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Interactions of cytokines, growth factors, and proteases in acute and chronic wounds
Abstract
A healing wound represents a complex series of interactions between cells, soluble mediators, and extracellular matrix. Within this multifaceted environment, there are multiple regulatory points which control the ordered series of events that lead to normal tissue repair. An alteration in this physiologic network can lead to the development of a chronic wound. This article presents an update on the numerous mediators that exist within the wound environment in both acute normal healing and chronic nonhealing wounds. We also present a hypothesis which may provide a conceptual pathophysiologic mechanism with which to understand all chronic wounds.
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“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 [19]
In the citing paper
“Chronic wounds are typically associated with a persistent inflammatory response that involves accumulation of Mp (19,26–28)”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [19]
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PERSPECTIVE ARTICLE: Growth factors and cytokines in wound healing
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BackgroundInfluentialWound bed preparation: a systematic approach to wound management
Schultz, G. S., Sibbald, R. G., Falanga, V., Ayello, E. A., Dowsett, C., Harding, K. G., Romanelli, M., Stacey, M. C., Téot, L., & Vanscheidt, W. (2003) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.11.s2.1.x · Cited by 1,440
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“Moreover, DFUs often exhibit deregulation and mislocalization of GF receptors [227–229], as well compartmentalization within microdomains (i.e., cave-olae), which prevent activation of downstream signaling events [230–232].”
BackgroundOxygen in acute and chronic wound healing
Schreml, S., Szeimies, R., Prantl, L., Karrer, S., Landthaler, M., & Babilas, P. (2010) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2010.09804.x · Cited by 817
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BackgroundChronic Wound Pathogenesis and Current Treatment Strategies: A Unifying Hypothesis
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Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing
Boniakowski, A. E., Kimball, A., Jacobs, B. N., Kunkel, S. L., & Gallagher, K. A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700223 · Cited by 564
“Furthermore, the abundance of proinflammatory cytokines increases MMP production and decreases inhibitors of MMPs; this imbalance further augments degradation of the extracellular matrix, impairs cell migration, and reduces fibroblast proliferation and collagen synthesis (93).”
BackgroundWound healing: Biologic features and approaches to maximize healing trajectories
Robson, M. C., Steed, D. L., & Franz, M. (2001) · Current Problems in Surgery · doi:10.1067/msg.2001.111167 · Cited by 520
Nitric Oxide Therapy for Diabetic Wound Healing
Malone‐Povolny, M. J., Maloney, S. E., & Schoenfisch, M. H. (2019) · Advanced Healthcare Materials · doi:10.1002/adhm.201801210 · Cited by 515
Wound healing and treating wounds
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Proteases and Delayed Wound Healing
McCarty, S. M., & Percival, S. L. (2013) · Advances in Wound Care · doi:10.1089/wound.2012.0370 · Cited by 498
“The deposition of connective tissue during the wound-healing process can be affected by TNF-a, since this cytokine influences the synthesis of collagen, MMPs, and TIMPs.18 The differences in levels of the proinflammatory cytokines in wound fluids between acute and chronic human wounds were highlighted by Tarnuzzer and…”
InfluentialMirza, R. E., Fang, M. M., Ennis, W. J., & Koh, T. J. (2013) · Diabetes · doi:10.2337/db12-1450 · Cited by 467
“levels in chronic wounds of humans and in wounds of diabetic mice (3,5,11,13,32,33), and our findings demonstrate that these elevated levels of IL-1b promote the proinflammatory wound environment and impaired healing associated with diabetes.”
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“For example, although acute human wounds in the euglycemic milieu were found to be virtually devoid of MMPs, fluids retrieved from diabetic nonhealing wounds displayed very high levels of MMPs.39 In db /db mice subjected to full-thickness excisional wounds, enhanced activity of MMP-2 and MMP-9 were observed on day 25…”
BackgroundInfluentialCytokines, chemokines and growth factors in wound healing
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“At each stage of healing, a different set of specific cytokines and growth factors are required [64], while several proteases activated in the wound area can degrade both endogenous and exogenous growth factors [65].”
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Nethi, S. K., Das, S., Patra, C. R., & Mukherjee, S. (2019) · Biomaterials Science · doi:10.1039/c9bm00423h · Cited by 379
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Self-citationRole of adipose‐derived stem cells in wound healing
Hassan, W., Greiser, U., & Wang, W.-X. (2014) · Wound Repair and Regeneration · doi:10.1111/wrr.12173 · Cited by 354
“6%).(132,133) In another study, Hipler et al.”
LADWIG, G. P., Robson, M. C., Liu, R., Kuhn, M. A., Muir, D., & Schultz, G. S. (2002) · Wound Repair and Regeneration · doi:10.1046/j.1524-475x.2002.10903.x · Cited by 355
Self-citationChronic Inflammation in Non-Healing Skin Wounds and Promising Natural Bioactive Compounds Treatment
Schilrreff, P., & Alexiev, U. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094928 · Cited by 389
“ECM degradation products promote further inflammation, creating a self-sustaining process [19].”
BackgroundDysregulation of monocyte/macrophage phenotype in wounds of diabetic mice
Mirza, R., & Koh, T. J. (2011) · Cytokine · doi:10.1016/j.cyto.2011.06.016 · Cited by 342
Mirza, R. E., Fang, M. M., Weinheimer-Haus, E. M., Ennis, W. J., & Koh, T. J. (2014) · Diabetes · doi:10.2337/db13-0927 · Cited by 319
“Elevated levels of IL-1b have been found in wounds of diabetic humans and mice (12,15,19,20), consistent with increased inflammasome activity.”
BackgroundSmart Bandages: The Future of Wound Care
Derakhshandeh, H., Kashaf, S. S., Aghabaglou, F., Ghanavati, I., & Tamayol, A. (2018) · Trends in biotechnology · doi:10.1016/j.tibtech.2018.07.007 · Cited by 320
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Davis, F. M., Kimball, A., Boniakowski, A. E., & Gallagher, K. A. (2018) · Current Diabetes Reports · doi:10.1007/s11892-018-0970-z · Cited by 334
Repositioning of cells by mechanotaxis on surfaces with micropatterned Young's modulus
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“In addition, inhibitors of metalloproteinases (TIMPs) are reduced, contributing to protease deregulation in these injuries [32,33].”
BackgroundBahadoran, M., Shamloo, A., & Nokoorani, Y. D. (2020) · Scientific Reports · doi:10.1038/s41598-020-64480-9 · Cited by 286
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Arginine Supplementation and Wound Healing
Stechmiller, J. K., Childress, B. B., & Cowan, L. J. (2005) · Nutrition in Clinical Practice · doi:10.1177/011542650502000152 · Cited by 264
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Oxidative stress in chronic venous leg ulcers
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Acute and Impaired Wound Healing
Demidova‐Rice, T. N., Hamblin, M. R., & Herman, I. M. (2012) · Advances in Skin & Wound Care · doi:10.1097/01.asw.0000418541.31366.a3 · Cited by 240
“In chronic wounds, inadequate levels of EGF and EGFR have been observed.(74) Because of this, exogenous EGF has been used in clinical trials for treatment of nonhealing wounds.”
BackgroundNovel silk fibroin/elastin wound dressings
Vasconcelos, A., Gomes, A. C., & Cavaco-Paulo, A. M. (2012) · Acta Biomaterialia · doi:10.1016/j.actbio.2012.04.035 · Cited by 236
“Partial-thickness burn wounds heal almost entirely by epithelialization from the skin periphery to the wound core [74,75], which was also observed in this study.”
BackgroundThe Role of Moisture Balance in Wound Healing
Okan, D., Woo, K. Y., Ayello, E. A., et al. (2007) · Advances in Skin & Wound Care · doi:10.1097/00129334-200701000-00013 · Cited by 232
“In chronic wounds, there is often a competing prolonged inflammatory stage that inhibits a nascent proliferative stage.(9,11) Therefore, the key to healing chronic wounds becomes not only balancing moisture levels in the wound bed, but also sequestering those compounds in chronic wound exudate that may be barriers to…”
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“84 Apart from such influences between wounds, the effects of phototherapy are not limited to the site of application, since through biological mediators the effect can be carried to other parts of the body by diffusion or systemically.”
Nanoparticle-Based Therapeutic Approach for Diabetic Wound Healing
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“In addition, as various biomolecules are engaged in wound healing progression, sometimes it may be inadequate to utilize a single growth factor to accelerate wound closure in diabetic ulcers [76,77].”
BackgroundHydrogel-based dressings designed to facilitate wound healing
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Pathophysiology of Chronic Nonhealing Wounds
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“This supports the hypothesis proposed initially by Mast and Schultz (18) that repeated injury of tissue leads to prolonged inflammation, which causes elevated levels of proteases that degrade molecules that are essential to healing , eventually leading to a failure of the wound to heal.”
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Adipose‐derived stem cells for wound healing
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“It has been shown that the compositions of acute wound fluids (AWFs) and chronic wound fluids (CWFs) are significantly different (Mast & Schultz, 1996) and this influences the ASC applicability.”
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“This promotes the establishment and maintenance of chronic wounds.(7,8,30,31) Alginate is able to bind TNF-a and IL-8 in a time-dependent manner.”
BackgroundCortisol synthesis in epidermis is induced by IL-1 and tissue injury
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The pro‐inflammatory environment in recalcitrant diabetic foot wounds
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Metal-organic frameworks for improving wound healing
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Mesenchymal Stem Cell Secretome as an Emerging Cell-Free Alternative for Improving Wound Repair
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“To date, only PDGF has received FDA approval for the treatment of diabetic foot ulcers, and its use is limited due to the need for dressing replacement and the potential increased risk of malignancy [88,89].”
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“c wounds (modified from Mast and Schultz (1996)).”
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“During chronic inflammatory myopathies, expression of TNFa, IL-6, and IL-1b persists and can lead to increased skeletal muscle catabolism and reduced regenerative capacity,((73)) as well as increased proliferation of recruited fibroblasts.((74)) The elevated and prolonged expression in Acvr1 lesions of the same proinf…”
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Therapeutic advances in wound healing
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“Also, it has been found that degradation can be blocked by the addition of MMP inhibitors (101).”
BackgroundBacteriology, Inflammation, and Healing
Sibbald, R. G., Contreras‐Ruiz, J., Coutts, P. M., Fierheller, M., Rothman, A. I., & Woo, K. Y. (2007) · Advances in Skin & Wound Care · doi:10.1097/01.asw.0000294757.05049.85 · Cited by 156
“These proteases can shift the wound healing balance away from the proliferative stage and into a continuing chronic inflammatory phase.(46) The concept of using the antimicrobial effect of nanocrystalline silver to stimulate healing has been tested previously on mixed etiology chronic wounds.”
BackgroundInflammation in Nonhealing Diabetic Wounds
Pierce, G. F. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61709-9 · Cited by 153
“thesis and remodeling, essential for progression to a healed wound.(26,30,34,35) Matrix metalloproteinases (MMPs) are members of the zinc-dependent endopeptidase family, contain at least 20 members, and can degrade most extracellular matrix constituents.”
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“It has often been assumed that excess proteolytic activity, characterized as inflammation, is secondary to an increased microbial burden in the wound, but the evidence from studies such as those described above and others suggests that elevated MMP levels can also occur in the absence of infection.(17,34) In 2002, Wri…”
ResultSelf-citationGlucose Toxic Effects on Granulation Tissue Productive Cells: The Diabetics’ Impaired Healing
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“In this highly proteolytic milieu, �bronectin, collagens, growth factors, and their receptors are degraded while the wound is way down to a catabolic state [95].”
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“Prolonged presence of macrophages in chronic wounds of humans suggests that dysfunctional macrophages likely contribute to impaired healing (Mast and Schultz, 1996).”
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Scarless wound healing: Transitioning from fetal research to regenerative healing
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“Interestingly, TNFA levels are elevated in chronic wounds (Mast & Schultz, 1996), suggesting that it may have a detrimental effect on healing and may perpetuate inflammation and inhibit tissue growth.”
BackgroundDavis, T. A., Stojadinovic, A., Anam, K., Amare, M. F., Naik, S., Peoples, G. E., Tadaki, D. K., & Elster, E. A. (2008) · International Wound Journal · doi:10.1111/j.1742-481x.2008.00540.x · Cited by 147
Topical advances in wound care
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“When combined with impaired cellular and systemic host responses to stress, it establishes a deleterious pathophysiological cycle that perpetuates chronic non-healing [9,10].”
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Metadata
- Authors
- Mast, B. A., & Schultz, G. S.
- Affiliations
- University of Florida Health (US)
- University of Florida (US)
- Corresponding author
- Mast, Bruce A.
- Venue
- Wound Repair and Regeneration
- Publisher
- Wiley
- Published
- 1996-10
- Volume
- 4
- Issue
- 4
- Pages
- 411-420
- ISSN
- 1067-1927 (ISSN-L)
- 1524-475X
- OpenAlex
- W1970955409
- Cited by
- 598
- References
- 0
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 26 · 2023: 23 · 2022: 23 · 2021: 37 · 2020: 32 · 2019: 31 · 2018: 39 · 2017: 24 · 2016: 25 · 2015: 24 · 2014: 24 · 2013: 33 · 2012: 30
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Wound Repair and Regeneration (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- chronic wounds, acute wound healing, cytokines, growth factors, proteolytic enzymes, extracellular matrix, tissue repair
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