Summary of Factors and Effects during Each Phase of Wound Healing in Chronic Wounds (continued ) 2.2
TABLE
Chronic Infl ammatory Phase
Chronic Epithelialization
Phase Chronic Proliferative Phase Chronic Remodeling Phase
Substrates relationship to stalling or plateauing:
a. Inadequate substrates b. Bacterial competition for
substrates necessary for tissue repair
c. Continued lysis of new growth faster than synthesis of new material
Long-term wound hypoxia effects:
a. Negative effect on collagen production
b. Decreased fi broblast proliferation
c. Decreased tissue growth Impaired wound contraction:
a. Wound remains large b. Delayed reepithelialization
Adapted from Bates-Jensen B. A Quantitative Analysis of Wound Characteristics as Early Predictors of Healing in Pressure Sores. Dissertation Abstracts International, Volume 59, Number 11, University of California, Los Angeles; 1999, with permission.
communicate with and attract responder cells and regulate the repair process. Growth factors are explained more fully on page 20.
Figure 2.22 shows an algorithm of healing through a distinct but overlapping series of processes, leading to scar formation and normal wound healing. The following is a description of the key processes of the acute infl ammatory phase, including
• Coagulation cascade to achieve platelet activation and hemostasis
• Hypoxia and regulation via the oxygen-tension gradient
• Oxygen and antibacterial effects
• Nitric oxide and cellular signaling
• Vasodilation
• Hypothermia
Degradation
Healed Wound Macrophages
Metalloproteinases Collagenases
Remodeling Phase (Scar Formation) Collagen cross-linking
Capillary resorption Collagen lysis
Epithelialization Phase (Resurfacing)
Keratinocytes Melanocytes Hemostasis (Coagulation Cascade)
Platelets
Chemotaxis (bioactive mediators) Fibrin
Fibronectin
Galvanotaxis (current of injury)
Inflammation Phase Neutrophils
Lymphocytes Macrophages
Plasma proteins (complement components)
Mast cells
Proliferation Phase (Tissue Deposition) Granulation Tissue
Fibroblasts Endothelial cells Angiogenesis
Extracellular matrix (ECM) synthesis Myofibroblasts
Wound contraction
Injury FIGURE 2.22 The phases of acute wound healing.
• Complement system activation to control infection
• Neutrophil, mast, macrophage, and fi broblast cell functions
• Growth factors and other regulatory proteins
• “Current of injury” stimulus for the repair process
As noted earlier, after describing normal infl ammation, we will discuss the attributes and processes that may be responsible for chronic wound healing during the infl ammatory phase.
Platelets, Hemostasis, and the Coagulation Cascade
The coagulation cascade begins with clotting and vasocon- striction lasting 5 to 10 minutes after skin incision, to produce hemostasis at the site of wounding immediately after injury to control hemorrhaging and reduce blood loss (Figure 2.23).
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A B
C D
FIGURE 2.23 Growth factors and the healing cascade.
Hemostasis is initiated as the fi rst major function of the plate- lets. Platelets, white blood cells that are normally present in the intravascular space, are activated by collagen or microfi brils from the subendothelial layers that are exposed when injury occurs resulting in platelet aggregation (clotting) and degranula- tion. This process known as platelet activation induces changes in platelet structure and function necessary for coagulation to occur, including thrombin, fi brinous clot production, and, ultimately, hemostasis.39 The fi brin clot becomes the primary foundation for collagen deposition, which will be necessary for tissue repair, and the pathway for the infl ux of monocytes and fi broblasts to the wound site.40 The second, equally important
function of the platelet is the secretion of cytokines and growth factors with multiple functions, including recruitment of leu- kocytes, and fi broblasts to the injury site.41 Growth factors and other regulatory peptides like cytokines are discussed on page 20. Fibrin clots also seal off the lymphatic fl ow to prevent spreading of infection. However, immediately after the forma- tion of the fi brinous clot, the process of fi brinolysis to lyse the clot begins.42 Unplugging of the capillaries and vasodilation follows and permits entrance of fl uid into the wound space, which activates the complement system that is explained on page 22. Coagulation and the ensuing events described above are known as the coagulation cascade.
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release of angiogenic growth factors (AGFs) by macrophages to attract fi broblasts to the wound site.50,51
Signs of local hypoxia often go undetected. One example is the case of perioperative hypothermia-induced vasoconstric- tion and tissue hypoxia, which have been shown to triple the incidence of perioperative surgical wound infection.43
Thus, it should not be surprising that research on the activi- ties of GFs shows that they provide the key biochemistry for the wound healing process. Platelets, macrophages, and epidermal cells are the primary cells that produce and release GFs. As such, they are the critical components initiating the wound healing cas- cade. These include platelet-derived growth factor (PDGF), epider- mal growth factor (EGF), transforming growth factor-ß (TGF-ß), heparin-binding epidermal growth factor (HB-EGF), and insulin- like growth factor-1 (IGF-1), all of which facilitate cell migration of neutrophils and macrophages to the area of injury.39,41 PDGF is multifunctional, playing multiple roles in wound healing, including release of endothelial growth factor (VEGF) and basic fi broblast growth factor (bFGF) early in the infl ammatory phase.
For example, TGF-ß and PDGF are specifi c chemoattractants for macrophages during the infl ammatory phase continuing into the proliferative phase (discussed on page 23)39 (see Figure 2.23).
A key role of GFs is to act as intercellular communicators.
GFs can act on distant cells (endocrine stimulation), adjacent cells (paracrine stimulation), and themselves (autocrine stim- ulation).39 They deliver messages that are released to nonim- mune cells and result in cell proliferation, such as the synthesis of granulation tissue.
Cells have the ability to increase (upregulate) or decrease (down regulate) their receptors in response to environmental signals. Cell receptors are not stationary on the cell surface, and their numbers can vary from time to time. They also can bind with one or more kinds of messages.52 Cell surface recep- tors on the target cell receive the message, bind to the cell, and produce a biological response in the receiving cell. Some GFs deliver messages related to cell proliferation like cell reproduc- tion by mitosis (mitogenesis), others cause cell migration (via chemotaxis) or cell synthesis, and still others perform regula- tory functions.
Cytokines are signaling molecules—peptides, proteins, or glycoproteins—that are essential in cellular communication throughout the body that play two critical roles in infl ammation:
Proinfl ammatory cytokines communicate with immune system cells and attract those cells to the area of injury for the purpose of mounting an infl ammatory response to destroy foreign organ- isms and debris. In acute wounds, the level of proinfl ammatory cytokines peaks in a few days and remains low in the absence of infection.53 Anti-infl ammatory cytokines have powerful inhibi- tory actions on the infl ammatory cells. Table 2.3 is a key to growth factor acronyms used for representation of the infl ammatory phase, indicating the release of multiple cytokines, the cytokines, and an identifi cation of their cellular sources and functions.
A third group of regulatory proteins is collectively known as chemokines. Chemokines have two primary functions: they regulate the traffi cking of leukocyte populations during normal health and development, and direct the recruitment and acti- vation of neutrophils, lymphocytes, macrophages, eosinophils, and basophils during infl ammation.53 Together GFs, cytokines, and chemokines are the key molecular regulators of wound healing. These multiple cell types associated with wound healing