Acute Inflammation - Lecture notes week 2 - general pathology PDF

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Summary

Acute Inflammation Inflammation  Description o Physiological response to tissue injury o Vascular and cellular components o Acute or Chronic o Terminates in resolution, repair or continues  Cyclic Process o Vascular changes  Vasodilation  Transient vasoconstriction then vasodilation  Starts in ...

Description

Acute Inflammation

Inflammation  Description o Physiological response to tissue injury o Vascular and cellular components o Acute or Chronic o Terminates in resolution, repair or continues  Cyclic Process o Vascular changes  Vasodilation  Transient vasoconstriction then vasodilation  Starts in arteries  Increased blood flow  Due to histamine, NO on vascular smooth muscle  Increased vascular permeability o Contraction of endothelial cells o Increased inter-endothelial spaces o Mediated by histamine, bradykinin, substance P o Endothelial injury in severe injuries o Injury can be caused by neutrophils o Increased transcytosis  Permits escape protein rich fluid exudate into extravascular tissue  Vascular congestion/stasis  Slower flow, increased concentration  Endothelial activation  By mediators produced during inflammation  Increased levels of adhesion molecules o Formation of an exudate o Cellular factors and release of mediators  Cellular factors  Margination o White cells more peripheral due to stasis  Rolling o White cells stick and detach from wall o Mediated by selectins o Upregulated by IL-1 and TNF (from Macro/PMNs)  Histamine, thrombin, PAF  Binds L-Selectin on leukocytes  Adhesion o Mediated by Integrins o Stimulated by Il-1 and TNF o Chemokines also facilitate binding (directly released at site of injury) o Reorganisation of cytoskeleton  Migration (diapedesis) o Chemokines act on leukocytes to stimulate to migration across endothelium  Chemotaxis

Travel along a chemical gradient  Bacterial products  Cytokines IL-8  Complement  Leukotriene B (from arachidonic acid) o Removal of damaged tissue o Repair and resolution, suppuration, organisation or ongoing chronic inflammation o Vascular Changes etc.  Role in pathology/physiology o Infection  bacterial, fungal, parasitic, viral o Tissue Necrosis  burns, radiation injury, trauma o Foreign material o Immune reactions  inflammatory diseases, autoimmune diseases  Clinical features o Redness  dilation of small blood vessels o Heat  increased blood flow due to vasodilation and fever o Swelling  accumulation of fluid in extracellular matrix o Pain  stretching of tissue due to oedema, mediators such as bradykinin and serotonin stimulate pain receptors o Loss of function  movement is inhibited by pain, severe swelling can immobilise the inflamed area o

Leukocyte activation and recognition of microbes at the site of inflammation  Toll-like receptors o Receptors for microbial products on surface leukocytes o Stimulate microbe killing and cytokine production  G-protein coupled receptors on PMNs and macrophages o Recognise products of short-bacterial peptides, complement, prostaglandins o Induce migration of cells and production of respiratory burst  Receptors for opsonins on surface of leukocytes o Coating a particle to target for ingestion o Coating includes antibodies and complement  Receptors for cytokines on surface of leukocytes o E.g. IFN-gamma activates macrophages Removal of an offending agent  Phagocytosis o Opsonisation o Engulfment using pseudopodia o Formation of phagosomes o Material destroyed and removed from cell by pinocytosis (removal of fluid)  Engulfment  Killing and degradation o ROS, NO, elastases Termination of acute response  Removal of stimulus  Neutrophils have a short half life  Variation in cytokine stimuli  Neural impulses

 Macrophages are activated to perform different functions Mediation of Inflammation  These come in cascades and are short lived  Can be Derived from cells  intracellular granules or synthesised o Vasoactive amines  histamines and serotonin o Arachidonic acid metabolites o Nitric oxide o Cytokines (TNF, IL-1, IL-6, chemokines)  Can also be derived from plasma proteins  secreted from liver in inactive state o Complement factors o Coagulation and Kinin Systems Mediator Histamine

Principal Sources Mast cells, basophils, platelets

Serotonin Prostaglandins Leukotrienes

Platelets Mast cells, leukocytes Mast cells, Leukocytes

Platelet activating factor

Leukocytes, Mast cells

Nitric Oxide

Endothelium, macrophages

IL-1, TNF, IL-6

Macrophages, endothelial cells, mast cells Leukocytes, activated macrophages Plasma  produced in liver Plasma  produced in liver

Chemokines Complement Kinins

Actions Vasodilation, increased vascular permeability, endothelial activation Vasodilation, increased vascular permeability Vasodilation, pain, fever Increased vascular permeability, chemotaxis, leukocyte adhesion and activation Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst Vascular smooth muscle relaxation, killing of microbes Endothelial activation, fever, pain, shock Chemotaxis, leukocyte activation Leukocyte chemotaxis and activation, vasodilation Increased vascular permeability, smooth muscle contraction, vasodilation, pain

Types of Exudate  LIGHT’S criteria  Exudate is extra-cellular fluid with a high protein and cellular content  Transudate is extra-cellular fluid with a low protein and cellular content  Examples: o Serous  usually a transudate, found in pleural, pericardial, peritoneal spaces o Fibrinous exudate  fluid rich in fibrin, an exudate due to high protein content, often on serosal surfaces, meninges o Suppurative exudate  pus forming, an exudate rich in neutrophil polymorphs (abscess) o Haemorrhagic  severe vascular injury or depletion of coagulatory factors o Membranous  the epithelium becomes coated in membrane formed by fibrin, epithelial cells and inflammatory cells o Pseudomembranous (ulceration)  surface exudate on mucosal/epithelial sites  E.g. C.Diff colitis o Necrotising (gangrenous)  high tissue pressure leading to vascular occlusion and thrombosis

 Necrosis and bacterial putrefaction leads to gangrene  An exudate allows delivery of nutrients, dilution of toxins, entry of antibodies and stimulates the immune response Mediators Continued  Neutrophil polymorphs o Opsonisation o Phagocytosis o Intra-cellular killing of micro-organisms  Oxygen dependent  Oxygen independent o Release of lysosomal products, propagating the response  Mast cells o Reside in tissues o Contain histamine and heparin in preformed granules o Stimulated to release of contents by injury, complement, IgE o Role  allergy/anaphylaxis o Also make eicosanoids to propagate immune response  Macrophages/Monocytes  Macrophages  tissue resident  Monocytes  circulating o Chemotaxis o Synthesise TNF, IL-1, IL-6 o Phagocytosis o Antigen presenting cells, link between innate and adaptive immune response  Complement o Activated by:  Classical pathway  Ag/Ab complexes  Alternative pathway  bacterial products  Products of dying cells in tissue necrosis  Components of kinin, coagulation and fibrinolytic systems can also activate o C5a  chemotactic for neutrophils, increases vascular permeability, releases histamine from mast cells o C3a  similar to C5a o C5, C6, C7, C8, C9  Cytolytic activity o C4b, C2a, C3b  opsonisation of bacteria  Plasma factors o Kinin system  Activated by coagulation factor XII  Bradykinin alters vascular permeability and mediates pain o Coagulation system  Process causing conversion of fibrinogen to fibrin  Fibrin forms part of inflammatory exudate  Factor XII can interact with extra-cellular material to activate kinin, coagulation and fibrinolytic systems o Fibrinolytic system  Plasmin lyses fibrin into fibrin degradation products Effects of acute inflammation  Beneficial

o Dilution of toxins by oedema fluid o Increased entry of antibodies and drug transport o Fibrin traps micro-organisms o Delivery of nutrients o Stimulation of immune response  Detrimental o Digestion of normal tissues o Swelling  e.g. epiglottis o Inappropriate response  e.g. type 1 hypersensitivity response (allergic rhinitis) How infection may spread  Localised infection o Remain at initial site o Spread to local lymph nodes via draining lymphatics o Five cardinal signs  redness, pain, swelling, heat, loss of function  Systemic infection o Haematogenous  i.e. spread through blood/lymph to cause systemic inflammatory response o Track through tissue to form abscess/infection elsewhere  e.g. psoas abscess  Controlled by how virulent the organism is, the host condition  i.e. immunosuppression, low protein levels, poor vascular supply and treatment given  Systemic inflammatory response has 4 key clinical features o Increased respiratory rate o Increased heart rate o High or low temperature o Low or raised white cell count  MEWS score, sepsis, septic shock etc. Outcome of acute inflammation  Resolution  complete restoration of tissue to normal o If minimal tissue damage o If occurs in tissue with regenerative capacity  i.e. skin o If cause is rapidly removed or destroyed o If there is good vascular drainage  Healing by fibrosis o After substantial tissue damage o Tissue incapable of regeneration o Abundant fibrin exudate  Progression to chronic inflammation o Persistent stimulus o Tissue destruction leading to ongoing inflammation

ILOs Describe inflammation and its role in pathology/physiology

Explain how changes in the vasculature and cells (neutrophils, macrophages, mast cells) occur and how they contribute to the clinical signs; and describe the various types of exudates

Describe the main concepts of how infection may spread

Outline, with examples, how various chemical mediators affect the inflammatory response

Describe how the inflammatory response is controlled (at a basic level), including various possible sequelae...