Inflammation and Repair Lecture PDF

Inflammation and Repair Lecture 6 Annabel Vila, M.D Associate Professor of Pathology  Learning Objectives 1. Describe the two types of tissue repair-regeneration and connective tissue deposition(scar formation) 2. Describe the signals/mechanisms and factors...

Inflammation and Repair Lecture 6 Annabel Vila, M.D Associate Professor of Pathology  Learning Objectives 1. Describe the two types of tissue repair-regeneration and connective tissue deposition(scar formation) 2. Describe the signals/mechanisms and factors involved in tissue regeneration in different tissue types (epithelial, parenchymal) and Liver Regeneration. 3. Describe the Steps in repair by Scarring (Inflammation, Cell proliferation and Remodeling), and the process of Angiogenesis and intervening factors (Growth factors, Notch signaling, ECM proteins and Enzymes). 4. Describe the two steps of Activation of Fibroblasts and Deposition of Connective Tissue – migration and proliferation of fibroblasts at the injury site & deposition of ECM proteins by these cells. 5. Describe the process of Connective Tissue Remodeling, in order to increase scar strength and contraction, the active role of matrix metal proteinases, and the morphology of Granulation tissue. 6. Describe the factors that Impair Tissue Repair and give Clinical Examples of Abnormal Wound Healing and Scarring (sores and ulcers) and examples of Excessive scarring (Keloid) and Fibrosis in Parenchymal organs.  Inflammation and Repair Restoration of normal structure This occurs when the connective tissue infrastructure remains relatively intact It requires that the surviving affected parenchymal cells have the capacity to regenerate Cellular proliferation This process is mediated by an assemblage of growth factors The repair process Removal of debris Formation of granulation tissue Scarring Factors that delay or impede repair  Tissue repair: definition and important points Definition Restoration of tissue architecture and function after an Injury Repair is often used for parenchymal and connective tissues and healing for surface epithelial Repair of damaged tissues occurs by (2) types of reactions (1) Regeneration Proliferation of residual (uninjured cells) and maturation of stem cells (2) Repair with Scar formation Replacement of damaged tissue with connective tissue to form a fibrous scar  Repair of damaged tissues Regeneration and Scar formation  Regeneration Tissues: Important point Replacement of damaged tissue with native tissue is determined by their intrinsic proliferative capacity Three types of tissues based on regenerative capacity Labile Stable Permanent  Cell and tissue regeneration: labile tissues and cells Labile cells These cells divide actively throughout life to replace lost cells They are capable of regeneration after injury Cells of the epidermis Gastrointestinal mucosa Cells lining the surface of the genitourinary tract Hematopoietic cells of the bone marrow  Cell and tissue regeneration: stable tissues The Torture of Prometheus, painting by Salvator Rosa (1646 –1648) Cells are capable of division when activated They can regenerate from G0 cells when needed Parenchyma of most solid tissues Kidney Pancreas Liver It regenerates, after partial hepatectomy This process is driven by cytokines such as IL-6 produced by Kupffer cells, and by hepatocyte growth factor (HGF) produced by many cell types  Cell and tissue regeneration: Permanent cells Permanent cells They are terminally differentiated and nonproliferative in postnatal life Neurons Gliosis in the central nervous system, after irreversible injury and cell loss Cardiac muscle Skeletal muscle They are replaced by scar tissue: fibrosis  Cellular proliferation This process is 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 on concurrent stimulation by progression factors (e.g., other growth factors) Indirectly in this manner, promotes the synthesis of collagen Synthesized by platelets and several other cell Epidermal growth factor (EGF) Promotes the growth of endothelial cells and fibroblasts, as well as epithelial cells Transforming growth factors (TGFs) is similar to EGF growth inhibitor for many cell types and aid in modulating the repair process chemotactic factor for macrophages and fibroblasts  Cellular proliferation This process is mediated by an assemblage of growth factors Fibroblast growth factors synthesis of extracellular matrix protein (including fibronectin) by fibroblasts, endothelial cells, monocytes, and other cells Fibronectin It is chemotactic for fibroblasts and endothelial cells It links other extracellular matrix components (e.g., collagen and proteoglycans) and macromolecules (e.g., fibrin and heparin) Macrophage-derived growth factors (IL-1 and TNF) promote the proliferation of fibroblasts, smooth muscle cells, and endothelial cells  Repair process (A) Inflammation (B) Proliferation of epithelial cells; formation of granulation tissue by vessel growth and proliferating fibroblasts (C) Remodeling to produce the fibrous scar  Repair of damaged tissues: scar formation Scar formation If a repair cannot be accomplished by regeneration alone repair by scarring occurs Scar formation is a response that “patches” rather than restores the tissue Examples Most often used in connection to wound healing in the skin Replacement of parenchymal cells in any tissue by collagen, as in the heart after myocardial infarction  Morphologic characteristics of granulation tissue Gross Pink, soft, granular gross appearance, seen beneath the scab or skin wound Microscopy Proliferation of fibroblasts ( deposit type III collagen) Angiogenesis: new capillaries (provide nutrients) Myofibroblasts (contract wound) Angiogenesis Development of collateral circulations at sites of ischemia Allowing tumors to increase in size beyond the constraints of their original blood supply  Angiogenesis and Tissue repair Healing at sites of injury Development of collateral circulations at sites of ischemia Allowing tumors to increase in size beyond the constraints of their original blood supply Notch signaling “cross-talk” with Vascular endothelial growth factor (VEGF) regulates the sprouting and branching of new vessels and thus ensures that the new vessels that are formed have the proper spacing to effectively supply the healing tissue with blood In tissue repair, angiogenesis occurs mainly by the sprouting of new vessels Morphologic characteristics of a fibrous Scar Morphologic characteristics of a fibrous scar Macrophages: secrete cytokines to simulate the proliferation of fibroblast Collagen deposition Type III collagen is replaced with type I collagen Microscopy Inactive, spindle-shaped fibroblasts Dense collagen Elastic tissue, and other ECM components  Granulation tissue and fibrous scar: Microscopy (A) Granulation tissue showing numerous blood vessels, edema, and a loose extracellular matrix containing occasional inflammatory cells (B) Collagen is stained blue by the trichrome stain. Trichrome stain of mature scar, showing dense collagen (stained blue) and scattered vascular channels  Selected clinical examples: Healing of skin wounds Factors influencing the healing of skin wounds Nature and size of the wound Healing by first intention: primary union Epithelial regeneration with minimal scarring, as in well-apposed surgical incisions Healing by second intention: secondary union This repair process involves a combination of regeneration and scarring Large wounds Abscesses Ulceration Ischemic necrosis (infarction) in parenchymal organs  Selected Clinical Examples: Healing of skin wounds Steps in wound healing by first intention (left) and second intention (right). In the latter, note a large amount of granulation tissue and wound contraction  Factors that impair tissue repair: aberrant wound healing Nutritional status Protein malnutrition ↓ vitamin C deficiency inhibit collagen synthesis and retard the healing Cofactor in the hydroxylation of proline and lysine procollagen residues Important in collagen cross-linking Copper is a cofactor for lysyl oxidase cross-links lysine and hydroxylysine to form stable collagen Zinc is a cofactor for collagenase Replaces the type III collagen of granulation tissue with stronger type I collagen  Factors that impair tissue repair: aberrant wound healing Persistent infection S. aureus Metabolic disorders Diabetes Mellitus Glucocorticoids (steroids) anti-inflammatory effects, they inhibit TGF-β production and diminish fibrosis Mechanical factors Increased local pressure or torsion may cause wounds to pull apart (dehisce) Poor perfusion Arteriosclerosis Foreign bodies  Defects in Healing: Chronic Wounds Clinical examples of abnormal wound healing and scarring Healing by second intention (secondary union) Healing of skin ulcers  Abnormalities in tissue repair Excessive Scarring: hypertrophic scars and keloids Hypertrophic scar is contained to the original wound and may regress over time Keloids Scar that grows beyond the original biopsy/wound site Often erythematous, pruritic lesions ↑risk: African American patients Most common in patients < 30 years Typically follows ear piercing or other trauma by a few months  Abnormalities in tissue repair: excessive scarring: keloid Etiology Idiopathic Fibroblasts from keloids show ↓ apoptosis Many cytokines implicated in stimulating fibroblasts, including TGF-β and IL-15 Genetic influence is likely This patient shows a very large and disfiguring ear lobe keloid. Areas of scar and skin atrophy can be seen on the surface. Previous trauma (ear piercing) is a common reported finding  Excessive scarring: fibrosis in parenchymal organs Definition Excessive deposition of collagen and other ECM components in a tissue Fibrosis most often refers to the abnormal deposition of collagen that occurs in internal organs in chronic diseases Clinical consequences It may be responsible for substantial organ dysfunction and even organ failure Excessive scarring: fibrosis in parenchymal organs