Acute Inflammation PDF

Acute inflammation Prof Dr Thidar Aung Learning Objectives Students will be able to 1. Define acute inflammation 2. Describe the causes and cardinal signs (physical characteristics) of acute inflammation. 3. Explain the vascular and cellular events of acute inflammation with suitable diagrams. 4. Ex...

Acute inflammation Prof Dr Thidar Aung Learning Objectives Students will be able to 1. Define acute inflammation 2. Describe the causes and cardinal signs (physical characteristics) of acute inflammation. 3. Explain the vascular and cellular events of acute inflammation with suitable diagrams. 4. Explain the formation of the cellular exudates / stages of neutrophil (polymorph) emigration with a suitable diagram. 5. Explain the role of neutrophil in the formation of acute inflammatory infiltrate (chemotaxis, phagocytosis and killing) Manipal University College Malaysia 2 Definition Inflammation is a response of vascularized tissues that delivers leukocytes and molecules of host defense from the circulation to the sites of infection and cell damage in order to eliminate the offending agents.** Beneficial host response to foreign invaders and necrotic tissue May also cause tissue damage Manipal University College Malaysia ** Ref: Robbins and Cotran Pathologic Basis of Disease 10th Ed 3 Inflammation Acute - minutes to days Immediate and early response to injury Characterized by fluid and protein Polymorphonuclear cells (neutrophils) Chronic - weeks to years Mononuclear cells (Lymphocytes and macrophages) Manipal University College Malaysia 4 Causes of Acute Inflammation Principal causes 1. Microbial infections e.g., pyogenic bacteria, viruses 2. Hypersensitivity reactions e.g., parasites, tubercle bacilli 3. Physical agents e.g., trauma, ionizing radiation, heat, cold 4. Chemicals e.g., corrosives, acids, alkalis, reducing agents, bacterial toxins 5. Tissue necrosis e.g., ischaemic infarction Manipal University College Malaysia 5 Microbial Infections One of the most common causes of inflammation Viruses lead to death of individual cells by intracellular multiplication Bacteria release specific exotoxins, or endotoxins Exotoxins_ chemicals synthesized by them that initiate inflammation Endotoxins_ associated with their cell walls Some organisms causes immunologically mediated inflammation e.g., parasitic infections and tuberculous inflammations Manipal University College Malaysia 6 Microbe activation Microbes have regular patterns of molecular structure that are recognised by innate immune cells termed ‘pathogen-associated molecular patterns’ (PAMP) Macrophage, neutrophils and dendritic cells express a number of receptors that allow them to recognise different pathogens collectively called ‘Pattern Recognition Receptors’ (PRR) Activation of Innate immune cells Activation of innate immune cells Trigger the production of cytokines and chemokines Cytokines and Chemokines INITIATION of INFLAMMATION Hypersensitivity reactions An altered state of immunological responsiveness causes an inappropriate/ excessive immune reaction Damage the tissue Different types, have similar cellular or chemical mediators to those involved in inflammation Type I : immediate hypersensitivity or “allergy” due to activation of IgE antibody on mast cells or basophils Type II : antibody or cell bound antigen Type III : immune complex reactions Type IV : delayed hypersensitivity mediated by T cells Manipal University College Malaysia 8 Tissue injury Danger theory - Polly Matzinger 1994 Distressed/inj ured cell Release of self molecules Cells when damaged release self-molecules – the Danger signal! Self-molecules (mammalian DNA, heat shock proteins) act as an endogenous non-foreign alarm signal Recognised by Pattern Recognition Receptors on the surface of cells (e.g., TLRs –Toll-like receptors) Activation of Innate immune cells Cytokines and Chemokines Trigger the production of cytokines and chemokines INITIATION of INFLAMMATION Physical agents Physical trauma Ultraviolet or other ionizing radiation Burns Excessive coldness (frost bite) Manipal University College Malaysia Irritants and corrosive chemicals Corrosive chemicals (acids, alkalis, oxidizing agents) provoke inflammation through gross tissue damage Infecting agents  release specific chemical irritants directly lead to inflammation 10 Tissue necrosis Death tissue from lack of oxygen or nutrients (e.g., infarction) potent inflammatory stimulus The edge of an acute infarct shows an acute inflammatory response (in response to peptides released from dead tissue) Manipal University College Malaysia 11 Cardinal signs of inflammation Manipal University College Malaysia 12 Cardinal signs of inflammation Redness(Rubor) Acutely inflamed tissue appears red Due to dilatation of small blood vessels within the damaged area Heat (Calor) Due to ↑ed blood flow through the region vascular dilatation ↑ed T° is seen only in peripheral part of body skin Systemic fever contributes to the local T° Swelling(Tumor) Results from edema (accumulation of fluid in the extravascular space) fluid exudate Physical mass of the inflammatory cells migrating into the area Formation of new connective tissue Pain (Dolor) Due to stretching and distortion of tissue, inflammatory edema In abscess cavity due to pus under pressure Bradykinin, prostaglandins and serotonins  induce pain Loss of function: movement of an inflamed area is restricted due to pain, severe swelling Manipal University College Malaysia (MUCM) 13 Vascular and cellular events of acute inflammation Manipal University College Malaysia 14 Two major events in acute inflammation Vascular response Vasodilatation Increased vascular permeability Cellular response Formation of the cellular exudates (Extravasation of neutrophils) Manipal University College Malaysia (MUCM) 15 Vascular response 1. Vasodialation Changes in vessel calibre and flow begin early after injury Transient vasoconstriction- (few seconds) followed by vasodilatation Vasodilation is induced by chemical mediators such as histamine Dilation of small vessels leading to an increase in blood flow Is the cause of erythema and stasis of blood flow. Manipal University College Malaysia 17 2. Increased vascular permeability Induced by histamine, kinins, and other mediators Allows plasma proteins and leukocytes, the mediators of host defense, to enter sites of infection or tissue damage. Vasodilation↑ blood flow↑ hydrostatic pressure  ↓ in intravascular osmotic pressure fluid leak from blood vessels edema. Lymphatic vessels and lymph nodes are also involved in inflammation Manipal University College Malaysia 18 Cellular response A critical function of inflammation is to deliver leukocytes to sites of injury The type of leukocyte depends on the age of the inflammatory response and the original stimulus. Neutrophils predominate during the first 6-24 hours and macrophages after 24-48 hours Neurophils are more numerous, response rapidly to chemokines, attached firmly to the adhesion molecules short lived, undergo apoptosis after 24-48 hours Manipal University College Malaysia 19 Cellular response I. Neutrophil (polymorph) emigration Stages are, i. loose attachment to endothelium (margination) ii. rolling on endothelium (rolling) iii. firm attachment to endothelium (adhesion) iv. migration through inter-endothelial spaces (transmigration) II. Chemotaxis (Migration into interstitial tissue) Manipal University College Malaysia 21 Margination Leucocytes moving from the centre of the vessel towards the periphery Normal flow - RBC’s and WBC’s flow in the centre of the vessel As blood flow slows, WBC’s collect along the endothelium  Margination Endothelial activation The underlying stimulus causes release of mediators Activate the endothelium Selectins and other mediators move quickly to the surface Manipal University College Malaysia 22 Rolling Neutrophils bounce or roll along enodothelial cells Transiently adhere to endothelial cells Loose binding between selectin (endothelial) and carbohydrate (neutrophil) neutrophils slow down and ‘roll’ – Rolling adhesion Manipal University College Malaysia 23 Adhesion (Pavementing) Leucocytes firmly adhere to endothelial cells Tight binding is facilitated by ICAM (endothelial) and integrin (neutrophil), neutrophil can ‘extravate’ through the vessel wall into surrounding tissues Manipal University College Malaysia 24 Transmigration Neutrophils escape through the gaps between endothelial cells. Diapedesis (Cells crawling) Mediated by PECAM-1 (CD31) Manipal University College Malaysia 25 Chemotaxis Movement toward the site of injury after exiting the circulation is known as chemotaxis. The locomotion is along the chemical gradient of chemoattractants. Both exogenous and endogenous substances act as chemoattractants. Exogenous : bacterial products, peptides with N-formylmethionine terminal amino acids and some lipids. Endogenous: (1) cytokines, particularly those of the chemokine family (e.g., IL-8); (2) components of the complement system, particularly C5a; (3) arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4). All these chemotactic agents bind to specific seven transmembrane G protein–coupled receptors on the surface of leukocytes. Signals initiated from these receptors result in conformation changes of the cells and the leukocytes migrate in the direction of chemoattractants emanating from the site of the inflammatory stimulus. Manipal University College Malaysia 27 Whats the function of the neutrophils and macrophages once there? Leucocyte activation Opsonisation- coating a bacterium or a particle to facilitate its phagocytosis Immunoglobulins C3b (complement) Phagocytosis (to eat and destroy) Release of leucocytes products (tissue injury) Manipal University College Malaysia 30 Phagocytosis – engulfment and killing of microorganism 1. Engulfment 2. phagosome 3. Lysosome fuses with phagosome 4. Releases enzymes to digest bacteria 5. Digested products release Manipal University College Malaysia 31 Lysosome and killing Cellular organelle, Contains acid hydrolases – break down bacteria, viruses, proteins etc Also make antimicrobial peptides: - Super oxygen radicals generated by NADPH oxidase - Nitric oxide made by Nitric Oxide Synthase - Combine to form highly reactive peroxynitrite - ‘Respiratory Burst’ NO Lysosomal enzymes indirectly kill phagocytosed microbes by making reactive oxygen species and nitric oxide Nitric Oxide Synthase O2NADPH oxidase Manipal University College Malaysia 32 Neutrophil Extracellular Traps (NETs) NETs are extracellular fibrillar networks that concentrate antimicrobial substances at sites of infection and trap microbes, helping to prevent their spread.