2. FM2004 PM2004 Acute Inflammation 23-24.pdf

FM2004 & PM2004 Acute Inflammation Dr Collette Hand UCC Department of Pathology [email protected] January 2024 Dr C. Hand Textbooks R9 R10 Robbins & Cotran Pathologic Basis of Disease U6 U7 Underwood General & Systemic Pathology RBP9 RBP10 Kumar, Abbas, Aster Robbins Basic Pathology Robbins & Cotran Atl...

FM2004 & PM2004 Acute Inflammation Dr Collette Hand UCC Department of Pathology [email protected] January 2024 Dr C. Hand Textbooks R9 R10 Robbins & Cotran Pathologic Basis of Disease U6 U7 Underwood General & Systemic Pathology RBP9 RBP10 Kumar, Abbas, Aster Robbins Basic Pathology Robbins & Cotran Atlas of Pathology A2 W5 Young, Stewart, O’Dowd Wheater’s Basic Pathology Dr C. Hand Inflammation: what is it? A process of progressive changes in living tissues from the moment of injury to final healing The response of vascularised living tissue to injury -itis Dr C. Hand Purpose of Inflammation Localise & eliminate the causative agent Limit tissue injury Restore tissue to normality Destroys, dilutes or walls off the injurious agent Dr C. Hand Inflammation: 2 types Types: - Acute - Chronic Based on – time course – cellular components involved Not exclusive / some overlap Dr C. Hand Inflammation R10: Table 3.2; RBP10: Table 3.1 Feature Acute Chronic Onset Fast: minutes or Slow: days hours Monocytes/ macrophages and lymphocytes Cellular infiltrate Mainly neutrophils Tissue injury, fibrosis Usually mild and May be severe and self-limited progressive Local and systemic signs Prominent Less Dr C. Hand Causes of Acute Inflammation Physical agents: burns, radiation, trauma Chemicals: toxins, caustic substances Microbes: common cause Immunological reactions: hypersensitivity Necrosis Dr C. Hand Classical signs Celsus 30 BC - 38 AD Virchow Loss of function Redness (Rubor) – Functio laesa Heat (Calor) Swelling (Tumour) Pain (Dolor) Function to bring elements of immune system to injury site Caused by a rapid vascular response and characteristic cellular events Dr C. Hand Redness (rubor) Inflamed tissue appears red – eg skin affected by sunburn Due to dilation of blood vessels and increased blood flow Heat (calor) Increase in temperature Seen only in peripheral sites eg skin Due to increased blood flow Dr C. Hand Swelling (tumour) Results from oedema Migratory mass of inflammatory cells (lesser level) Pain (dolor) Stretching and distortion of tissue Pus under pressure in abscess cavity Some chemical mediators induce pain – bradykinin, prostaglandin, serotonin Dr C. Hand Loss of function (functio laesa) Movement of inflamed area is consciously and reflexly inhibited Severe swelling may immobilise tissue Dr C. Hand Inflammatory reaction Macrophages and other cells in the tissues recognise microbes and damaged cells and liberate mediators, which trigger the vascular and cellular reactions of inflammation. R10/RBP10: Fig 3.1 Sequence of events in an inflammatory reaction. Dr C. Hand Acute Inflammation 1 Vascular Response changes in vessel calibre and vascular flow changes in vascular permeability Cellular events leucocyte emigration phagocytosis Dr C. Hand Changes in Vascular Flow & Calibre Vasoconstriction (seconds) Vasodilation (15 min -> hrs) – – – – – Firstly arterioles Then capillary beds in area open Increased local blood flow (-> 10x) Redness and heat  hydrostatic pressure U6/U7: Fig 9.3 Dr C. Hand Acute Inflammation 2 Vascular Response changes in vessel calibre and vascular flow changes in vascular permeability Cellular events leucocyte emigration phagocytosis Dr C. Hand Changes in vascular permeability Increased vascular permeability leading to the escape of a protein-rich fluid (exudate) into the interstitium is the hallmark of acute inflammation Endothelial intracellular proteins (eg actin) contract under influence of chemical inflammatory mediators  fenestration (ie transient gaps) Net escape of protein-rich fluid (EXUDATION) – Fluid = EXUDATE (specific gravity > 1.020) – Protein = Immunoglobulins, coagulation factors Dr C. Hand Types of  vascular permeability U6/U7 Table 9.1 Rapid, short lived 15-30 min hours Delay of 2-12 hrs, Several hours/days Dr C. Hand Normally High hydrostatic pressure at arteriolar end Fluid -> extravascular space (transudate, low protein, specific gravity extravascular space (transudate, low protein, specific gravity oedema U6/U7: Fig 9.4 Dr C. Hand Acute Inflammation 3 Vascular Response changes in vessel calibre and vascular flow changes in vascular permeability Cellular events leucocyte emigration phagocytosis Dr C. Hand Slowing of circulation  permeability of microvasculature Protein-rich fluid → extravascular tissue  rbc conc,  viscosity of blood → small vessels packed with rbcs = STASIS Stasis → peripheral leucocyte margination blood flow slows, cells flow nearer to vessel wall cells adhere to vascular epithelium [described further in cellular events] Dr C. Hand Cellular Events: leucocyte emigration Steps in emigration Margination – Adhesion to endothelial cells – Cells tumble at edge adhesion molecules Emigration – pass between endothelial cells & basal lamina Dr C. Hand Leukocyte Migration Cytokines promote expression of ligands (selectins, integrins) on endothelium and promote migration of leukocytes RBP9: Fig 2.5; R9/R10/RPB10: Fig 3.4 Mechanisms of leukocyte migration. Selectins (rolling), integrins (adhesion), CD31 (transmigration).Dr C. Hand Chemotaxsis Leukocytes move towards site of injury along a chemical gradient. – Substances: bacterial products, cytokines / chemokines, complement RBP9: Fig 2.5; R9/R10/RPB10: Fig 3.4 Leukocytes migrate toward chemoattractants Dr C. Hand emanating from source of injury. Signs of Acute Inflammation Changes in vessel calibre & vascular flow – Rubor, Calor Changes in vascular permeability – Tumour, Dolor Leucocyte emigration – Tumour, Dolor Dr C. Hand Cellular Events: Phagocytosis Neutrophils & monocytes ingest debris and foreign particles at injury site Major benefit of accumulation of leucocytes Stages 1. Recognition & attachment Opsonins; Fab. Fc, C3b 2. Engulfment 3. Killing or degradation R9/R10: Fig 3.8 RBP9: 2.8; RBP10: Fig 3.7 Dr C. Hand Killing or degradation recognise, engulf and destory Oxygen-dependent H2O2 ***Neutrophils: myeloperoxidase (MPO) very good at killing microbes Presence of halide (Cl- ): – H2O2 → HOCl (hypochlorite) – H2O2 → OH (hydroxyl radical) Oxygen-independent Lysozyme: Hydrolyses bonds in bacterial cell wall Lactoferrin: chelates iron required for bacterial growth R9/R10: Fig 3.8 RBP9: 2.8; RBP10: Fig 3.7 Dr C. Hand Chemical Mediators of Inflammation Chemicals released from injured tissue Spread outwards into uninjured areas Dr C. Hand Chemical mediators 1 Mediator RBP9:Table 2.5; R9:Table 3.4; R10/RBP10:Table 3.5 Source Prostaglandins Action Vasodilation, increased vascular permeability, Mast cells, basophils, platelets endothelial activation Mast cells, leukocytes Vasodilation, pain, fever Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion, and activation Cytokines (TNF, IL-1, IL-6) Macrophages, endothelial cells, mast cells Local: endothelial activation (expression of adhesion molecules). Systemic: fever, metabolic abnormalities, hypotension (shock) Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst Complement Plasma (produced in liver) Leukocyte chemotaxis and activation, direct target killing (membrane attack complex), vasodilation (mast cell stimulation) Kinins Plasma (produced in liver) Increased vascular permeability, smooth muscle contraction, vasodilation, pain Histamine early thing available Platelet-activating factor Dr C. Hand Chemical mediators 2 U6/U7: Table 9.2 Dr C. Hand Chemical mediators Chemicals released from cells – histamine, prostaglandins, platelet activating factor, cytokines Plasma factors – complement, kinin, coagulation system Dr C. Hand Histamine Stored in mast cells, basophils, eosinophils – > early mediator Causes vascular dilation Immediate transient vascular permeability Serotonin – platelets – potent vasoconstrictor Dr C. Hand Prostaglandins & leukotrienes Long chain fatty acids from arachidonic acid Membrane phospholipids (neutrophils, mast cells) > prostaglandins and leukotrienes Vascular permeability Anti – inflammatory drugs work by inhibiting prostaglandin production (aspirin, NSAID) Dr C. Hand Platelet activating factor (PAF) made earlier so ready to be released Released from mast cells and neutrophils platelet aggregation vascular permeability leucocyte adhesion to endothelium synthesis of arachidonic acid derivatives Dr C. Hand Cytokines Released by activated lymphocytes and macrophages Major cytokines in acute inflammation – TNF, IL-1 ↑ expression of adhesion molecules on endothelial cells – IL-6 Acute phase proteins – Chemokines chemo attractants to recruit leucocytes Vasoactive / Chemotactic Dr C. Hand Chemical mediators sources Chemicals released from cells – histamine – prostaglandins – cytokines Plasma factors cascades* – – – – slower coagulation system kinin fibrinolytic system complement Dr C. Hand Coagulation system Soluble fibrinogen -> fibrin Coagulation factor XII (Hageman factor) – activated by contact with extracellular material eg basal lamina – > activates coagulation, kinin & fibrinolytic systems Dr C. Hand Kinin system Small vasoactive peptides Activated by coagulation factor XII Bradykinin – vascular permeability – chemical mediator of pain Dr C. Hand Complement Cascade of serum proteins activated by: – necrosis, endotoxins, ab-ab complexes, kinin & fibrinolytic systems C5a & C3a (less active) – chemotactic for neutrophils –  vascular permeability – releases histamine from mast cells Dr C. Hand Inflammation Q Benefits Harmful Effects ?? ?? Dr C. Hand Inflammation A Benefits Dilution of toxins Harmful Effects Digestion of normal tissues Not specific: we end up damaging normal cells Entry of antibodies Release of enzymes by inflammatory cells Delivery of nutrients & oxygen Inappropriate inflammatory response hay fever Fibrin formation Swelling (deadly in throat or brain) Drug transport Stimulation of immune response Dr C. Hand Acute Inflammation - Initial reaction to tissue injury - Vascular component: dilation of vessels - Exudate component: vascular leakage of protein rich fluid - Neutrophil polymorph is predominant cell - Outcomes: resolution, suppuration (abscess), healing, progress to chronic inflammation RBP9: Fig 2.2 Dr C. Hand Histopathology of Acute Inflammation R8: Fig 2.17 A: normal lung: thin blood vessels B: congested blood vessels (stasis) widen thicker more red C: large number of leucocytes in alveoli Dr C. Hand Outcomes of acute inflammation 1 R9/R10: Fig 3.17 RBP9: Fig 2.10 RBP10: Fig 3.16 Dr C. Hand Outcomes of acute inflammation 2 U7: Fig 9.12 Dr C. Hand Learning Objectives State the 5 classical signs of acute inflammation and describe the vascular and cellular processes that produce these signs. Describe the sequence of vascular changes in acute inflammation (vasodilation, increased permeability) and their purpose. Describe the steps involved in extravasation of leukocytes from the blood to the tissues. Define the terms oedema, transudate, and exudate. Describe the meaning and utility of chemotaxis. Understand the role that chemokines play in inflammation. Chemical mediators of inflammation are numerous. You should learn the cellular sources and major effects of the mediators and, conversely, list the most likely mediators of each of the steps of inflammation. Dr C. Hand Canvas Lecture presentation files, quizzes, discussion boards Other useful sites: department website and links WebPath https://webpath.med.utah.edu/ – Notes, links to images, examinations (with feedback*) www.pathguy.com – Notes, links to images Dr C. Hand Video clips Acute Inflammation – https://www.youtube.com/watch?v=suCKm97yvyk White blood cells chasing bacterium – https://www.youtube.com/watch?v=uqyIIVhKiYs Neutrophil chemotaxsis – https://www.youtube.com/watch?v=ZUUfdP87Ssg Dr C. Hand