Wound healing initially appears so very simple.57-59 The human body is designed to heal, repair, and in some cases regenerate lost tissue through a well-orchestrated sequence of events. When it proceeds as planned—though infinitely complex—healing is at once elegant, rapid, and efficient. The following phases of wound healing are delineated by the pertinent vascular, cell-signaling, cellular activity, and clinical response as previously defined.
With an acute injury, the small blood vessels respond initially with vasoconstriction to stem further blood loss and tissue injury. (FIGURE 2-22) Activated platelets adhere to the endothelium and eject adenosine diphosphate (ADP), which promotes the clumping of thrombocytes and further ensures clot formation. The clot is composed of various cell types, including red blood cells, white blood cells, and platelets. The clot is stabilized by fibers of fibrin.17 (See FIGURES 2-23 and 2-24).
Cross-section of an arteriole during vasoconstriction. The initial response to injury is reflex vasoconstriction, and the exposed vascular endothelium stimulates platelet adhesion.
During primary hemostasis:
Adhesion molecules are expressed and bind platelets.
Platelets adhere to the exposed basement membrane.
Granular release (ADP) occurs.
Further recruitment of platelets occurs.
Complete aggregation with fibrin forms a hemostatic plug.
Stable fibrin clot, or coagulum The dark red fibrin clots on the surface of this skin tear prevent further bleeding and tissue damage.
Alpha granules containing platelet-derived growth factor (PDGF), platelet factor IV, and transforming growth factor beta (TGF-β) are liberated from the platelets. Dense bodies contained within the thrombocytes release vasoactive amines, including histamine and serotonin. PDGF is chemotactic for fibroblasts, and in coordination with TGF-β modulates mitosis of fibroblasts,60 thereby increasing the number of fibroblasts in close proximity to the wound. Fibrinogen is cleaved into fibrin. Fibrin undergirds the structural support for the completion of the coagulation process and provides an active lattice for the important cellular components during the inflammatory phase. The fibrin will further serve as a scaffold for other infiltration cells and proteins. (See TABLE 2-5.3,10,61) Clinically, a full thickness wound bed with a stable clot functions to mitigate blood loss. Clear proteinaceous exudate may or may not be present.
Platelet Binding and Activation
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Platelet Binding and Activation
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Platelet α-granules secrete:
Platelet-derived growth factor
Transforming growth factor
Insulin-like growth factor
von Willebrand factor
|The dense bodies contain vasoactive amines like serotonin, which lead to increased vascular permeability and vasodilatation. |
Inflammation presents clinically as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). These signs along with the cellular mechanisms responsible are highlighted in the tables, figures, and text that follow. At the immune cellular level several cells arrive, depart, up-regulate, or down-regulate during the phases of healing. The orchestrated arrival and departure of important cell mediators is depicted in FIGURE 2-25. Important changes that permit the initiation of inflammation and result in the clinical findings associated with inflammation are summarized in TABLE 2-6.
Arrival and departure of migratory cell during wound healing
The overall orchestrated arrival and departure of important cells (vertical axis) is correlated with the phases of wound healing (horizontal axis).
Within the first six to eight hours after injury, polymorphonuclear leukocytes (PMNs) or neutrophils flood the wound. TGF-β (released from platelets) facilitates PMN migration and extrusion from surrounding intact blood vessels to the interstitial wound space. PMNs are phagocytic cells, functioning to cleanse the wound of debris, including both necrotic cells and pathogens. The highest number of PMNs within the wound is observed between 24 and 48 hours post injury. By 72 hours, PMN numbers are significantly reduced, just as macrophages are infiltrating.56,62,63 FIGURE 2-26 summarizes factors that promote neutrophil adherence and migration. These factors are a combination of cellular activity, chemokines, cytokines, and proteases. TABLE 2-7 summarizes PMN function and cellular events in healing.
Factors related to neutrophil migration and adherence
The combination of factors imperative for neutrophil extravasation, migration, and adherence at the site of injury and beyond are depicted.
Polymorphonuclear Cells in Wound Healing
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Polymorphonuclear Cells in Wound Healing
▪ PMNs are not essential to wound healing
▪ First infiltrating cells to enter the wound site, peaking at 24 to 48 hours
▪ Neutrophil migration is stimulated by
Major source of cytokines during early inflammation, especially TNF-α
Also release proteases such as collagenases
▪ Following functional activation neutrophils scavenge:
•If wound contamination persists or secondary infection occurs, then continuous activation of the complement system and other pathways provides a steady supply of chemotactic factors
•Result is sustained influx of PMNs into the wound
•Once wound contamination is resolved, PMN migration halts
▪ PMNs do not survive longer than 24 hours
▪ Stimulated neutrophils
Mast cells are activated by antibodies and move rapidly from vascular circulation to the site of injury. Upon activation, mast cells become “sticky” and adhere to the endothelial surface. (FIGURE 2-27) Mast cells can influence the local environment by degranulation or through the products that they synthesize. Histamine, a product of degranulation, increases the permeability of endothelial cells, thus facilitating extravasation of PMNs and macrophages. The three major product categories synthesized by mast cells are prostaglandins, thromboxanes, and leukotrienes.3
Mast cell structure and function
Mast cells are early responders along with PMNs and, once activated, mast cells may either (1) synthesize prostaglandins, leukotrienes, and thromboxanes, or (2) degranulate releasing histamine and chemotactic factors for leukocytes. The resulting actions increase permeability of the endothelial cells and provide a means for cells and plasma to move from the intravascular space to the extracellular compartment.
Neutrophils play a noteworthy role in the early phagocytosis of pathogens and in the recruitment of macrophages by programmed apoptosis. Neutrophils are also capable of expelling a neutrophil extracellular trap (NET) that is composed of DNA and loosely aggregated chromatin. The NET is somewhat like flypaper, trapping would-be invaders and allowing increased clearance by recruited macrophages or neighboring neutrophils.45
Autolytic wound debridement begins immediately post-injury and includes the use of cells and enzymatic proteins to break down necrotic tissue. Cells typically involved in debridement include neutrophils, macrophages, and mast cells.36,64 Enzymatically active proteins, including proteinases and collagenases, degrade the damaged tissue and ECM, thus providing a migratory path to the site of injury for the key cells needed to complete the healing process.17,19
PDGF, released by platelets, is chemotactic for monocytes, causing the monocytes to exude from adjacent vessels and transform into wound-activated macrophages (WAMs). WAMs continue the process of debris removal, and more importantly, begin the signaling that will orchestrate the remaining transitions and events central to healing. (FIGURE 2-28)27,60 Macrophage numbers will remain high for approximately three to four days, releasing various tissue growth factors, cytokines, interleukin-1 (IL-1), tumor necrosis factor (TNF), and PDGF.63 In addition to the phagocytic function, the macrophages provide a unifying script for the multiplication of endothelial cells and the sprouting of new blood vessels, both of paramount importance for continued cell migration and proliferation.3,5,65-67
Wound-activated macrophage functions
Wound-activated macrophages (WAMs) are derived from monocytes that may be activated by integrin expression, a process that promotes adhesion-mediated gene induction in monocytes. The monocytes then transform into wound-activated macrophages (WAMs). The changes include pseudopodia, increased number of phagosomes and lysosomes, and appearance of phagolysosomes. Phagocytosis is the primary function, resulting in increased numbers of appropriate cell organelles suited for increased phagocytic activity as well as the manufacture and release of pro-inflammatory cytokines.
The controlled liquefaction of the ECM continues during the debridement process until all of the damaged cells are removed and cells central to repair are in place. The rate of autolytic debridement will decline as debris is cleared, new cells proliferate, and healing ensues. The pro-inflammatory cytokines and their effects are found in TABLE 2-3 by cell and in TABLE 2-2 by phase of wound healing.
Just as the re-epithelialization process begins a few hours after wounding, so, too, does neo-angiogenesis.68 Keratinocytes from the wound edges migrate beneath the fibrin clot and over the wound. Activated fibroblasts migrate to the site of injury in response to TGF-β1,11,60,69 and, in combination with macrophages, form granulation tissue.16,68 Both macrophages and fibroblasts produce vascular endothelial growth factor (VEGF). In addition, fibroblasts produce connective tissue growth factor (CTGF),70 which results in their proliferation via an autocrine loop.12 The formation of new vasculature requires both extracellular matrix and basement membrane degradation followed by migration, mitosis, and maturation of endothelial cells. Basic FGF and VEGF are believed to be central in modulating angiogenesis.10,28,71-74 As a critical component of healing, new vessel formation will both (1) supply the oxygen and nutrients required and (2) remove the waste products of autolysis. FIGURES 2-29 and 2-30 provides a broad overview of the key events involved in angiogenesis while clinically a well-vascularized, early granulating wound bed.
Two parallel signaling pathways, one mediated through the injured endothelial cells and the other via the endothelium itself, are necessary for angiogenesis to occur.
Granulating wound bed When the signaling pathways occur in a timely sequence, healthy, beefy red granulation forms in the wound bed, supporting the migration of epithelial cells at the edges.
The proliferation phase of healing consists of four subphases: angiogenesis, fibroplasia, matrix deposition, and re-epithelialization.59,68 FIGURE 2-16 illustrates a broad overview of the events occurring in the proliferation phase, which is characterized by the formation of granulation tissue. This tissue consists of a rich capillary bed, fibroblasts, macrophages, and a loose arrangement of collagen, fibronectin, and hyaluronic acid.
Angiogenesis is mandatory to supply necessary nutrients and to remove waste products. Angiogenesis, although discussed as part of the inflammatory and proliferative phases, begins immediately after injury and is paramount to ensuring endothelial cell migration, which results in capillary sprouting. Injured endothelial cells, adhering blood cells, and numerous soluble factors trigger a cascade of events resulting in matrix remodeling and concurrent endothelial cell growth and differentiation. Capillary tube formation is a complex process involving cell-to-cell and cell-to-matrix interactions, many of which are modulated by progenitor endothelial cell adhesion molecule (PECAM-1) and stimulated by VEGF. ?1 Integrin acts to stabilize the cell-to-cell and cell-to-matrix contacts. As new capillaries sprout, they are differentiated into arterioles and venules, while others undergo involution and apoptosis with subsequent ingestion by macrophages.
Fibroplasia is characterized by the presence of fibroblasts, specialized cells that differentiate from resting mesenchymal cells located in connective tissue. FIGURE 2-31 provides a broad overview of fibroplasia. By approximately the fifth day, fibroblasts have migrated into the wound and are laying down new collagen, either sub-type I or III. Early in normal wound healing, type III collagen predominates and is later replaced by type I collagen. The process of collagen formation begins within the fibroblast cell's rough endoplasmic reticulum, where tropocollagen (the precursor to all collagen types) has its proline and lysine hydroxylated. Establishing disulfide bonds allows three tropocollagen strands to form a triple left-handed helix, termed procollagen. The procollagen is secreted into the extracellular space, passing through the cell wall where peptidases cleave the terminal peptide chains, creating true collagen fibrils.16,15,65,75,76 (FIGURE 2-32)
The pyramid of activities specific to fibroplasia culminate in the manufacturing of the ECM.
Collagen synthesis occurs primarily in the fibroblast. This figure illuminates both the intracellular and extracellular steps required to produce collagen fibers, which are an integral part of the ECM.
The wound is permeated with glycosaminoglycans (GAGs) and fibronectin produced by the fibroblasts. The GAGs include heparin sulfate, hyaluronic acid, chondroitin sulfate, and keratin sulfate. Proteoglycans are GAGs covalently bonded to a protein center. All of these constitute and contribute to matrix deposition. The ECM provides both the lattice infrastructure and key binding sites for cells and chemical messengers alike.14,16,19,77-79 (FIGURE 2-33) Although labile and stable cells are capable of regeneration, injury to these tissues results in restitution of the normal structure only if the ECM is not damaged. Disruption of the ECM leads to collagen deposition and scar formation.
Components of extracellular matrix
The two primary components of ECM are proteoglycans interlaced with collagen and elastin. The tissue cells are attached to fibronectin through integrins. These integrins are components of the cellular membrane and are attached to actin filaments in the cell cytoplasm.
Re-epithelialization of the wound begins within hours of injury. The wound is rapidly sealed by clot formation and subsequently by the migration of epithelial (epidermal) cells across the defect. Keratinocytes located within the basal layer of the remaining and undamaged epidermis migrate to resurface the wound. Keratinocytes undergo a sequence of changes to c-omplete re-epithelialization, which is depicted in FIGURES 2-34 and 2-35 and summarized in TABLE 2-8.
Re-epithelialization occurs sequentially and is actively displayed in keratinocytes. The keratinocytes detach, migrate, proliferate, differentiate, and finally stratify.
Re-epithelialization of a wound Re-epithelialization is visible at the wound edges, especially on both ends where the basement membrane and the new epithelial cells are migrating toward the center. Some of the edges have hypergranulation and may need to be treated with pressure or calcium nitrate in order to decrease the granulation cells so that the epithelial cells can move toward full closure.
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▪ Epidermal cells express integrin receptors that allow them to interact with ECM proteins (fibronectin and others)
▪ Migrating cells dissect the wound by separating the desiccated eschar from viable tissue
▪ Path of dissection is determined by the integrins that the epidermal cells express on their cell membranes
▪ Degradation of the ECM, required if epidermal cells are to migrate between the collagenous dermis and fibrin eschar, is driven by epidermal cell production of collagenase (MMP-1) and plasminogen activator, which activates collagenase and plasmin
▪ Migrating cells are also phagocytic and remove debris in their path
▪ Cells behind the leading edge of migrating cells begin to proliferate. The epithelial cells move in a leapfrog and tumbling fashion until the edges establish contact
▪ If the basement membrane zone is not intact, it will be repaired first
▪ Absence of neighbouring cells at the wound margin may be a signal for the migration and proliferation of epidermal cells
▪ Local release of EGF, TGF-α, and KGF and increased expression of their receptors may also stimulate these processes
▪ Basement membrane proteins, such as laminin, reappear in a highly ordered sequence from the margin of the wound inward
▪ After the wound is completely reepithelialized, the cells become columnar and stratified again while firmly attaching to the reestablished basement membrane and underlying dermis
Epidermal cells express integrin receptors, thus allowing them to interact with ECM proteins. The migrating epidermal cells dissect the wound, separating desiccated eschar from living or viable tissue. The migratory path is determined by both the degradation of injured tissue and the integrins expressed on the epidermal cell surfaces. Epidermal cells also secrete collagenases and metalloprotease-1 (MMP-1) to degrade the ECM ahead of their migratory path. Studies have also demonstrated that the edge-leading epidermal cells can phagocytize debris. Cells behind the leading cells are stimulated to proliferate, thus resulting in epithelial cells moving in a tumbling motion across the wound surface until contact is established with the opposite edge. If the basement membrane is not intact, it is repaired prior to migration. Local release of epidermal growth factor (EGF), tissue growth factor alpha (TGF-α), and keratinocyte growth factor (KGF), along with the increased expression of their receptors, may also stimulate this process. TABLE 2-9 summarizes in detail the growth factors secreted and the cells responsible for their production, as well as the cells influenced by those growth factors.
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|Factor ||Principal Source ||Primary Activity ||Comments |
|Epidermal growth factor (EGF) ||Submaxillary gland, Brunner gland, platelets and macrophage ||Promotes proliferation of fibroblast, keratinocyte, and epithelial cells in wound healing || |
|Fibroblast growth factor (FGF) ||Wide range of cells including fibroblast, macrophage, mast cells, and endothelial cells |
Protein is associated with the ECM
|Fibroblast proliferation |
Chemotactic for fibroblasts
Mitogenic for fibroblasts and keratinocytes
Stimulates keratinocyte migration, angiogenesis, wound contraction, and matrix deposition
|At least 18 family members. Uses five distinct receptors |
|Insulin growth factor (IGF-1) ||Macrophages and fibroblasts ||Stimulates synthesis of sulfated proteoglycans, collagen, keratinocyte migration, and fibroblast proliferation |
Endocrine effects are similar to those of growth hormone
Promotes cell proliferation. Related to IGF-2 and proinsulin, also called somatomedin C
|Keratinocyte growth factor (KGF) ||Fibroblasts ||Stimulates keratinocyte migration, proliferation, and differentiation || |
|Platelet-derived growth factor (PDGF) ||Platelets, endothelial cells, macrophages, keratinocytes, placenta ||Promotes proliferation of connective tissue and smooth muscle cells |
Chemotactic for monocytes, PMNs, and fibroblasts
Activates PMNs, macrophages, and fibroblasts
Neoangiogenesis—mitogenic for fibroblasts and endothelial cells
Wound remodeling—stimulates production of MMPs, fibronectin, and HA
|X-ray crystal structure is very similar to that of VEGF13,66 |
Two different protein chains, which form three distinct dimers: AA, AB, BB
SMALL molecule PDGF is active during the initial stages of hemostasis, while LARGE molecule PDGF is activated during the later stages of proliferation and remodeling
|Transforming growth factor (TGF-β) ||Activated Th1 cells (T-helper), natural killer (NK) cells, platelets, macrophages, keratinocytes, and fibroblasts ||Anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing |
Chemotactic for PMNs, macrophages, lymphocytes, and fibroblasts
Inhibits macrophage and lymphocyte proliferation7
Stimulates TIMP synthesis, keratinocyte migration, angiogenesis, and fibroplasia
Inhibits production of MMPs and keratinocyte proliferation
Induces TGF-β production
| Over 100 different family members |
Promotes differentiation of fibroblast into myofibroblast10
|Transforming growth factor (TGF-α) ||Occurs in transformed cells |
Macrophages, T lymphocytes, keratin
|Important for normal wound healing ||Related to EGF |
|Vascular endothelial cell growth factor (VEGF) ||Keratinocytes ||Increases vasopermeability, mitogenic for endothelial cells || |
Basement membrane proteins, like laminin, appear in a highly ordered sequence proliferating from the wound margin inward. Laminins are a family of glycoproteins that provide an integral part of the structural scaffolding of the basement membrane in almost every animal tissue. Each laminin is a heterotrimer assembled from alpha, beta, and gamma chain subunits, secreted and incorporated into cell-associated extracellular matrices. The laminins are unique in that they can self-assemble, bind to other matrix macromolecules, and have shared cell interactions mediated by integrins and other receptors. Through the interactions with other cells, laminins critically contribute to cell differentiation, cell shape and movement, and maintenance of tissue phenotypes, as well as promote tissue survival. After the wound is completely re-epithelialized, the cells again become columnar, stratified, and firmly attached to the newly constructed basement membrane and underlying dermis.17,80 Although the wound may be fully re-epithelialized and closed, it is not referred to as healed until the next, final stage of wound healing is completed.
Maturation and Remodeling
The final stage of the wound healing process consists of dermal regeneration, wound contraction, and programmed involution of the granulation tissue. Wound contraction occurs in a centripetal fashion, involving the full thickness of the wound and periwound tissue (FIGURE 2-36). The primary goal of wound contraction is to aid in the reduction of wound size and reduce the amount of disorganized scar tissue. Wound contraction occurs through complex interactions between the ECM and fibroblasts; however, the interactions have not been completely elucidated. It is understood that aborted cell locomotion, phenotypic change from fibroblast to myofibroblast, and the expression of TGFβ-1 and MMP3 are all important. Aborted cell locomotion results in the bunching and contraction of collagen fibers. Phenotypically fibroblasts undergo cellular changes and become myofibroblasts, cells that express α-smooth muscle actin (αSMA). TGFβ-1 promotes wound contraction by increasing the expression of β1 integrin. Stromyelysin, or MMP3, through the utilization of integrin β1, allows for the modification of attachment sites between fibroblasts and collagen fibers.
Maturation and remodeling A fasciotomy wound on the lower extremity is in the remodeling phase of healing. Although the wound is fully epithelialized, it is not considered healed until the granulation tissue scar recedes, the Type III collagen matrix is replaced with Type I, and optimal function to the tissue is restored with tensile strength sufficient to prevent epithelial cracking and tearing.
During remodeling, the number of fibroblasts and myofibroblasts decrease, the dense capillary network regresses, and wound strength gradually increases. The early epidermal–-dermal interface is fragile because it lacks the interlocking rete pegs. Without rete pegs, the newly healed wound is at risk for avulsion with minor trauma. Apoptosis of myofibroblasts, endothelial cells, and macrophages results in tissue composed primarily of ECM proteins, particularly collagen type III. Metalloproteinases produced by the epidermal cells, endothelial cells, fibroblasts, and macrophages that remain in the scar will continue the process of remodeling, replacing collagen type III with collagen type I.58,59,61,81 The resulting tissue “patch” will have approximately 80% of the tensile strength of the original tissue but will have completely reestablished function.82-85
Clearing and Containing the Invader
Most pathogenic microorganisms have evolved mechanisms to overcome innate immune responses and thus continue to grow. An adaptive immune response is required to eliminate the pathogenic invader and prevent subsequent re-infection. Both the innate and adaptive immune responses are discussed as they pertain to each phase of wound healing.
Immediately During Clot Formation
The formation of a clot is critical for two reasons. The first obvious reason is to stem the loss of blood as discussed previously. The second more obtuse but equally important reason is to recruit the innate immune system to clear debris and pathogens. Platelets are central in the following three areas: (1) initiation of the clotting cascade, (2) formation of a platelet plug (the outer surface of activated platelets becomes sticky with a mucopolysaccharide coating), and (3) release of cytokines and alpha granules. The fibrin provides an infrastructure for the clot and mechanical entrapment of debris and invaders. TGF-β1 and TGF-β2, released by the platelets, attract macrophages to the site of injury. Macrophages in turn express IL-1, which stimulates antigen-presenting cells (APCs) to produce IL-8. IL-8 both signals and directs neutrophil migration and margination while simultaneously up-regulating “sticky factors” and vascular permeability to expedite the process. The recruitment of both macrophage and neutrophils (PMNs) immediately to the site of injury begins the process of invader identification and clearing.3
The innate immune response occurs with the migration and extravasation of PMNs from the neighboring vasculature. The extravasation, migration, and proliferation are facilitated by TGF-β1, a growth factor released by the platelets and macrophages that have migrated to the wounded tissue. Neutrophils are the first inflammatory, innate immune system cells to infiltrate a wound; they do so in large numbers in response to the numerous inflammatory cytokines produced by endothelial cells, activated platelets, and degradation products from invading pathogens.64 Neutrophils undergo programmed cell death (apoptosis) shortly after infiltration, thus releasing additional cytokines that recruit macrophages to the wound site.63
Neutrophils, or PMNs, exhibit several important defense mechanisms. Three of the many defense mechanisms are highlighted here: (1) neutrophil extracellular traps (NETs), (2) the release of azurophilic pore-forming granules, and (3) phagocytosis and programmed apoptosis.4 NETs are the result of the neutrophils expelling chromatin, a very sticky substance, and thus serve to mechanically entrap the pathogen. (FIGURE 2-37) Once entrapped, proteases, elastases, pore-forming granules, and other cytotoxic molecules lyse the invader. Both the entrapment and the lysis of the invader serve to increase the visibility of the intruder to the host immune system.86 Neutrophils are also capable of direct phagocytosis of an invader. The programmed apoptosis of neutrophils releases pro-inflammatory cytokines, attracts additional macrophages, and up-regulates the key activities of macrophages. Th1 (innate system) neutrophils produce interferon gamma (IFN-γ), which also up-regulates macrophage activity, and alters the macrophage phenotype to a WAM, which characteristically produces increased nitric oxide and H2O2.Both nitric oxide and H2O2acidify the environment and the lower pH serves to increase phagocytosis. In addition, the WAMs display increased MHCII for the presentation of antigens specific to the invader to the adaptive immune system.87,88 Both neutrophils and macrophages are important to the immediate containment of the invader and the activation of the adaptive (memory/B-cell) immune system of the host.
Neutrophil extracellular traps
Neutrophils expel chromatin, a very sticky substance, which results in the formation of neutrophil extracellular traps (NETs). The NET is expressed in response to the stimulation of receptors, the adhesion of neutrophils, and the disintegration of intracellular membrane and expulsion of cytoplasm and nucleoplasm. The NET mechanism thus serves as a means to trap pathogenic bacteria.
T-lymphocytes are another population of inflammatory immune cells that routinely invade the wound. Although less numerous than macrophages, they bridge the transition from the inflammatory to proliferative phase. Depletion of most wound T-lymphocytes decreases wound strength and collagen content. T-lymphocytes affect fibroblast function by producing stimulatory cytokines like IL-2, fibroblast activating factor, and inhibitory cytokines (including TGF-β, TNF-α, and IFN-γ). The role of IFN-γ secreted by T-lymphocytes is illustrated in FIGURE 2-38. The effects of IFN-γ are far-reaching and may be an important mediator of chronic non-healing wounds.
Role of IFN-γ
IFN-γ is an important cytokine intimately involved in the inflammatory response. IFN-γ stimulates macrophages while simultaneously suppressing collagen synthesis and the release of prostaglandin. At the same time, IFN-γ activates T cells and hence the innate immune response.
Adaptive immunity, or learned immunity, is triggered by the first responders, namely macrophages. Macrophages enhance APC's activity, thereby aiding in the presentation of antigens (antibody generator) to the host immune system T cells. Bacterial proteins degraded by host proteases are ingested by macrophages and become antigens, which are then presented to T cells via Class II MHC receptors on the macrophage surface. Once a T cell binds to the loaded Class II MHC receptor, the T cell becomes activated and begins secreting IL-2. IL-2 simulates T cells to divide and activates the T cell phenotypic expression of IL-2 receptors, thus resulting in autocrine lymphocyte proliferation and activation. This is illustrated in FIGURE 2-39.
Role of macrophages in antigen presentation
Macrophages also have a role in presenting antigen. This schematic demonstrates the process by which a macrophage activates the innate immune system. Antigen (bacterial components, PAMPs) uptake by the macrophage is processed and coupled to a class II MHC protein on the cell surface of the macrophage. The antigen–class II MHC complex is recognized by circulating T cells. Once coupled, the T cell is activated and the production of IL-2 results. IL-2 stimulates the expression of T cell IL-2 receptors and T cell mitosis.
The dendritic cells, another important APC, traffic to local lymph nodes and present the antigens to resident cells. If the antigen presented is recognized by existing memory B cells, those B cells are activated and clonal expansion is triggered. In addition, macrophages produce IL-2, a powerful cytokine that drives T cells to become Th2 helper cells, and thereby increases the effectiveness of B cells.3
The B cells produce and release antibodies resulting in an increase in the number of circulating antibodies specific to the pathogen (eg, MRSA, MSSA). As a result, either neutralization or opsonization can more effectively occur. Neutralization occurs with the binding of an antibody to the pathogen, thus blocking access to host cells. Opsonization refers to the coating of the pathogen with antibody, thereby increasing the ease of identification and subsequent clearance and phagocytosis.3