Acute Inflammation PDF

Acute inflammation (I) Textbook chapter 3 Pgs 59-70 Objectives To understand: ❖Features of acute inflammation ❖Cellular and vascular changes associated with acute Inflammation ❖Morphology of Acute inflammation and be able to give examples ❖Dysfunction of the inflammatory process Overview Steps Recog...

Acute inflammation (I) Textbook chapter 3 Pgs 59-70 Objectives To understand: ❖Features of acute inflammation ❖Cellular and vascular changes associated with acute Inflammation ❖Morphology of Acute inflammation and be able to give examples ❖Dysfunction of the inflammatory process Overview Steps Recognition Recruitment Removal Regulation Repair & Signs Rubor: Calor: Tumor: Dolor: Functio laesa: Redness Heat Swelling Pain Loss of function Recognition ❖ Recognition of microbes, and of damaged or necrotic cells by receptors and circulating protein ❖ Local cells: sentinel cells (dendritic, mast, few macrophages), endothelial and epithelial cells Receptors  Microbe receptors :Toll-like receptors (TLRs)  recognize general patterns in microbes (not very specific)  produce cytokines to induce inflammation, help activate immune cells, direct antiviral (interferons)  present microbe fragments to immune cells  Damage & danger receptors:  Membrane AND cytosolic receptors - recognize molecule released by cell damage (uric acid, ATP, DNA, ↓intracellular K+) or other pro-inflammatory molecules  Inflammasome: recruiting cytokines (IL-1)  Mechanoreceptors (e.g. Piezo1): altered mechanical tension (stiffness) in the ECM or in the Cell membrane of the local cells  change Mcf activity [Atcha et all, Nature Communications, 2021]  change smooth muscle tones in blood vessel wall  ? Nerves ? Circulating proteins recognize microbes and stimulate inflammation & microbes removal (opsonins) ▪ Participate in direct destruction of certain blood-borne pathogens,  Complement system (both)  Coagulation cascade (both)  Collectines (for circulating pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs)).  Manose binding lectine (microbial sugars) Acute inflammation Tissue Injury Recognition Vascular component  Parallel vascular and cellular component  (Minor) neurologic component  (Minor) mechanobiological component Vasoconstriction Vasodilation Transudate Increased vascular Permeability Exudate Cellular component Recruitment Margination Rolling Adhesion Emigration Chemotaxis Phagocytosis Recognition Engulfment Microbial killing Possible outcomes Resolution Abscess Scar formation Chronic Inflammation Vascular Response ❖ Transient vasoconstriction - neurogenic & miogenic reflex ❖ Vasodilation -arterioles, (venules constriction) -slow blood flow & increased pressure Initial: histamine, serotonin Later: bradykinin, NO, prostaglandins Altered ECM / mechanotransduction Transudate ~ interstitial tissue type fluid, few protein and cells Increased Vascular Permeability Retraction of endothelial cells Mechanotransduction of intercellular adhesions proteins histamine, bradykinin, leucotrienes direct ECM signals Endothelial injury: direct and indirect (PMN) Exudate: Protein & Cell rich fluid Decreased blood flow, increased viscosity + the effect of the recruiting signals (Tumor Necrosis Factor (TNF), Interleukin-1(IL-1) → Margination and cellular response What interventions will ensure a proper offender recognition and vascular response (MACA)  Molecular  Neurological  Mechanobiological  Magnetical Acute inflammation (II) Textbook chapter 3 Pgs 59-70 Acute inflammation Tissue Injury Recognition Vascular component  Parallel vascular and cellular component  (Minor) neurologic component  (Minor) mechanobiological component Vasoconstriction Vasodilation Transudate Increased vascular Permeability Exudate Cellular component Recruitment/Migration Margination Rolling Adhesion Emigration Chemotaxis Phagocytosis Recognition Engulfment Microbial killing Possible outcomes Resolution Abscess Scar formation Chronic Inflammation Cell recruitment leucocytes capable of phagocytosis Neutrophils Macrophages Origin Bone marrow →blood Bone marrow →blood (monocytes) Some already in the tissue (resident) Lifespan 1-2 days Inflammatory: days-weeks Residents: years Response Rapid, short, degranulation and enzymatic Prolonged, multimolecular, with gene transcription ROS Rapid & intense (respiratory burst) Less prominent NO Low or none Increased after gene transcription Cytokines Low or none Major function, Increased after gene transcription Secretion of lysosomal enzymes Prominent Less prominent Extracellular traps NETosis Blood vessels migrations ❖ Margination ❖ Rolling & margination Adhesion ❖ Firm adhesion, pavementing ❖ Emigration / Transmigration ❖ Chemotaxis Chemotaxis Chemotaxis Leukocyte activations Damage signals To include Mechanorectors & mechanotransduction Phagocytosis ❖Recognition ❖Engulfment ❖Microbial killing ❖ ROS (O21, O2-, H2O2, OCl-) ❖ NO, ONOO (peroxynitrite) ❖ Oxygen independent Lysozyme, lactoferrin ❖Microbial digestion NADPH oxidase converts O2 to superoxide (O2-). SOD converts super oxide to hydrogen peroxide MPO converts H2O2 to hypochlorite (OCl-) Progression of events in Acute Inflammation, Associated events  Feedback through adrenergic and cholinergic receptors  Feedback through mechanosensitive ion channels  Lymphocytes cooperation subset of T cells (through IL-17)  Lymphatic vessels & nodes fluid drainage and extra cleansing Termination of the Acute Inflammatory Reaction Tightly controlled to minimize damage ❖ Chemical mediators are produced only as long as offending agent persists have short half-lives are degraded rapidly after release ❖ Neutrophils: short half-lives in tissues die by apoptosis within a few hours after leaving the blood ❖ Switch from proinflammatory to anti-inflammatory cytokines from Arachidonic Acid ❖ Macrophage switch to produce growth factors ❖ Neural impulses (cholinergic and adrenergic) Tissue Damage ❖ “hyper-reaction” against environment substances (allergies/asthma) ❖Inflammatory response may exacerbate injury – ischemia (MI) ❖“frustrated phagocytosis” - release of lysosomal enzymes and ROS into extracellular tissue material that is difficult to eliminate (Tuberculosis, immune complexes) Inaccessible offenders (e.g. attached to membranes) Acute Inflammation: Morphology ❖Dolor - release of prostaglandins and neuropeptides ❖Rubor – calor – tumor Dilation of small blood vessels, increased blood flow to site of injury, and increased vascular permeability Accumulation of leukocytes and fluid in the extracellular tissue, and later degradation products or other molecules Acute Inflammation: Morphology ❖ Serous watery, protein poor fluid (skin blister from burn) ❖ Fibrinous large molecules pass endothelial barrier Inflammation of the lining of body cavities (meninges, pericardium) ❖ Suppurative (purulent) Pus formation which contains neutrophils, necrotic cells Abscess ❖ Ulcerative At the surface of an organ, shedding necrotic tissue Serous Inflammation Fibrinous Inflammation Purulent Inflammation Ulcerative Inflammation Outcomes of Acute Inflammation Abscess Ulcer New cell growth also need survival signals: Neurological Mechanical Outcomes of Acute Inflammation  Complete resolution  Scarring/fibrosis extensive necrosis, abundant fibrin deposit, decreased resources for regeneration, reduced clearance  Abscess or ulcer formation  Progression to chronic inflammation Acute to Chronic Inflammation Defects in Leukocyte Function Leukocyte adhesion deficiency ▪ Type 1 (LAD-1) is caused by defective integrins on leukocytes recurrent infections, poor wound healing, delay in detachment of umbilical cord, life threatening ▪ Type 2 (LAD-2) is caused by an absence sialyl-Lewis X recurrent infections, growth and mental retardation Defects in Leukocyte Function Chronic Granulomatous Disease (CGD) genetic deficiency in NADPH oxidase Defects in Leukocyte Function Chediak-Higashi syndrome (defects of the phagolysosome) Autosomal recessive defective trafficking of organelles phagosome does not pair with lysosome, T-cells also affected severe immunodeficiency is seen leading to partial albinism, neuropathy and pyogenic infections Objectives To understand: ❖Features of acute inflammation ❖Cellular and vascular changes associated with acute Inflammation ❖Morphology of Acute inflammation and be able to give examples ❖Dysfunction of the inflammatory process Video- Acute Inflammation https://www.youtube.com/watch?v=suCKm97yvyk