Responses to Injury and Inflammation Lecture Notes PDF

# **Responses to Injury and Inflammation** ## **I. Control of Normal Cell Proliferation** ### A. Regeneration and repair ### B. Stem cells: biology & therapeutic applications ### C. Cell cycle and regulation of cell replication ### D. Growth factors and signaling mechanisms ## **II. Mechanisms of...

# **Responses to Injury and Inflammation** ## **I. Control of Normal Cell Proliferation** ### A. Regeneration and repair ### B. Stem cells: biology & therapeutic applications ### C. Cell cycle and regulation of cell replication ### D. Growth factors and signaling mechanisms ## **II. Mechanisms of Tissue and Organ Regeneration** ## **III. Extracellular Matrix and Cell-Matrix Interactions** ## **IV. Repair of Tissues After Injury** ### A. Angiogenesis and fibrosis ### B. Normal wound healing in the skin ### C. Local and systemic factors influencing wound healing ### D. Pathologic repair ## **Tissue Repair by Fibrosis** - Why fibrosis? Severe or chronic tissue damage alters cells and ECM of organ, such that repair cannot be accomplished by regeneration of parenchymal cells only. Fibrosis fills the “gaps” in injured tissues that are not replaced by regenerating cells. - Fibrosis is repair by deposition of collagen and ECM components = "scar” ### **Processes Involved in Tissue Repair by Fibrosis:** 1. Induction of inflammation (removes dead or damaged cells) 2. Formation of new blood vessels (angiogenesis) 3. Migration and proliferation of fibroblasts 4. Scar formation 5. Connective tissue remodeling ## **Direct Observation of Fibrous Repair** ### **A. Angiogenesis: 2 Mechanisms ** - **Angiogenesis:** Formation of new blood vessels after infancy. - **Angioblast:** Embryonic precursor of endothelial cells, pericytes, vascular smooth muscle cells #### **Mechanism A:** Sprouting new vessels from pre-existing vessels #### **Mechanism B:** Angioblast-like endothelial-precursor cells (EPCs) recruited from bone marrow, homing to site of angiogenesis. ## **Angiogenesis** - A series of four images illustrating the process of angiogenesis. ## **Tissue Repair by Fibrosis** ### **Processes Involved in Tissue Repair by Fibrosis:** 1. Induction of inflammation (removes dead or damaged cells) 2. Formation of new blood vessels (angiogenesis) 3. Migration and proliferation of fibroblasts 4. Deposition of extracellular matrix 5. Connective tissue remodeling ## **Fibrosis: 3 Sequential Phases** ### **Phase 1: Migration & Proliferation of Fibroblasts** - Fibroblasts migrate into injured tissue and replicate. - Proliferation is stimulated by growth factors secreted by macrophages (main source), activated endothelial cells, and platelets: TGF-beta, PDGF, EGF, FGF ; cytokines IL-1 and TNF. ### **Phase 2: Deposition of Extracellular Matrix** - Fibroblasts become less mitotic and more synthetic. - Collagen synthesis begins 3-7 days post-injury and continues for weeks. ### **Phase 3: Maturation and Remodeling** - Balance between ECM synthesis and degradation - Decreasing vascularity and fibroblast proliferation - Increasing collagen synthesis and cross-linking: fibrosis gradually acquires tensile strength ## **Histology of Early & Late Repair: Balance of Angiogenesis & Fibrosis** - Early response (3-7 days): Granulation tissue, proliferating capillaries & fibroblasts with minimal mature collagen. - Late response (> 4 weeks): Fibrosis, Mature collagen dominates the picture, with decreased vessel density. ## **I. Control of Normal Cell Proliferation** ### A. Regeneration and repair ### B. Stem cells: biology & therapeutic applications ### C. Cell cycle and regulation of cell replication ### D. Growth factors and signaling mechanisms ## **II. Mechanisms of Tissue and Organ Regeneration** ## **III. Extracellular Matrix and Cell-Matrix Interactions** ## **IV. Repair of Tissues After Injury** ### A. Angiogenesis and fibrosis ### B. Normal wound healing in the skin ### C. Local and systemic factors influencing wound healing ### D. Pathologic repair ## **Wound Healing** 1. Healing by first intention, or primary union 2. Healing by second intention, or secondary union ## **Wound Healing by Primary Union (First Intention)** - First intention: Wound damages few keratinocytes and dermal cells, disrupts short segment of basement membrane. - Example: Surgical incision. - Result: Thin fibrous union. ## **Healing by Secondary Union (Second Intention)** - Second intention: Wounds that create a large defect. - Healing requires: More inflammation, larger volume granulation tissue, more collagen deposition, wound contraction. - Example: Deep traumatic abrasion. - Result: Wide scar, often with skin depression, or wound contraction. ## **3 Phases of Wound Healing in Skin** - **Inflammation:** Clot formation, chemotaxis. - **Proliferation:** Re-epithelialization, angiogenesis and granulation tissues, provisional matrix. - **Maturation:** Collagen deposition, collagen matrix, wound contraction ## **Application: Surgical Closure of Wounds** ### **Goal of Suturing Wounds:** Restore normal anatomic relationships to minimize size of the defect that will be filled by granulation tissue and subsequent fibrosis. - **Left:** Simple suture closing a superficial - **Right:** Subcuticular suture approximating edges of dermis in a deep clean laceration. ## **Phases of Wound Healing and Wound Strength** - **Inflammation:** Fibronectin, Collagent II - **Proliferation:** Collagen I - **Maturation:** Wound breaking strength - Beyond 10 days, accumulation of collagen type I and remodeling control wound healing. - At 10 days, wound strength is 10% of normal, but increases to 70-80% of normal by 3 months. ## **IV. Repair of Tissues After Injury** ### A. Angiogenesis and fibrosis ### B. Normal wound healing in the skin ### C. Local and systemic factors influencing wound healing ### **D. Pathologic repair ** ## **Systemic Factors Influencing Wound Healing** | Factor | Effect | |-----------------|:---------------------------------------------------------------------------------------------------| | Nutrition | **Profound effect:** Deficiencies of protein and vitamin C deficiency inhibit collagen synthesis | | Metabolic status | Diabetes mellitus delays healing (insulin necessary for nucleic acid & protein synthesis) | | Circulatory status | Inadequate blood supply slows healing; arterial atherosclerosis (limiting the inflow of arterial blood) or venous stasis (limiting outflow) | | Steroid hormones | Glucocorticoids inhibit wound healing, but can be beneficial in certain locations, e.g., the eye. | ## **Local Factors Influencing Wound Healing** | Factor | Effect | |----------------|:---------------------------------------------------------------------------------------------------------------------| | Infection | Persistent inflammation; single most important cause of delayed healing | | Mechanical | Early tension applied to wound may separate edges, delaying wound healing | | Foreign bodies | Fragments of metal, glass, wood, bone: prolong the inflammatory response and inhibit healing | | Anatomic location | Sites with rich vascularity (e.g., face) heal faster than sites with reduced vascularity (e.g., foot) | | Type of wound | Sharp incisions (e.g., surgical) heal faster than larger wounds (e.g., traumatic deep abrasion) | ## **IV. Repair of Tissues After Injury** ### A. Angiogenesis and fibrosis ### B. Normal wound healing in the skin ### C. Local and systemic factors influencing wound healing ### **D. Pathologic repair ** ## **Pathologic Wound Repair: Spectrum** - **Deficient scar formation due to:** - **a) Wound dehiscence:** Separation of wound edges due to mechanical forces, e.g., vomiting or coughing after abdominal surgical incision - **b) Wound necrosis:** Infection vs. Inadequate blood supply - **Excessive repair: Hypertrophic scar or keloid** - **Contracture formation:** Deformity of tissues due to excessive or exaggerated wound contraction ## **Deficient Scar Formation: Chronic Ulceration** - Chronic ulcer associated with arterial atherosclerosis and compromised inflow. - Chronic ulcer associated with venous stasis. ## **Hypertrophic Scar (Keloid)** - Keloid formation has a genetic predisposition; more common in African-Americans. - Keloid: Excess deposition of abnormally thick bundles of collagen in dermis. ## **Wound Contracture, Post-Burn** - Occur in large surface wounds that heal by secondary union - Mechanism: Network of myofibroblasts at edges of wound, contracting tissues and producing excess ECM. ## **Summary: Responses After Injury & Inflammation** - **Injury** - **Cellular and vascular response** - **Stimulus removed (acute injury)** - Parenchymal cell death (intact tissue framework) - Superficial wounds - Some inflammatory processes - **Regeneration:** Restitution of normal structure (Liver regeneration after partial hepatectomy, superficial skin wounds, etc.) - **Persistent tissue damage** - Parenchymal cell death (damaged tissue framework) - Deep wounds - **Repair:** Scar formation (deep excisional wounds, myocardium infarction, etc.) - **Fibrosis:** Tissue scar (chronic inflammatory diseases: cirrhosis, etc). ## **Summary: Fibrosis Associated With Chronic Inflammation** - **Persistent stimulus (chronic inflammation)** - **Activation of macrophages and lymphocytes** - **Growth factors (PDGF, FGF, TGF-β)** - **Cytokines (TNF, IL-1, IL-4, IL-13)** - **Decreased metalloproteinase activity ** - **Proliferation of fibroblasts, endothelial cells, and specialized fibrogenic cells** - **Increased collagen synthesis** - **Decreased collagen degradation** - **FIBROSIS** ## **Thank You**