Originally Published: Primary Intention
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Authors:

Gregory S Schultz and Bruce A Mast

Summary:

This article, “Molecular Analysis of the Environments of Healing and Chronic Wounds: Cytokines, Proteases and Growth Factors” by Gregory S. Schultz and Bruce A. Mast, discusses the complex biological process of wound healing and the molecular differences between acute (healing) and chronic wounds.

Key points:

• Phases of Wound Healing: Wound healing involves four general phases: hemostasis, inflammation, proliferation/repair, and remodeling. These phases overlap and are regulated by growth factors, cytokines, proteases, and hormones.
• Roles of Cytokines and Growth Factors: Platelets initiate healing by releasing growth factors (PDGF, IGF-I, EGF, TGF-β) that promote chemotaxis of inflammatory cells and tissue repair. Inflammatory cells (neutrophils, macrophages) and other cells (fibroblasts, endothelial cells, keratinocytes) then release additional cytokines and growth factors (TNFα, IL-1β, IFN-γ, HB-EGF, bFGF, KGF, VEGF) that stimulate cell migration, proliferation, extracellular matrix synthesis, and capillary formation.
• Roles of MMPs (Matrix Metalloproteinases): MMPs are essential for wound healing, facilitating cell migration, removing damaged matrix, and remodeling new scar tissue. Four major classes are collagenases, gelatinases, stromelysins, and membrane-type MMPs. Their activity is regulated by synthesis rates, activation of latent forms, and specific inhibitor proteins called TIMPs (Tissue Inhibitors of Metalloproteinases).
• Roles of Endocrine Hormones: Endocrine hormones (e.g., insulin, glucocorticoids, estrogen) also influence wound healing. Alterations in these hormones, such as in diabetic patients or post-menopausal women, can impair healing.
• Biochemical Differences in Chronic Wounds:
  • Reduced Mitogenic Activity: Chronic wound fluids have reduced ability to stimulate DNA synthesis in cells compared to acute wound fluids.
  • Pro-inflammatory Environment: Chronic wounds exhibit significantly higher levels of pro-inflammatory cytokines (TNFα, IL-1β, IL-6) and lower ratios of their natural inhibitors.
  • Elevated Protease Activity: Chronic wounds have significantly elevated protease activity (MMPs, neutrophil elastase) compared to acute wounds. This excessive protease activity can degrade essential extracellular matrix proteins, growth factors, and their receptors, hindering healing.
  • Degradation of Growth Factors: Growth factors like EGF and TGF-β1 are found at lower immunoreactive levels in chronic wounds, likely due to degradation by elevated proteases.
• Biological Response of Chronic Wound Cells: Fibroblasts from chronic wounds, especially those of long duration, show a decreased ability to respond to growth factors and have a reduced capacity to divide (premature senescence).
• Future Treatment Concepts: New treatment strategies for chronic wounds could involve reducing elevated protease levels (e.g., synthetic MMP inhibitors, recombinant TIMP-1, α1-antitrypsin), using recombinant growth factors (e.g., PDGF-BB), and employing engineered tissue replacements. The goal is to re-establish a “healing wound” environment characterized by high mitogenic activity, low inflammatory cytokines and proteases, high growth factor levels, and mitotically competent cells.