Inflammation and Repair Past Paper 2024 - ParaMed PDF

1 119 3 IL-6 IL-2 TNF-α IFN-γ... 4 5 Overview of inflammation: Definitions & general features* The purpose of inflammation 1. To isolate, neutralize & destroy invading & harmful agents. 2. To limit the spread of harmful a...

1 119 3 IL-6 IL-2 TNF-α IFN-γ... 4 5 Overview of inflammation: Definitions & general features* The purpose of inflammation 1. To isolate, neutralize & destroy invading & harmful agents. 2. To limit the spread of harmful agents to other tissue. 3. To prepare any damaged tissue for repair. 6 Overview of inflammation: Definitions & general features* Inflammation↓ Protective response → Survival Inflammation (response/duration)↑ -Infections would go unchecked → Disease -Wounds would never heal -Injured tissues → Permanent festering sores -Atherosclerosis, obesity, diabetes mellitus, autoimmune diseases, allergic ❑ Leukemias & metastatic tumors, & suppression disorders, vasculitis, hepatitis, arthritis, of the marrow by therapies for cancer & glomerulonephritis, inflammatory bowel graft rejection → Leukocyte deficiency disease, cancer… ❑ Immunodeficiency diseases… Notes: Examples of words in –itis Hepatitis = Inflammation of the liver Appendicitis = Inflammation of the appendix Vasculitis = Inflammation of the vasculature Nephritis = Inflammation of the kidney 7 Overview of inflammation: Definitions & general features* The typical inflammatory reaction (“the five Rs”) Regulation & terminate develops through a series of sequential steps: ❑ The offending agent, which is located in extravascular Offending agents → Tissue tissues, is recognized by host cells & molecules. Recognize by host ❑ Leukocytes & plasma proteins are recruited from the cells & molecules circulation to the site where the offending agent is located. Leukocytes & plasma proteins ❑ The leukocytes & proteins are activated & work together to destroy & eliminate the offending substance Recruit → The site (= remove). (= offending agents) ❑ The reaction is regulated & terminated. Activate & Work ❑ The damaged tissue is repaired. together Removal of offending substances Damaged tissue → Repair 8 Overview of inflammation** Monocyte Lymphocyte Neutrophils Fundamental properties 9 10 Acute inflammation Cellular reactions Chemotaxis of leukocytes Nature of leukocyte infiltrates in inflammatory reactions Neutrophils predominate in the inflammatory infiltrate during the first 6 to 24 h → Replace by monocytes in 24 to 48 h ??? Neutrophils ❑ Number (in blood) > Other leukocytes ❑ They respond more rapidly to chemokines ❑ They may attach more firmly to the adhesion molecules that are rapidly induced on ECs ❑ After entering tissues, neutrophils are short-lived (apoptosis & disappear within 24 to 48 h). Monocytes ❑ They survive longer ❑ They proliferate in the tissues Exceptions !!! ❑ Pseudomonas bacteria = Continuously recruited neutrophils for several day ❑ Virus Lymphocytes = First cells to arrive ❑ Allergic reactions Eosinophils = Main cell type 11 Overview of inflammation Fundamental properties 12 Overview of inflammation Fundamental properties Harmful consequences of inflammation ❑Misdirection (e.g., against self tissues in autoimmune diseases) ❑ Occurs against normally harmless environmental substances (e.g., in allergies) ❑ Inadequate control Disorders Cells & molecules involved in injury Acute Acute respiratory distress syndrome Neutrophils Asthma Eosinophils; IgE antibodies Glomerulonephritis Antibodies & complement; neutrophils, monocytes Septic shock Cytokines Chronic Arthritis Lymphocytes, macrophages; antibodies? Asthma Eosinophils; IgE antibodies Atherosclerosis Macrophages; lymphocytes Pulmonary fibrosis Macrophages; fibroblasts 13  Overview of inflammation Fundamental properties Termination of inflammation ❑ Inflammation is terminated when the offending agent is eliminated -Mediators = Broke down + dissipate → Short life spans -Leukocytes = Short life spans in tissues -Antiinflammatory mechanisms↑ Initiation of tissue repair ❑ Eliminate the offending agents → Tissue repair/healing Repair = A series of events that heal damaged tissue 1) Regeneration = Proliferation of residual (uninjured) cells + Maturation of tissue stem cells 2) Scar formation = Filling of residual defects with connective tissue (CNT) 14 Overview of inflammation Causes of inflammation 1. Infections (bacterial, viral, fungal, parasitic) & microbial toxins Burns The most common & medically important causes of inflammation 2. Tissue necrosis Ischemia, trauma, physical & chemical injury (burns, frostbite, irradiation…) Frostbite 3. Foreign bodies Splinters, dirt, sutures… → Themselves/ traumatic tissue injury /carry microbes 4. Immune reactions Directed against self Ags → Autoimmune diseases Inappropriate reactions against environmental substances, Sutures → Allergies Inappropriate reactions against microbes Infection Splinters Dirt Allergies 15 Overview of inflammation Recognition of offending agents = The 1st step in all inflammatory reaction Cellular receptors for microbes Receptors: plasma membrane (for extracellular microbes), endosomes (for ingested microbes) & cytosol (for intracellular microbes) = The family of Toll-like receptors (TLRs) TLRs (Epithelial cells, dendritic cells, macrophages, other leukocytes…) → Engagement of these receptors → Production of adhesion molecules, cytokines & other mediators Sensors of cell damage Cell damage → Molecules are liberated /altered Uric acid (= a product of DNA breakdown) ATP (Damaged mitochondria) Intracellular K+ concentrations↓ (plasma membrane injury → Loss of ion) Production of interleukin-1 (IL-1) Recognize by cytosolic receptors Recruits leukocytes → Inflammation Activate a multiprotein cytosolic complex (inflammasome) 16 Overview of inflammation Recognition of offending agents Sensors of microbes & dead cells: Phagocytes, dendritic cells, & many types of epithelial cells express different classes of receptors that sense the presence of microbes and dead cells. A, Toll-like receptors (TLRs) located in the plasma membrane & endosomes & other cytoplasmic and plasma membrane receptors (members of families other than TLRs) recognize products of different classes of microbes. B, The inflammasome is a protein complex that recognizes products of dead cells & some microbes and induces the secretion of biologically active interleukin-1 (IL-1). 17 Overview of acute inflammation* Causes: Infection, trauma, physical & chemical agents, necrosis, foreign bodies & immune reactions 18 Overview of acute inflammation* Major components: 19 Overview of acute inflammation* The morphologic hallmarks of acute inflammation 1. Dilation of small blood vessels 2. Accumulation of leukocytes in the extravascular tissue 3. Accumulation of fluid in the extravascular tissue Formation of the acute inflammatory exudate. Early vascular changes (HP). N = Neutrophil 20 Overview of acute inflammation* Cardinal signs of inflammation 21 22 Acute inflammation Vascular reactions Interstitial colloid Interstitial hydrostatic osmotic pressure pressure = 0 Capillary hydrostatic Plasma proteins pressure Capillary colloid osmotic pressure Interstitial fluid 23 Acute inflammation* Vascular reactions ❑ Pus/purulent exudate = Inflammatory exudate rich in leukocytes (neutrophils…), the debris of dead cells & microbes Edema 24 Acute inflammation* Vascular reactions Mediators (histamine, prostacyclin/PGI2, nitric oxide/NO…) Vascular smooth muscle cells (SMCs) Arteriolar vasodilation Opening of new capillary beds Capillary hydrostatic Blood flow↑ pressure↑ Edema Heat+Redness (erythema) 25 26 Acute inflammation* Vascular reactions 1.Changes in vascular flow & caliber 2) Vascular permeability (vascular leakage)↑ Delayed prolonged leakage (burns, Histamine UV/irradiation & bacterial toxins) Bradykinin Leakage begins after a delay of 2 to 12 hours Leukotrienes… & lasts for several hours/even days Severe injury (burns), 1. Endothelial infections, neutrophils… contraction Postcapillary venules = Most common 2. Endothelial injury Vascular endothelial Venules, capillaries & growth factor (VEGF). … Immediate-transient arterioles response, short lived (15-30 minutes) 3. Transcytosis Immediate → Sustain (transport of fluids & (several hours) → proteins → Intracellular Interendothelial Thrombosis & repair channels → ECs) spaces↑ EC necrosis & detachment Interstitial colloid Permeability ↑ osmotic pressure↑ Edema Capillary colloid Protein-rich fluid → Extravascular tissues osmotic pressure↓ 27 Acute inflammation Vascular reactions 1.Changes in vascular flow & caliber 3) Stasis (engorgement of small vessels with slowly moving red cells) Loss of fluid + Vessel diameter↑ -Slower blood flow -Concentration of red cells in small vessels -Viscosity of the blood↑ Begin to accumulation of leukocytes Stasis (principally neutrophils) Vascular congestion Localized redness Accumulate along the endothelium ECs = Activation + Adhesion molecules ↑ Sites of infection/tissue damage → Mediators 28 29 Acute inflammation* Cellular reactions ❑ The recruitment (journey of) of leukocytes from the vascular lumen to the extravascular space 30 Acute inflammation* Cellular reactions 1. Margination Normal: Smaller red cells (central axial column) tend to move faster than the larger white cells (peripheral position) Stasis Rouleaux Opportunity to interact with lining ECs↑ Margination = Process of leukocyte accumulation at the periphery of vessels 31 Acute inflammation* Cellular reactions 2. Rolling Margination Rolling = Adhere (bind) transiently to the endothelium (selectins) → Flowing blood → Detach → Bind → “Rolling” Slow down the leukocytes + The Opportunity to bind more firmly to the endothelium 32 Acute inflammation* Cellular reactions 3. Firm adhesion/pavementing = Tight, constant contact of white blood cells with endothelium. Chemokines Cytokines Integrins (leukocyte cell surfaces) Ligands on ECs (ICAM, VCAM…) Integrin affinity↑ + Expression of integrin ligands ↑ Firm integrin-mediated binding of the leukocytes to the endothelium Leukocytes stop rolling ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesion molecule. 33 Acute inflammation* Cellular reactions 4.Transmigration/diapedesis = Migration of the leukocytes through the endothelium. ❑ Occurs mainly in postcapillary venules. Chemokines Act on the adherent leukocytes & stimulate the cells to migrate through interendothelial spaces toward the chemical concentration gradient. → Site of injury/infection CD31/PECAM-1 (ECs & leukocytes) Vascular basement membrane Leukocytes to traverse the endothelium Leukocytes → Collagenases → Vascular basement membrane Accumulation PECAM-1, platelet endothelial cell adhesion molecule. 34 Acute inflammation* Cellular reactions Chemotaxis of leukocytes = After extravasating from the blood, leukocytes move toward sites of infection or injury along a chemical gradient. Vascular basement membrane Moving leukocyte in culture showing a filopodium (upper left) 35 Acute inflammation* Cellular reactions Chemotaxis of leukocytes 1) Exogenous chemoattractants Bacterial products -Peptides with N-formylmethionine termini -Some lipids 2) Endogenous chemoattractants C5a, Leukotriene B4 (LTB4), IL-8… Chemoattractants + Recptors (leukocytes) Assembly of cytoskeletal contractile elements (actin & myosin) Move by extending filopodia [Chemoattractants]↑ 36 37 Acute inflammation Cellular reactions Leukocyte activation = Once leukocytes have been recruited to the site of infection or tissue necrosis, they must be activated to perform their functions 1. Recognition of the offending agents by TLRs & other receptors 2. Receptors → Signals → Activate the leukocytes to phagocytose & destroy the offending agents Leukocyte activation. Different classes of cell surface receptors of leukocytes recognize different stimuli IFN-γ, Interferon-γ; LPS, lipopolysaccharide 38 Acute inflammation Cellular reactions Leukocyte activation: Phagocytosis (1) Recognition & attachment of the particle to be ingested by the leukocyte (2) Engulfment (pseudopods) → Formation of a phagocytic vacuole Phagosome → Lysosome = Phagolysosome (3) Killing or degradation of the ingested material. -Lysosomal enzymes (lysozymes) -Reactive oxygen & nitrogen species (ROS & RNS) NO, nitric oxide; iNOS, inducible NO synthase; ROS, reactive oxygen species. 39 Acute inflammation* Mediators of inflammation = The substances that initiate & regulate inflammatory reactions. ❑ They are either secreted by cells or generated from plasma proteins 1) Cell-derived mediators 1.1) Intracellular granules → Granule exocytosis (e.g., histamine in mast cell granules) 1.2) They are synthesized de novo (e.g., prostaglandins & leukotrienes, cytokines) 2) Plasma-derived mediators (e.g., complement proteins) -They are produced mainly in the liver -They are present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties. 40 Acute inflammation Mediators of inflammation 1. Vasoactive amines: Histamine & serotonin ❑ They have important actions on blood vessels Trauma, heat, IgE, Anaphylatoxins (C3a & C5a), Substance P, IL-1, IL-8… Platelets, neurons, enterochromaffin cells… Mast cells, basophils, platelets… Serotonin (5-hydroxytryptamine) Histamine Vasoconstriction during clotting H1 receptor Dilation of Permeability of arterioles venules↑ 41  Acute inflammation* Cellular reactions 2. Arachidonic acid (AA) metabolites: Prostaglandins & leukotrienes ❑ AA-derived mediators = Eicosanoids (they are derived Mechanical, chemical & from 20-carbon fatty acids; Greek eicosa = 20) + physical stimuli or other mediators (e.g., C5a) 1) Cyclooxygenase (COX) pathway → Prostaglandins (PGs) 2) Lipoxygenase pathway → Leukotrienes (LTs), Lipoxins ❑ Mast cells, macrophages, ECs… → PGs ❑ Leukocytes, mast cells… → LTs ❑ Leukocytes → Lipoxins COX-1, COX-2, Cyclooxygenase 1 and 2; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid 42 Acute inflammation* Mediators of inflammation 3. Cytokines & chemokines Cytokines = Proteins produced by many cell types (activated lymphocytes, macrophages, dendritic cells, ECs, epithelial cells & CNT cells..) that mediate & regulate immune & inflammatory reactions. TNF IFN-γ Chronic inflammation IL-1 Cytokines IL-12 TNF, tumor necrosis factor; IL, Interleukin; Acute IFN-γ, interferon-γ inflammation IL-6 IL-17 Chemokines = A family of small (8 to 10 kD) proteins that act primarily as chemoattractants for specific types of leukocytes. = A group of chemoattractant cytokines IL-8 MCP-1 Lymphotactin Chemokines MCP-1, monocyte chemoattractant protein; MIP-1α, macrophage inflammatory protein-1α; RANTES, regulated and normal T-cell expressed Eotaxin RANTES and secreted MIP-1α 43 Acute inflammation Mediators of inflammation 3. Cytokines & chemokines ❑ Cytokines in inflammation Cytokine Principal sources Principal actions in inflammation In Acute Inflammation TNF Macrophages, mast cells, T Stimulates expression of endothelial lymphocytes adhesion molecules & secretion of other cytokines; systemic effects IL-1 Macrophages, endothelial cells, some Similar to TNF; greater role in fever epithelial cells IL-6 Macrophages, other cells Systemic effects (acute phase response) Chemokines Macrophages, endothelial cells, T Recruitment of leukocytes to sites of lymphocytes, mast cells, other cell inflammation; migration of cells in types normal tissues IL-17 T lymphocytes Recruitment of neutrophils and monocytes In Chronic Inflammation IL-12 Dendritic cells, macrophages Increased production of IFN-γ IFN-γ T lymphocytes, NK cells Activation of macrophages (increased ability to kill microbes & tumor cells) IL-17 T lymphocytes Recruitment of neutrophils & monocytes IFN-γ, Interferon-γ; IL-1, interleukin-1; NK cells, natural killer cells; TNF, tumor necrosis factor. 44 Acute inflammation Mediators of inflammation 3. Cytokines & chemokines ❑ Major roles of cytokines in acute inflammation 45 Acute inflammation Mediators of inflammation 4. Complement system ❑ A collection of soluble proteins/complement proteins (C1-C9) & membrane receptors that function mainly in host defense against microbes & in pathologic inflammatory reactions Inactive forms in the plasma → Proteolytic enzymes → Active forms Triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex polysaccharides, cobra venom, and other substances, in the absence of antibody Fixation of C1 to antibody Mannose-binding lectin binds to carbohydrates on microbes 46 47 Acute inflammation* Special morphologic patterns of acute inflammation Serous inflammation = The exudation of cell-poor fluid into spaces created by cell injury or into body cavities lined by the peritoneum, pleura, or pericardium Serous inflammation. Low-power view of a cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion. 48 Acute inflammation* Special morphologic patterns of acute inflammation Fibrinous inflammation = With greater increase in vascular permeability, large molecules such as fibrinogen pass out of the blood, and fibrin is formed and deposited in the extracellular space. ❑ Fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum. Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P). 49 Acute inflammation* Special morphologic patterns of acute inflammation Purulent (suppurative) inflammation, abscess = The production of pus, an exudate consisting of neutrophils, the liquefied debris of necrotic cells, & edema fluid ❑ The most frequent cause of purulent (also called suppurative ) inflammation is infection with bacteria that cause liquefactive tissue necrosis, such as staphylococci; these pathogens are referred to as pyogenic (pus-producing) bacteria Purulent inflammation. A, Multiple bacterial abscesses (arrows) in the lung in a case of bronchopneumonia. B, The abscess contains neutrophils & cellular debris, & is surrounded by congested blood vessel. 50 Acute inflammation* Special morphologic patterns of acute inflammation Ulcer = An ulcer is a local defect, or excavation, of the surface of an organ or tissue that is produced by the sloughing (shedding) of inflamed necrotic tissue. ❑ During the acute stage there is intense polymorphonuclear infiltration & vascular dilation in the margins of the defect. ❑ With chronicity, the margins and base of the ulcer develop fibroblastic proliferation, scarring, and the accumulation of lymphocytes, macrophages, & plasma cells The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section view of a duodenal ulcer crater with an acute inflammatory exudate in the base. 51 52 Overview of chronic inflammation* = A response of prolonged duration (weeks/months) in which inflammation, tissue injury & attempts at repair coexist, in varying combinations. ❑ It may follow acute inflammation. ❑ It may begin insidiously, as a low-grade, smoldering (= asymptomatic) response without any manifestations of a preceding acute reaction. 53  Overview of chronic inflammation Causes: 1) Persistent infections by microorganisms that are difficult to eradicate (bacteria, viruses, fungi & parasites). Mycobacteria → Mycobacterium tuberculosis Treponema pallidum → Syphilis Mycobacteria Treponema pallidum 2) Hypersensitivity diseases (excessive + inappropriate activation of the immune system) Rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, bronchial asthma… 3) Prolonged exposure to potentially toxic agents, (exogenous /endogenous) Particulate silica → Inflammatory lung disease (silicosis) Excessive production + tissue deposition of lipids → Atherosclerosis 4) Mild forms of chronic inflammation → Alzheimer disease, atherosclerosis, metabolic syndrome and the associated type 2 diabetes, cancer… 54 Overview of chronic inflammation* Morphologic features 1. Infiltration with mononuclear cells (macrophages, lymphocytes & plasma cells) 2. Tissue destruction, induced by the persistent offending agent/inflammatory cells 3. Attempts at healing [CNT + Fibrosis + Angiogenesis (small blood vessels↑) ] 55 Overview of chronic inflammation Morphologic features A, Chronic inflammation in the lung. (1) Collection of chronic inflammatory cells (*) (2) Destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads ) (3) Replacement by connective tissue (fibrosis, arrows ). B, In acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested. 56 Chronic inflammation* Chronic inflammatory cells & mediators Complex interactions between several cell populations & their secreted mediators 57 Chronic inflammation Chronic inflammatory cells & mediators 1. Role of macrophages ❑ The dominant cells of chronic inflammation ❑ Circulating blood monocytes → Transformation → Macrophages (tissue cells) ? Lifespan (months/years) + Capacity for phagocytosis > Blood monocytes (half-life ≈ 1 day) ❑ Filters → Particulate matter, microbes & senescent cells Effector cells → Eliminate microbes (cellular & humoral immune responses) 58 Chronic inflammation Chronic inflammatory cells & mediators 1. Role of macrophages T cells ❑ General functions: Ingest & eliminate microbes & dead tissues. T cells → Activate macrophages = The most important phagocytes in the cell- mediated arm of adaptive immune responses. T cells Initiate the process of tissue & other cells repair & are involved in scar formation & fibrosis. Two major pathways of macrophage activation Secrete inflammatory mediators (TNF, IL-1, chemokines, eicosanoids…) = Central to the initiation & propagation of all inflammatory reactions Display Ags to T cells & respond to signals from T cells → Against many microbes by cell-mediated immune responses 59 Chronic inflammation Chronic inflammatory cells & mediators 2. Role of lymphocytes ❑ They are mobilized in the setting of any specific immune stimulus (i.e., infections) as well as non–immune-mediated inflammation (e.g., due to ischemic necrosis or trauma), and are the major drivers of inflammation in many autoimmune & other chronic inflammatory diseases. ❑ Role of T cells: T H 1 cells → IFN-γ, → The classical pathway of macrophage activation T H 2 cells → IL-4, IL-5 & IL-13→ -Recruit & activate eosinophils responsible -The alternative pathway of macrophage activation. T H 17 cells → IL-17, TNF & other cytokines → Secretion of chemokines → Recruiting Neutrophils Monocytes neutrophils & monocytes into the reaction. Macrophage–lymphocyte interactions in chronic inflammation T H 1 & T H 17 cells → Fuel & sustain chronic inflammation -Defense against many types of & viruses -Autoimmune diseases T H 2 cells → -Defense against helminthic parasites -Allergic inflammation 60 Chronic inflammation* Important type of chronic inflammation: Granulomatous inflammation = Collections of activated macrophages, often with T lymphocytes & sometimes associated with central necrosis. Causes: Mycobacteria, fungi, immune-mediated inflammatory diseases (Crohn disease), sarcoidosis (unknown etiology), foreign bodies (suture, splinter, silica...).... Granuloma formation = A cellular attempt to contain an offending agent that is difficult to eradicate. Strong activation of T lymphocytes Macrophage activation Injury to normal tissues Activated macrophages → (1) Abundant cytoplasm → Epithelioid cells (large flat) (2) Fuse → Multinucleate giant cells (large mass of cytoplasm + many nuclei) Langhans giant cells = The nuclei are arranged in a coronate/horseshoe-shaped pattern 61 Chronic inflammation* Granulomatous inflammation Morphology ❑ Aggregates of epithelioid macrophages are surrounded by a collar of lymphocytes. ❑ Older granulomas may have a rim of fibroblasts & CNT. ❑ Multinucleate giant cells/Langhans giant cells ❑ Mycobacterium tuberculosis → Caseous necrosis (amorphous, structureless, eosinophilic, granular debris & loss of cellular details). ❑ Crohn disease, sarcoidosis & foreign body reactions tend to not have necrotic centers (= noncaseating) 62 Chronic inflammation Granulomatous inflammation Tuberculosis granuloma & giant multinucleated Multinucleated giant cells of the Langhans type. cell. 63 การเปลีย่ นแปลงทางโครงสร้างทัว่ ไปของ chronic 1. 2. 3. เซลล์อะไรที่เข้ามามีบทบาทได้................................................................................ Granuloma รอยโรคตัวอย่าง chronic มีองค์ประกอบหรือพยาธิ สภาพอย่างไร มีเซลล์........................................................................................................................... 64 Systemic effects of inflammation* The acute-phase response consists of several clinical & pathologic changes: NSAIDs (aspirin) 1. Fever (= Body temperature↑, 1° to 4°C) Exogenous pyrogens Leukocytes Endogenous pyrogens (bacterial products = LPS… ) (macrophage…) (IL-1,TNF-α… ) Reset the temperature Production of AA → COX set point at a higher level neurotransmitters Prostaglandins (hypothalamus) ( PGE 2…) Temperature-raising Core body temperature responses (vasoconstriction, reaches to new set point shivering, metabolism↑…) 65 Systemic effects of inflammation* The acute-phase response consists of several clinical & pathologic changes: 2. Production of acute-phase proteins (= Plasma proteins, mostly synthesized in the liver) Fibrinogen IL-6 Hepatocytes C-reactive protein (CRP) IL-1 Hepatocytes TNF Serum amyloid A (SAA) protein 3. Leukocytosis (= Increase in the number of leukocytes in the blood, especially during an infection) Prolonged Colony-stimulating Bone marrow output Compensation → The consumption infection factors (CSFs)↑ of leukocytes↑ of these cells in the inflammatory reaction Most bacterial infections Neutrophilia Bronchial asthma, hay fever & parasite Eosinophilia infestations 66 Systemic effects of inflammation* The acute-phase response consists of several clinical & pathologic changes: 4. Other manifestations of the acute-phase response -Pulse & blood pressure↑ -Redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin → Sweating↓ -Rigors (shivering), chills (search for warmth), anorexia, somnolence, malaise … 5. In severe bacterial infections (sepsis) → Shock Bacteria + their -DIC products↑ TNF, IL-1…↑ -Hypotensive shock Septic shock (blood) -Insulin resistance & hyperglycemia 67 68 69 Overview of tissue repair* 1.Regeneration = Some tissues are able to replace the damaged components & essentially return to a normal state ❑ Regeneration occurs by proliferation of cells that survive the injury & retain the capacity to proliferate, for example, in the rapidly dividing epithelia of the skin & intestines, & in some parenchymal organs, notably the liver. ❑ Tissue stem cells may contribute to the restoration of damaged tissues. 70 Overview of tissue repair* 71 Overview of tissue repair* Proliferation of uninjured cells Maturation of tissue stem cells CNT Mechanisms of tissue repair: regeneration and scar formation. Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation. 72 Tissue repair 73 74 Tissue repair Cell & tissue regeneration ❑ The regeneration of injured cells & tissues 1) Cell proliferation ← Growth factors/GFs (cells near the site of damage macrophages, epithelial cells, stromal cells…) & ECM 2) The integrity of the ECM 3) The development of mature cells from stem cells ❑ Several cell types proliferate during tissue repair. 3) Fibroblasts 1) Remnants of the 2) Vascular ECs injured tissue Fibrous tissue New vessels Restore normal structure Scar → Fill defect Nutrients → Repair process 75 Tissue repair* Repair by CNT Deposition Repair = Regeneration + Replacement of the injured cells with CNT → Scar formation Steps in scar formation Tissue injury & the inflammatory response → 1) Angiogenesis (= formation of new blood vessels) → nutrients & oxygen → The repair process Incomplete interendothelial junctions & VEGF → Vascular permeability↑ → Edema 2) Formation of granulation tissue (pink, soft & granular gross appearance). = Migration & proliferation of fibroblasts & deposition of loose CNT, together with the vessels (new thin-walled, delicate capillaries) & interspersed leukocytes (macrophage…) Formation of vascularized granulation tissue 3) Remodeling of CNT Maturation & reorganization of the CNT (remodeling) produce the stable fibrous scar. CNT in the granulation tissue↑ → Scar VEGFs, Vascular endothelial growth factors 76 77 Overview of tissue repair Important mediators in repair ❑ Epidermal growth factor (EGF): Stimulates granulation tissue formation. ❑ Vascular endothelial growth factor (VEGF): Induces blood vessel formation. ❑ Platelet-derived growth factor (PDGF): Promotes migration & proliferation of fibroblasts, smooth muscle cells, and monocytes. ❑ Fibroblast growth factor (FGF): Stimulates blood vessel formation and wound repair through macrophages, fibroblasts, and endothelial cell migration. ❑ Transforming growth factor beta (TGF-β): Synthesis of ECM↑ & degradation of ECM↓ 78 Tissue repair Factors that influence tissue repair ❑Tissue repair may be altered by a variety of influences, frequently reducing the quality or adequacy of the reparative process. Variables that modify healing may be extrinsic (e.g., infection) or intrinsic to the injured tissue, and systemic or local: ❑ Infection → Delay in healing & Local tissue injury ❑ Diabetes → Abnormal wound healing ❑ Nutritional status Vitamin C deficiency → Inhibits collagen synthesis & retards healing. ❑ Glucocorticoids (steroids) = Antiinflammatory effects, inhibition of TGF-β production → Weakness of the scar & fibrosis↓ ❑ Mechanical factors Local pressure /torsion↑ → Wounds to pull apart/dehisce 79 Tissue repair* Selected clinical examples of tissue repair & fibrosis ❑ Healing of skin wounds = Epithelial regeneration & formation of CNT scar 1) Healing by first intention/primary union = Healing of a wound that has clean edges, close reapproximation of margins & minimal tissue disruption. Example: Healing of surgical incision. Result: Small to nonexistent scar. 2) Healing by second intention/secondary union = Healing of a wound that has unclean edges, extensive tissue disruption & tissue necrosis. Example: Healing of a cutaneous ulcer or a large laceration inflicted by a blow from a baseball bat. Result: Larger, more prominent scar. 80 Tissue repair Selected clinical examples of tissue repair and fibrosis ❑ Primary union Wounding → Rapid activation of coagulation pathways = Stop bleeding & Scaffold for migrating cells Within 24 h: -Neutrophils → Incision margin → Clear the debris -Basal cells → Mitotic activity↑ Within 24-48 h: Epithelial cells → Migrate & Proliferate along the dermis By day 3: Macrophage+ Granulation tissue progressively invades the incision space By day 5: Neovascularization During the 2nd week: Continued collagen accumulation + Fibroblast proliferation. By the end of the 1st month: The scar comprises a cellular CNT largely devoid of inflammatory cells and covered by an essentially normal epidermis. 81 Tissue repair Selected clinical examples of tissue repair and fibrosis ❑ Secondary union -Inflammatory reaction is more intense -Development of abundant granulation tissue -Accumulation of ECM -Formation of a large scar -Wound contraction by the action of myofibroblasts 82 Tissue repair Healing of skin ulcers. A, Pressure ulcer of the skin, commonly found in diabetic patients. The histologic slides show a skin ulcer with a large gap between the edges of the lesion (B), a thin layer of epidermal reepithelialization & extensive granulation tissue formation in the dermis (C), and continuing reepithelialization of the epidermis & wound contraction (D). 83 Tissue repair* Abnormalities in tissue repair 1.Inadequate formation of granulation tissue/formation of a scar → Wound dehiscence & ulceration ❑ Dehiscence/rupture of a wound After abdominal surgery, abdominal pressure↑, vomiting, coughing... ❑ Inadequate vascularization during healing → Wounds ulceration Atherosclerotic peripheral vascular disease → ulcerate 84 Tissue repair* Abnormalities in tissue repair 2. Excessive formation of the components of the repair process → Hypertrophic scars & keloids ❑ Thermal/traumatic injury → Hypertrophic scars = The accumulation of excessive amounts of collagen → Scar 85 Tissue repair* Abnormalities in tissue repair 2. Excessive formation of the components of the repair process → Hypertrophic scars & keloids ❑ Keloids = If the scar tissue grows beyond the boundaries of the original wound & does not regress Keloid. A, Excess collagen deposition in the skin forming a raised scar known as keloid. B, Note the thick connective tissue deposition in the dermis. 86 87 119 Quiz time ??? 89  ถูกหรือผิดเกีย่ วกับกระบวนการอักเสบ??? 1. Recognition เป็ นหลัก “the five Rs”?............................. 2. Epithelial cell เกิดการ chemotaxis ไปกาจัดเชือ้ โรค?............................. 3. Pressure หรือ diabetic ulcer คือ แผลเป็ นขนาดใหญ่นนู เกิน?...................... 90 การเปลีย่ นแปลงของเซลล์ ใดมีบทบาทเด่ นใน acute inflammation ? A. T-cell B. Neutrophil C. Macrophage D. Lymphocyte E. I have no idea. 91 เซลล์ เม็ดเลือดขาวอาศัยโมเลกุลใดดังต่ อไปนี้ ใน กระบวนการ transmigration? A. Integrins B. Selectins C. CD & DVD D. Sealect tuna E. CD31 92 The image above shows a section from the skin of a 20 year-old patient with a burn blisters. Which process i illustrated? A. Fibrinous inflammation B. Sliced pork inflammation C. Purulent inflammation D. Serous inflammation E. Granulomatous inflammation 93 เซลล์ ใดที่พบในรอยโรค granuloma ได้ ? A. Multinucleate small cell B. Epithelioid cell C. Islets of Langerhans D. เซลล์เจ้าอาวาด with ที่คาดผม D. ถูกทุกข้อ 94 ข้ อใดดังต่ อไปนีเ้ ป็ นกระบวนการ regeneration ของเนื้อเยื่อ? A. การพัฒนาการของ stem cell B. การสร้าง connective tissue C. สร้าง keloid D. สร้าง scar E. สร้างปั ญญาเพื่อความเข้มแข็งของชุมชน 95 96