HSC2008 2024 Sep Injury and Inflammation PDF

SIT Internal Inflammation and Healing HSC2008 Pathophysiology & Pharmacology Ong Hwee Kuan Assoc Prof, HSS, SIT Senior Principal Physiotherapist, SGH  SIT Internal Content 1. Overview of Body defense system 2....

SIT Internal Inflammation and Healing HSC2008 Pathophysiology & Pharmacology Ong Hwee Kuan Assoc Prof, HSS, SIT Senior Principal Physiotherapist, SGH  SIT Internal Content 1. Overview of Body defense system 2. Cellular response to stress & injury 3. Phases of repair in acute wound 3.1 Haemostasis 3.2 Inflammation 3.3 Pharmacotherapy for inflammation 3.4 Proliferation 3.5 Remodelling 4. Irreversible injury 5. Summary  SIT Internal Body defense system Non-Specific (general) defense system Mechanical barrier Non-specific phagocytosis Inflammation Interferons Specific defense system Humoral immunity – mediated by macromolecules in extracellular fluids (e.g, unique antibodies, complement proteins) Cell-mediated immunity (sensitized lymphocytes) VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Cellular response to stress & injury Normal cell Reversible Injury (homeostasis) stress Injurious stimulus Mild transient Adaptation Cell Injury Inability Severe progressive to adapt Irreversible Injury Cell death Necrosis Apoptosis Lazaro RT & Burke-Doe (2014). Injury, inflammation, healing and repair. In C. Goodman & K. Fuller (Eds.), Pathology- Implications for the Physical Therapist (4th Ed) Saunders  SIT Internal Types of cellular adaptation Reduction in size Vascular insufficiency, malnutrition, immobilization, hormone level changes Bone loss, muscle wasting, brain cell loss Increase in number  functional demand in cells capable of dividing / hormonal stimulation Estrogen  uterus thickness, callus on skin Increase in size  functional demand Heart & muscle hypertrophy VanMeter, K. C., & Hubert, R. J. (2014). Cp 1 Introduction to Pathophysiology. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Types of cellular adaptation Change in morphology & function Smoke change the ciliated pseudostratified columnar epithelium  stratified squamous epithelium  in numbers & change in cell types Considered pre-neoplastic changes In chronically injured tissue New growth (uncontrolled cell division) Benign or Premalignant or Malignant (cancer) VanMeter, K. C., & Hubert, R. J. (2014). Cp 1 Introduction to Pathophysiology. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Causes of cell injury Ischemia or infarction Infection- microorganisms (bacteria, virus & parasites) Immune / allergic reactions Direct physical damage- thermal, mechanical pressure/ tear, radiation, electricity Chemical toxins – exogenous or endogenous Genetic factors Nutritional factors Fluid/ electrolyte imbalance Foreign bodies (e.g., splinter, glass) VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Phases of repair in acute wound healing 3 Cell Proliferation & Matrix deposition 2 Inflammation 4 matrix remodelling Four overlapping but well-defined phases 1. Haemostasis I Haemostasis 2. Inflammation 3. Proliferation 4. Remodelling http://www.worldwidewounds.com/2004/august/Enoch/images/enochfig1.jpg  SIT Internal 1. Haemostasis – clot formation to stop bleeding Endothelial injury Primary Haemostasis Platelet activation Platelet plug Secondary Haemostasis Coagulation cascade Fibrinogen  Fibrin 1:00-6:24 Hemostasis | Advanced hematologic system physiology | Health & Medicine | Khan Academy https://www.youtube.com/watch?v=rLIEeUP_e-Y  SIT Internal Phases of repair in acute wound healing 3 Cell Proliferation & Matrix deposition 2 Inflammation 4 matrix remodelling Four overlapping but well-defined phases 1. Haemostasis I Haemostasis 2. Inflammation 3. Proliferation 4. Remodelling http://www.worldwidewounds.com/2004/august/Enoch/images/enochfig1.jpg  SIT Internal Inflammation – “itis” A normal protective mechanism Important basic concept in pathophysiology AIM: to eliminate the initial cause of injury, the necrotic cells and tissue resulting from the original insult, and to initiate the process of repair Inflammatory response ceases when the injurious agent is removed NOT the same as infection. Inflammare (Latin): to set on fire VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Steps of Inflammatory response Bradykinin and histamine  capillary dilation ( flow) & permeability  redness/heat/swelling/pain Vascular event Cellular event Neutrophils & Macrophages leave the bloodstream by Tissue injury  release bradykinin  stim pain receptor chemotaxis  phagocytose Mast cell  release Histamine microbes Macrophage and Neutrophils  release Prostaglandins, Leukotrienes & chemotactic factors VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders. (Fig 5-2, p68)  SIT Internal Vascular event: Cardinal signs of acute inflammation Results of immediate vascular event post injury 1. Redness (Erythema) ( vasodilation) 2. Heat ( vasodilation) 3. Swelling ( cap permeability & protein leakage) 4. Pain ( pressure & nerve irritation by chemical mediators, esp bradykinin)  Loss of function Lazaro RT & Burke-Doe (2014). Injury, inflammation, healing and repair. In C. Goodman & K. Fuller (Eds.), Pathology- Implications for the Physical Therapist (4th Ed) Saunders  SIT Internal Cellular event 1. Exudate of fluid from blood vessel 2. Stasis: Engorgement of RBC in blood  vessel  / diapedesis 3. Margination: Leukocytes (WBC) accumulate & adhere to vessel wall Endothelial cells (through expression of adhesion molecules) Chemotaxis  4. Diapedesis: Oozing of WBC out of blood vessel 5. Chemotaxis: Directional migration of Order of WBCs First neutrophils (last 24hr) WBC to source of injury Monocytes & macrophages https://cdn.lupusnewstoday.com/wp-content/uploads/2015/06/shutterstock_242909029.jpg  SIT Internal Function of cellular elements in inflammatory response Tyles of cells Activity Leukocytes Neutrophils Phagocytosis of microorganisms (WBC) Basophils Release of histamine leading to inflammatory response Eosinophils Increase in allergic responses Lymphocytes T lymphocytes Active in cell mediated immune response B lymphocytes Produce antibodies Macrophages Matured monocytes that migrated into tissue from blood- active in phagocytosis VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders (Table 5-2, p70).  SIT Internal Goals of inflammation Inflammation is an early nonspecific response to tissue injury with 2 main goals 1. Eliminate the cause of injury Degradation & removal of necrotic tissue Neutrophils & macrophages 2. Initiate the repair process Secretion of chemical mediators and growth factors Inflammatory cells & Macrophages The growth factors are essential for cell division during the proliferative phase  SIT Internal Inflammation & Tissue repair 1. Bacteria & other pathogens enter wound 2. Platelets from blood release blood clotting proteins at wound site 3. Mast cells secrete factors that mediate vascular constriction and vasodilation.  Delivery of blood plasma, and cells to injured area 4. Neutrophils secrete factors that kill and degrade pathogens 5. Neutrophils and macrophages remove pathogens by phagocytosis 6. Macrophages secret hormones cytokines that attract immune system cells to the site and activate cellular tissue repair 7. Inflammatory response continue until the foreign material is eliminated and would is repaired https://thumbs.dreamstime.com/z/inflammation-tissue-repair-chemical-cellular-factors-involved- inflammatory-response-to-damage-created-adobe-62002173.jpg  SIT Internal Diagnostic test for Inflammation Can distinguish viral from bacterial infection Allergic reaction - eosinophils Pyogenic bacterial infection – neutrophils Viral infection - lymphocytes Parasitic infection – basophils Nonspecific changes of inflammation- unable to tell the cause or site of inflammation. Serve as screening / monitoring parameters Some are helpful in locating the site of necrotic cells (e.g, Isoezyme CK-MB specific for MI; ALT for liver) Some are not site specific: AST- elevated in both liver Dz & acute MI VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Local vs Systemic effects of inflammation Local Systemic Redness Low grade fever Heat Malaise (feeling unwell) Swelling Fatigue Pain Headache Anorexia (loss of appetite)  SIT Internal Acute vs. Chronic Inflammation Acute inflammation Chronic inflammation Sudden onset & short duration Follows acute episode of inflammation with continued tissue destruction Characteristics Exudation of fluid & plasma protein Characteristics (edema) Less swelling and exudate Migration of leukocytes (esp neutrophils) Presence of more lymphocytes, macrophages, and fibroblasts More severe/ on going tissue destruction More collagen & fibrous scar tissue VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Causes of chronic inflammation Persistent infection (e.g., Mycobacterium tuberculosis) Persistent indigestible material Endogenous e.g., necrotic bone, calcium and uric acid deposits Exogenous e.g., Asbestos, Silica, Immune mediated reactions Autoimmune reactions e.g., RA, SLE Organ transplant rejection Unregulated immune responses e.g., Inflammatory Bowel, ulcerative colitis Hypersensitivity reactions e.g., bronchial asthma Following an acute inflammation where the cause persist Repeated episodes of acute inflammation e.g., repeated acute pancreatitis / acute cholecystitis https://www.youtube.com/watch?v=Ie30O6zvEnk  SIT Internal Treatment of Inflammation ACUTE management R - rest I - Ice C - Compression E- Elevation VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Anti-inflammatory effects of NSAIDs : Cox-1 & Cox-2 pathway Mechanism: by inhibiting cyclooxygenase enzymes COX– 2 isoforms Normally Induced during present in inflammation Bilayer phospholipids most tissues of cell membrane Inflammation Advserse effect from COX-1 inhibition Desired NSAID s effect from COX-2 GI Bleeding Gastric ulcers inhibition Non selective COX inhibitors (Naproxen, Ibuprofen) Selective COX-2 inhibitors (Diclofenac, Etoricoxib)  SIT Internal Anti-inflammatory effects of NSAIDs : Cox-1 & Cox-2 pathway Mechanism: by inhibiting cyclooxygenase enzymes COX– 2 isoforms Bilayer phospholipids of cell membrane Inflammation Advserse effect from COX-1 inhibition Desired NSAID s effect from COX-2 GI Bleeding Gastric ulcers inhibition Non selective COX inhibitors (Naproxen, Ibuprofen) Selective COX-2 inhibitors (Diclofenac, Etoricoxib)  SIT Internal Pharmacological effects of NSAIDs Due to decrease synthesis of prostaglandin (PGE2, PGD2) that increase Anti inflammatory vasodilation Due to inhibition of COX-2 in the hypothalamus Anti pyretic IL-1 will stimulate PG in hypothalamus which leads to  body temperature Due to reduction in peripheral PG synthesis which sensitize nociceptors to Analgesic inflammatory mediators (e.g., bradykinin)  SIT Internal Anti-Inflammatory effects of Glucocorticoids Multiple modes of administration: PO, IM, IV, topical, inhalation, rectal, injection into joints Anti-inflammatory Mechanisms of GCS Inhibits NFkB  inhibits production of inflammatory cytokines, chemokines, adhesion molecules Inhibits Phospholipase A2 and Cox enzyme   production of PG, thromboxane (inflammatory mediators)  the transcription of anti-inflammatory proteins: lipocortin-1, IL-10, IL-1 receptor antagonist and neutral endopeptidase What Makes Corticosteroids so Beneficial? | Johns Hopkins https://www.youtube.com/watch?v=LuLNsDJGhvw  SIT Internal Mechanism of anti-inflammatory Action ASA Acetaminophen NSAID Glucocorticoids COX-2 Irreversibly inhibits Exact Competitive Inhibits NFkB Competitive COX-1 and COX- mechanism in inhibitors of COX- COX-2 inhibitor at 2 unknown 1 and COX-2 ↑ transcription of therapeutic dose anti-inflammatory Weakly selective has selective Both ibuprofen proteins IL-1 to COX-1 COX-2 inhibitor and naproxen receptor property are weakly antagonist, IL-10 selective to COX- 1  SIT Internal Common synthetic corticosteroid Features / potency Cortisone / Short-acting corticosteroids. half-life is 6-12 hours. Hydrocortisone Cortisone is a prodrug that is converted into hydrocortisone, or cortisol, in the liver. Prednisone/ Intermediate-acting drug. half-life is 12-36 hours. Prednisolone Prednisone is a pro drug processed in the liver to prednisolone (the active metabolite). Prednisolone are 5X more potent than hydrocortisone Dexamethasone Long-acting drug. half-life is 36-72 hours. 25X more potent than hydrocortisone Betamethasone A long-acting corticosteroid. half-life is 36-72 hours. Used topically to manage inflammatory skin conditions such as eczema, and parenterally to manage several disease states including autoimmune disorders.  SIT Internal Other effects of corticosteroid  inflammation Retain Na+  Blood sugar Corticosteroid Regulates  immunity metabolism  Ca  Serotonin absorption Pharmacology basic on Corticosteroid , https://youtu.be/aR-Z06L-F10 The Bad of Corticosteroids | Johns Hopkins, https://www.youtube.com/watch?v=lfQoqg-WizY  SIT Internal Therapeutic effects and side effects of glucocorticoids Atrophy of lymphoid tissue; reduced hemopoiesis  Anxiety http://tmedweb.tulane.edu/pharmwiki/doku.php/glucocorticoids (Adapted from Buttgereit et al, 2005).)  SIT Internal Therapeutic effects and side effects of glucocorticoids Atrophy of lymphoid tissue; reduced hemopoiesis  Anxiety http://tmedweb.tulane.edu/pharmwiki/doku.php/glucocorticoids (Adapted from Buttgereit et al, 2005).)  SIT Internal Phases of repair in acute wound healing 3 Cell Proliferation & 2 Inflammation Matrix deposition Four overlapping but well-defined phases 4 matrix remodelling 1. Haemostasis 2. Inflammation Fibroblast migration  collagen Angiogenesis 3. Proliferation Epithelialisation Granulation tissue formation I Haemostasis 4. Remodelling http://www.worldwidewounds.com/2004/august/Enoch/images/enochfig1.jpg  SIT Internal The 3 Rs of Healing Resolution Mild-moderate tissue damage & recover within a short period of time Regain original structure after healing (most ideal) Resolution happens in tissues that are capable of regeneration with intact extracellular matrix framework Regeneration Occurs in cells capable of mitosis (e.g., hepatocytes) Damaged tissue replaced by identical tissues from proliferation of nearby cells New replacement cells are functional No fibrosis / scaring Replacement In tissues that are unable to generate Functional tissue replaced by connective tissue scar tissue (except brain) Loss of function In many cases, tissue healing is achieved by both cell regeneration & replacement process VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders. More detail in med Today Youtube video: https://www.youtube.com/watch?v=G3B0ApUsYag  SIT Internal Types of healing according to regenerative capability Labile Tissues Stable Tissues Permanent Tissues Stem cells/ Undifferentiated cells Normally low proliferative activity Left the cell cycle and cannot proliferate Capable of division & replace the Can undergo division if stimulated damaged tissue following an injury Examples: Examples Examples: Skeletal & cardiac muscle (by fibrosis) Epithelia cells (skin, GI , Parenchymal tissue (kidney, liver, genitourinary tract) pancreas) Nervous tissue (heal by cavitation & not fibrosis) Hemopoietic tissues (bone marrow) Mesenchymal cells – fibroblasts, smooth muscle, vascular endothelium Unable to regenerate Able to regenerate Hence heal by fibrosis (scar tissue formation) https://www.youtube.com/watch?v=G3B0ApUsYag  SIT Internal Cell proliferation processes Formation of granulation tissue Collagen synthesis & laydown by fibroblasts Compose of proliferating capillaries, Starts within 3-5 days post injury & continues for fibroblasts & residual inflammatory cells weeks depending on wound size Metabolically active with angiogenesis With increasing collagen mass, the cellularity and and proliferation of fibroblasts vascularity reduces https://www.youtube.com/watch?v=G3B0ApUsYag  SIT Internal Key building blocks of tissue healings Fibronectin & proteoglycans Glycoprotein of the extracellular matrix Forming a scaffold that provide tensile strength Glue substances & cells together Elastin Cross-linking to form fibrils – provide elasticity to tissue Collagen Provide structural support & tensile strength Key determinant of the structural stability of extracellular matrix VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Phases of repair in acute wound healing 3 Cell Proliferation & Four overlapping but well-defined phases Matrix deposition 2 Inflammation 4 matrix remodelling 1. Haemostasis 2. Inflammation Formation of correct 3. Proliferation amount of collagen and extracellular matrix proteins 4. Remodelling I Haemostasis Parallel process of synthesis & degradation The degradation is primarily mediated by Matrix metalloproteinases (MMP) Early scar – Type III collagen Late scar – Type I collagen http://www.worldwidewounds.com/2004/august/Enoch/images/enochfig1.jpg  SIT Internal Factors affecting healing Promote healing Delay healing Youth Advanced age Good nutrition: protein, Vit A & C Poor nutrition, dehydration Adequate Hb Anemia Effective circulation Circulatory problems Clean, undisturbed wound Chronic disease or comorbidities (e.g DM, cancer No infection or further trauma Irritation, bleeding or excessive mobility Infection, foreign material Chemotherapy treatment Prolonged use of glucocorticosteroid VanMeter, K. C., & Hubert, R. J. (2014). Cp 5 Inflammation and healing. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal 3 determinants of “COMPLETE” healing The involved tissue – Whether it is capable of regeneration labile, stable or permanent tissue Extent of tissue injury (were the extracellular matrix framework is intact) Nature of injury Acute vs chronic Persistent ibjuries https://www.youtube.com/watch?v=G3B0ApUsYag  SIT Internal Cellular response to stress & injury Normal cell Reversible Injury (homeostasis) stress Injurious stimulus Mild transient Adaptation Cell Injury Partial restoration Inability Severe progressive to adapt Irreversible Injury Cell death Necrosis Apoptosis Lazaro RT & Burke-Doe (2014). Injury, inflammation, healing and repair. In C. Goodman & K. Fuller (Eds.), Pathology- Implications for the Physical Therapist (4th Ed) Saunders  SIT Internal Irreversible injury Feature Necrosis Apoptosis Cell size Enlarge Reduce Nucleus Pyknosis (clumped) Fragmentation into  karyorrhexis nucleosome-size (fragmented) fragments Karyolysis (dissolution) Plasma Disrupted Intact membrane Cellular Enzymatic digestion Intact, packaged content into apoptatic body Inflammation Frequent No Causes Pathologic Often Physiologic Can be pathologic Lazaro RT & Burke-Doe (2014). Injury, inflammation, healing and repair. In C. Goodman & K. Fuller (Eds.), Pathology- Implications for the Physical Therapist (4th Ed) Saunders  SIT Internal Necrosis Rupturing of cell membrane & nucleus disintegration  lysis of cellular content  inflammation Coagulative necrosis Liquefactive Fat necrosis Gangrenous Caseous Ischemia Pyogenic bacteria Acute pancreatitis Ischemia Mycobacterium or fungal VanMeter, K. C., & Hubert, R. J. (2014). Cp 1 Introduction to Pathophysiology. In Gould's Pathophysiology for the Health Professions (5th ed.). Philadelphia, PA: Saunders.  SIT Internal Summary NSAIDs / Corticosteroid