice.
“Elevated levels of IL-1β have been found in wounds of diabetic humans and mice (12,15,19,20)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [20]
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- Authors
- Trengove, N. J., Stacey, M. C., Macauley, S., Bennett, N., Gibson, J., Burslem, F., Murphy, G., & Schultz, G.
- Affiliations
- The University of Western Australia (AU)
- Venue
- Wound Repair and Regeneration
- Publisher
- Wiley
- Published
- 1999-11
- Volume
- 7
- Issue
- 6
- Pages
- 442-452
- ISSN
- 1067-1927 (ISSN-L)
- 1524-475X
- OpenAlex
- W1980923037
- Cited by
- 908
- References
- 40
- Citations by year
- 2026: 24 · 2025: 27 · 2024: 23 · 2023: 22 · 2022: 27 · 2021: 38 · 2020: 30 · 2019: 36 · 2018: 43 · 2017: 32 · 2016: 46 · 2015: 36 · 2014: 55 · 2013: 60 · 2012: 50
- FWCI
- 11.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Wound Repair and Regeneration (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pineapple and bromelain studies
- Keywords
- chronic wounds, acute wounds, matrix metalloproteinases, MMP-9, MMP-2, TIMP-1, protease inhibitors, wound fluid, venous leg ulcers, diabetic foot ulcer, pressure ulcers, wound healing, proteolytic activity
- MeSH terms
- Acute Disease, Adult, Aged, Aged, 80 and over, Chronic Disease, Pressure Ulcer, Enzyme-Linked Immunosorbent Assay, Female, Humans, Leg Ulcer, Male, Mastectomy, Middle Aged, Endopeptidases, Wound Healing, Cytokines, Diabetic Foot, Statistics, Nonparametric, Leukocyte Elastase, Tissue Inhibitor of Metalloproteinases, Matrix Metalloproteinases
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