Inflammatory Phase
The early
events of wound healing are characterized by the inflammatory phase, a
vascular and cellular response to injury. An incision made through a
full thickness of skin causes a disruption of the microvasculature and
immediate hemorrhage. Following incision of the skin, a 5- to 10-minute
period of vasoconstriction ensues, mediated by epinephrine,
norepinephrine, prostaglandins, serotonin, and thromboxane.
Vasoconstriction causes temporary blanching of the wound and functions
to reduce hemorrhage immediately following tissue injury, aid in
platelet aggregation, and keep healing factors within the wound.
Endothelial cells retract to expose the subendothelial collagen surfaces; platelets attach to these surfaces. Adhesion to exposed collagen surfaces and to other platelets occurs through adhesive glycoproteins: fibrinogen, fibronectin, thrombospondin, and von Willebrand factor. The aggregation of platelets results in the formation of the primary platelet plug. Aggregation and attachment to exposed collagen surfaces activates the platelets. Activation enables platelets to degranulate and release chemotactic and growth factors, such as platelet-derived growth factor (PDGF), proteases, and vasoactive agents (eg, serotonin, histamine).
The coagulation cascade occurs via 2 different pathways. The intrinsic pathway begins with the activation of factor XII (Hageman factor) when blood is exposed to extravascular surfaces. The extrinsic coagulation pathway occurs through the activation of tissue factor found in extravascular cells in the presence of factors VII and VIIa. Both pathways proceed to the activation of thrombin, which converts fibrinogen to fibrin. The fibrin product is essential to wound healing and is the primary component of the wound matrix into which inflammatory cells, platelets, and plasma proteins migrate. Removal of the fibrin matrix impedes wound healing.
In addition to activation of fibrin, thrombin facilitates migration of inflammatory cells to the site of injury by increasing vascular permeability. By this mechanism, factors and cells necessary for healing flow from the intravascular space and into the extravascular space.
The result of platelet aggregation and the coagulation cascade is clot formation. Clot formation is limited in duration and to the site of injury. Clot formation dissipates as its stimuli dissipate. Plasminogen is converted to plasmin, a potent enzyme that aids in cell lysis. Clot formation is limited to the site of injury because uninjured nearby endothelial cells produce prostacyclin, an inhibitor of platelet aggregation. In uninjured adjacent areas, antithrombin III binds thrombin, and protein C binds factors of the coagulation cascade, namely, factors V and VII.
The vasoconstriction period is followed by a more persistent period of vasodilation mediated by histamine, prostaglandins, kinins, and leukotrienes. Vasodilation is responsible for the erythema, edema, and heat observed after tissue injury. Vasodilation is an important means by which the wound can be exposed to increased blood flow, accompanied by the necessary inflammatory cells and factors that fight infection and debride the wound of devitalized tissue. Alterations in pH (secondary to tissue and bacterial degradation), swelling, and tissue hypoxemia at the injury site contribute to the sensation of wound pain.
Following injury, the products of the earliest cellular events activate intricately related inflammatory pathways that modify subsequent events in the wound-healing process. For example, Hageman factor activates the kinin pathway, which produces bradykinin. Bradykinin stimulates vasodilation and increased vascular permeability. Histamine released from platelets and circulating mast cells increases vascular permeability and indirectly stimulates vasodilation through the production of prostaglandins E1 and E2. Prostaglandins cause vasodilation through the activation of the adenylate cyclase pathway via the production of cyclic adenosine monophosphate. Prostaglandins also accumulate at the area of injury through the activation of phospholipases located on injured cell membranes. Phospholipases stimulate the release of arachidonic acid, ultimately leading to the production of prostaglandins, leukotrienes, and other factors.
Hageman factor also activates the classic complement pathway during the inflammatory phase. Inactive proteins of the complement system (ie, C1-C9) are activated by means of a cascade of reactions. These proteins stimulate important inflammatory events such as chemotaxis, degranulation of mast cells, and cytolysis. C5a and C567 are chemotactic agents for neutrophil migration. C3a, C4a, and C5a cause degranulation of mast cells, leading to release of histamine and increased vascular permeability. The membrane attack complex, C5b6789, is responsible for cytolysis. The cellular aspect of the inflammatory phase occurs within hours of injury. Neutrophils are the predominant cell type for the first 48 hours after injury but do not appear essential to the wound-healing process. Neutrophils cleanse the wound site of bacteria and necrotic matter and release inflammatory mediators and bactericidal oxygen-free radicals. The absence of neutrophils does not prevent healing.
Macrophages are essential to wound healing and perhaps are the most important cells in the early phase of wound healing. Macrophages phagocytose debris and bacteria. Macrophages also secrete collagenases and elastases, which break down injured tissue and release cytokines. In addition, macrophages release PDGF, an important cytokine that stimulates the chemotaxis and proliferation of fibroblasts and smooth muscle cells. Finally, macrophages secrete substances that attract endothelial cells to the wound and stimulate their proliferation to promote angiogenesis. Macrophage-derived growth factors play a pivotal role in new tissue formation, as evidenced by the fact that new tissue formation in macrophage-depleted animal wounds demonstrates defective repair. In studies in which experimental wounds are rendered monocytopenic, subsequent stages of fibroplasia and granulation tissue formation are impaired and the overall rate of wound healing is delayed.
T lymphocytes migrate into the wound during the inflammatory phase, approximately 72 hours following injury. T lymphocytes are attracted to the wound by the cellular release of interleukin 1, which also contributes to the regulation of collagenase. Lymphocytes secrete lymphokines such as heparin-binding epidermal growth factor and basic fibroblast growth factor. Lymphocytes also play a role in cellular immunity and antibody production.
Endothelial cells retract to expose the subendothelial collagen surfaces; platelets attach to these surfaces. Adhesion to exposed collagen surfaces and to other platelets occurs through adhesive glycoproteins: fibrinogen, fibronectin, thrombospondin, and von Willebrand factor. The aggregation of platelets results in the formation of the primary platelet plug. Aggregation and attachment to exposed collagen surfaces activates the platelets. Activation enables platelets to degranulate and release chemotactic and growth factors, such as platelet-derived growth factor (PDGF), proteases, and vasoactive agents (eg, serotonin, histamine).
The coagulation cascade occurs via 2 different pathways. The intrinsic pathway begins with the activation of factor XII (Hageman factor) when blood is exposed to extravascular surfaces. The extrinsic coagulation pathway occurs through the activation of tissue factor found in extravascular cells in the presence of factors VII and VIIa. Both pathways proceed to the activation of thrombin, which converts fibrinogen to fibrin. The fibrin product is essential to wound healing and is the primary component of the wound matrix into which inflammatory cells, platelets, and plasma proteins migrate. Removal of the fibrin matrix impedes wound healing.
In addition to activation of fibrin, thrombin facilitates migration of inflammatory cells to the site of injury by increasing vascular permeability. By this mechanism, factors and cells necessary for healing flow from the intravascular space and into the extravascular space.
The result of platelet aggregation and the coagulation cascade is clot formation. Clot formation is limited in duration and to the site of injury. Clot formation dissipates as its stimuli dissipate. Plasminogen is converted to plasmin, a potent enzyme that aids in cell lysis. Clot formation is limited to the site of injury because uninjured nearby endothelial cells produce prostacyclin, an inhibitor of platelet aggregation. In uninjured adjacent areas, antithrombin III binds thrombin, and protein C binds factors of the coagulation cascade, namely, factors V and VII.
The vasoconstriction period is followed by a more persistent period of vasodilation mediated by histamine, prostaglandins, kinins, and leukotrienes. Vasodilation is responsible for the erythema, edema, and heat observed after tissue injury. Vasodilation is an important means by which the wound can be exposed to increased blood flow, accompanied by the necessary inflammatory cells and factors that fight infection and debride the wound of devitalized tissue. Alterations in pH (secondary to tissue and bacterial degradation), swelling, and tissue hypoxemia at the injury site contribute to the sensation of wound pain.
Following injury, the products of the earliest cellular events activate intricately related inflammatory pathways that modify subsequent events in the wound-healing process. For example, Hageman factor activates the kinin pathway, which produces bradykinin. Bradykinin stimulates vasodilation and increased vascular permeability. Histamine released from platelets and circulating mast cells increases vascular permeability and indirectly stimulates vasodilation through the production of prostaglandins E1 and E2. Prostaglandins cause vasodilation through the activation of the adenylate cyclase pathway via the production of cyclic adenosine monophosphate. Prostaglandins also accumulate at the area of injury through the activation of phospholipases located on injured cell membranes. Phospholipases stimulate the release of arachidonic acid, ultimately leading to the production of prostaglandins, leukotrienes, and other factors.
Hageman factor also activates the classic complement pathway during the inflammatory phase. Inactive proteins of the complement system (ie, C1-C9) are activated by means of a cascade of reactions. These proteins stimulate important inflammatory events such as chemotaxis, degranulation of mast cells, and cytolysis. C5a and C567 are chemotactic agents for neutrophil migration. C3a, C4a, and C5a cause degranulation of mast cells, leading to release of histamine and increased vascular permeability. The membrane attack complex, C5b6789, is responsible for cytolysis. The cellular aspect of the inflammatory phase occurs within hours of injury. Neutrophils are the predominant cell type for the first 48 hours after injury but do not appear essential to the wound-healing process. Neutrophils cleanse the wound site of bacteria and necrotic matter and release inflammatory mediators and bactericidal oxygen-free radicals. The absence of neutrophils does not prevent healing.
Macrophages are essential to wound healing and perhaps are the most important cells in the early phase of wound healing. Macrophages phagocytose debris and bacteria. Macrophages also secrete collagenases and elastases, which break down injured tissue and release cytokines. In addition, macrophages release PDGF, an important cytokine that stimulates the chemotaxis and proliferation of fibroblasts and smooth muscle cells. Finally, macrophages secrete substances that attract endothelial cells to the wound and stimulate their proliferation to promote angiogenesis. Macrophage-derived growth factors play a pivotal role in new tissue formation, as evidenced by the fact that new tissue formation in macrophage-depleted animal wounds demonstrates defective repair. In studies in which experimental wounds are rendered monocytopenic, subsequent stages of fibroplasia and granulation tissue formation are impaired and the overall rate of wound healing is delayed.
T lymphocytes migrate into the wound during the inflammatory phase, approximately 72 hours following injury. T lymphocytes are attracted to the wound by the cellular release of interleukin 1, which also contributes to the regulation of collagenase. Lymphocytes secrete lymphokines such as heparin-binding epidermal growth factor and basic fibroblast growth factor. Lymphocytes also play a role in cellular immunity and antibody production.
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