Wound Healing: First vs. Second Intention

• Annabel Vila, M.D, Associate Professor of Pathology, presents Lecture 6 on Inflammation and Repair

Learning Objectives

• Describe the two types of tissue repair which are regeneration and connective tissue deposition, or scar formation.
• Describe the signals, mechanisms and factors involved in tissue regeneration in different tissue types such as epithelial, parenchymal, and liver regeneration.
• Describe the steps in repair by scarring including inflammation, cell proliferation and remodeling, as well as the process of angiogenesis and intervening factors such as growth factors, Notch signaling, ECM proteins and enzymes.
• Describe the two steps of activation of fibroblasts and deposition of connective tissue, which are migration and proliferation of fibroblasts at the injury site and deposition of ECM proteins by these cells.
• Describe the process of connective tissue remodeling to increase scar strength and contraction, the active role of matrix metal proteinases, and the morphology of granulation tissue.
• Describe the factors that impair tissue repair and give clinical examples of abnormal wound healing and scarring such as sores and ulcers and examples of excessive scarring like keloid and fibrosis in parenchymal organs.

Inflammation and Repair

• Restoration of normal structure occurs when the connective tissue infrastructure remains relatively intact.
• It requires that the surviving affected parenchymal cells have the capacity to regenerate.
• Cellular proliferation is mediated by an assemblage of growth factors.
• The repair process involves removal of debris, formation of granulation tissue, and scarring.
• Factors exist that delay or impede repair.

Tissue Repair

• Restoration of tissue architecture and function after an injury defines tissue repair.
• Repair is utilized for parenchymal and connective tissues and healing for surface epithelial tissues.
• Tissue repair occurs by two main mechanisms: regeneration and repair with scar formation.
• Regeneration involves the proliferation of residual, uninjured cells and maturation of stem cells.
• Repair with scar formation is the replacement of damaged tissue with connective tissue to form a fibrous scar.

Regeneration

• Replacement of damaged tissue with native tissue depends on their intrinsic proliferative capacity.
• Three tissue types based on regenerative capacity are labile, stable, and permanent.

Labile Cells

• These cells actively divide throughout life to replace lost cells, capable of regeneration after injury.
• Examples: cells of the epidermis, gastrointestinal mucosa, cells lining the genitourinary tract surface, and hematopoietic cells of the bone marrow.

Stable Tissues

• Cells are capable of division when activated.
• They can regenerate from G0 cells when needed.
• Parenchyma of most solid tissues, such as the kidney, pancreas, and liver, are stable tissues.
• The liver can regenerate after partial hepatectomy, driven by cytokines like IL-6 produced by Kupffer cells and hepatocyte growth factor HGF produced by many cell types.

Permanent Cells

• They are terminally differentiated and nonproliferative in postnatal life.
• Neurons undergo gliosis in the central nervous system after irreversible injury and cell loss.
• Cardiac and skeletal muscle are permanent cells.
• These cells are replaced by scar tissue, leading to fibrosis.

Cellular Proliferation

• Mediated by an assemblage of growth factors.
• Platelet-derived growth factor (PDGF) promotes the proliferative response and chemotactic migration of fibroblasts and smooth muscle cells when stimulated by progression factors, also promoting collagen synthesis and is synthesized by platelets and other cells.
• Epidermal growth factor (EGF) promotes the growth of endothelial cells, fibroblasts, and epithelial cells.
• Transforming growth factors (TGFs), similar to EGF, serve as growth inhibitors for many cell types and aid in modulating the repair process while also acting as a chemotactic factor for macrophages and fibroblasts.
• Fibroblast growth factors synthesize extracellular matrix proteins, including fibronectin, by fibroblasts, endothelial cells, monocytes, and other cells.
• Fibronectin is chemotactic for fibroblasts and endothelial cells, linking extracellular matrix components like collagen, proteoglycans, and macromolecules such as fibrin and heparin.
• Macrophage-derived growth factors (IL-1 and TNF) promote the proliferation of fibroblasts, smooth muscle cells, and endothelial cells.

Repair Process

• Involves inflammation, proliferation of epithelial cells, granulation tissue formation by vessel growth and proliferating fibroblasts, and remodeling to produce the fibrous scar.

Scar Formation

• Occurs when repair cannot be accomplished by regeneration alone, patching rather than restoring the tissue.
• Most commonly used in wound healing and collagen replacement of parenchymal cells in any tissue, such as in the heart after myocardial infarction.

Morphologic Characteristics of Granulation Tissue

• Appears pink, soft, and granular beneath a scab or skin wound.
• Microscopically show proliferation of fibroblasts depositing type III collagen, angiogenesis with new capillaries providing nutrients, and myofibroblasts contracting the wound.
• Angiogenesis involves the development of collateral circulations at sites of ischemia, promoting tumor growth.

Angiogenesis and Tissue Repair

• Healing at sites of injury occur this way Development of collateral circulations at sites of ischemia
• It allows tumors to increase in size beyond their original blood supply constraints.
• Notch signaling, in "cross-talk" with Vascular endothelial growth factor (VEGF), regulates sprouting and branching of new vessels, ensuring proper spacing to effectively supply the healing tissue with blood

Morphologic Characteristics of a Fibrous Scar

• Macrophages secrete cytokines to stimulate fibroblast proliferation.
• Collagen is deposited, with type III collagen being replaced by type I collagen.
• Microscopic features include inactive, spindle-shaped fibroblasts; dense collagen; and elastic tissue with other ECM components.

Selected Clinical Examples: Healing of Skin Wounds

• Factors that influence healing include nature and size of the wound.
• Healing occurs by first intention with primary union, where epithelial regeneration results in minimal scarring, like in well-apposed surgical incisions.
• Healing by second intention, or secondary union, involves a combination of regeneration and scarring for large wounds, abscesses, ulcerations, and ischemic necrosis or infarction in parenchymal organs.

Factors Impairing Tissue Repair: Aberrant Wound Healing

• Nutritional status affects this, particularly protein malnutrition and deficiencies in vitamin C, which inhibits collagen synthesis and retards healing.
• Vitamin C is a cofactor in the hydroxylation of proline and lysine procollagen residues.
• Copper is a cofactor for lysyl oxidase.
• It cross-links lysine and hydroxylysine to form stable collagen
• Zinc is a cofactor for collagenase.
• It replaces the type III collagen of granulation tissue with stronger type I collagen.
• Persistent infection and S. aureus present impaired tissue repair
• Metabolic disorders like diabetes mellitus
• Glucocorticoids or steroids have anti-inflammatory effects.
• They inhibit TGF-B production, diminishing fibrosis.
• Mechanical factors, such as increased local pressure or torsion, may cause wounds to pull apart (dehisce).
• Arteriosclerosis, causing poor perfusion
• Foreign bodies

Abnormalities in Tissue Repair

• Hypertrophic scars remain contained to the original wound and may regress over time.
• Keloids grow beyond the original biopsy or wound site, often erythematous and pruritic.
• African American patients have increased risk , and keloids are most common in patients under 30 years.
• They typically follow ear piercing or other trauma by a few months.
• Keloid etiology is often idiopathic, and fibroblasts from keloids show apoptosis
• Excessive deposition of collagen and other ECM components in a tissue, which is most often refers to the abnormal deposition of collagen that occurs in internal organs in chronic diseases, is fibrosis
• Fibrosis can lead to substantial organ dysfunction and failure.

Explore the differences between wound healing by first and second intention. This includes the role of collagen synthesis, zinc, and micronutrients. Angiogenesis and impaired collagen cross-linking in chronic wounds are also discussed.