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Acute and Chronic Inflammation

Dr. Pedrito Tagayuna

Type IV collagen Laminin Finronectin Proteoglycans Elastic fibers Collagen fibers Proteoglycans

Department

of

Pathology

and

Laboratory

PATTERNS OF INFLAMMATION

Diagnosis

Acute

HISTORY Celsus – 4 cardinal signs of inflammation Virchow – 5th cardinal sign John Hunter – inflammation is not a disease but a response. Julius Cohnheim – 1st noted an inflamed blood vessel Elie Metchnikoff – phagocytosis Paul Erlich – humoral immunity Sir Tomas Lewis – concept of chemical substanceAA

INFLAMMATION Complex reaction in the vascularized connective tissue brought about by exogenous and endogenous stimuli. Fundamentally a protective response the ultimate goal of which is to get rid of the organism

Short duration Exudation of fluid and plasma protein Emigration of leukocyte (neutrophils) Chronic

Mononuclears Proliferation of blood vessels Fibrosis Tissue necrosis

ACUTE INFLAMMATION

3 MAJOR COMPONENTS OF ACUTE INFLAMMATION Alteration in vascular caliber that lead to an increase in blood flow. Structural changes in microvasculature that permit the plasma proteins and leukocytes to leave the circulation. Emigration of leukocyte from the microcirculation and their accumulation in the focus of injury.

STRUCTURES INVOLVED IN INFLAMMATORY RESPONSE Connective tissue cells Circulating cells Connective tissue matrix

STIMULI FOR ACUTE INFLAMMATION Infections Bacterial, viral, fungal, parasitic Microbial toxins

VASCULAR CHANGES

CONNECTIVE TISSUE CELLS Mast cells Fibroblasts Macrophage

CIRCULATING CELLS Neutrophils Monocytes Eosinophils

Tissue necrosis Ischemia, trauma, physical and chemical injuries Foreign bodies Spinsters, dirt, sutures Immune reactions Hypersensitivity reactions Autoimmune disease

Changes in vascular flow and caliber

Lymphocytes Basophils

Inconstant

and

transient

Platelets

vasoconstriction,

followed

by

vasodilation.

CONNECTIVE TISSUE MATRIX

Slowing of the circulation - stasis

Endothelium

Leukocyte

margination,

rolling,

Basement membrane

migration

Increased vascular permeability Formation of endothelial gaps in venules

15 to 30 minutes, immediate transient response Delayed prolonged leakage, 2 to 12 hours Mild injury, ei.gi after burns, X-radiation, UV radiation) Cytoskeletal reorganization (endothelial retraction) Increased transcytosis Direct endothelial injury Delayed prolonged leakage Leukocyte mediated endothelial injury Leakage from new blood vessels

CELLULAR EVENTS Leukocyte extravasation and Phagocytosis Adhesion and transmigration Chemotaxis Leukocyte activation Phagocytosis

SEQUENCE OF EVENTS IN EXTRAVASATION Lumen: margination, rolling & adhesion. Diapedesis Migration in interstitial tissues towards a chemotactic stimulus.

ADHESION & TRANSMIGRATION

Four

molecules:

molecular

families

of

Selectins Immunoglobulins Integrins Mucin-like glycoproteins

adhesion

SELECTINS:

Characterized by an extracellular N terminal domain related to sugar binding mammalian lectins E selectin- ELAM 1- endothelium P selectin – GMP140 or PADGEM – endothelium & platelets L selectin – LAM 1 – most leukocytes

IMMUNOGLOBULINS:

Intercellular adhesion molecule 1 (ICAM 1) Vascular cell adhesion molecule 1 (VCAM 1)

INTEGRINS ICAM 1 - β integrins , LFA-1, MAC 1 VCAM 1 – a4B1 (VLA -4) & a4B7

MECHANISM Redistribution of adhesion molecules to the cell surface. Induction of the adhesion molecules on endothelium Increase avidity of binding

STEPS OF NEUTROPHIL ADHESION Endothelial activation Rolling Firm Adhesion Transmigration

Rolling Firm Adhesion Transmigration ADHESION MOLECULE DEFICIENCY Leukocyte adhesion

ADHESION MOLECULE DEFICIENCY Leukocyte adhesion deficiency 1 – defect in the biosynthesis of the Beta 2 chain shared by LFA1 & MAC 1 Leukocyte adhesion deficiency 2- absence of sialyl-Lewis X, ligand for Eselectin, generalized defect in fucose metabolism

LEUKOCYTE DIAPEDESIS Occurs predominantly in the venules except in the lungs where it also occurs in the capillaries.

CHEMOTAXIS Locomotion along a chemical gradient Exogenous bacterial products Endogenous Complement – C5a

Lipooxygenase pathway, LTB4 Cytokines, IL8

PHAGOCYTOSIS Recognition and attachment of the particle to be ingested by the leukocyte. Engulfment with subsequent formation of the phagocytic vacoule. Killing and degradation of the ingested material.

RECOGNITION OF MICROBES AND DEAD TISSUES Events in the Response of leukocytes:

Recognition of the offending agents Activation of leukocytes to ingest and destroy Receptors for microbial products

Toll-like receptors (TLRs)

G protein-coupled receptors Found on neutrophils, macrophages Receptors for opsonins Receptors for cytokines Interferon gamma secreted by natural killer cells

RECOGNITION AND ATTACHMENT Opsonins naturally occurring factors that coats the microorganisms to be recognized Enhance the efficiency of phagocytosis.

MAJOR OPSONINS Fc fragment of IgG C3b – opsonic fragment of C3 Mannan-binding lectin (Carbohydrate binding protein)

RECEPTORS ON LEUKOCYTES FcyR – recognize the Fc fragment of IgG Complement receptors 1,2 & 3 – interact with C3b & C3bi C1Q R – binds to collectins CR3 – recognizes C3bi Identical with the Beta2 integrin (MAC1/CD11b) involved in the adhesion of Endothelium

ENGULFMENT Binding of the opsonized particle to the FcyR triggers engulfment

Complement Receptors – markedly enhance engulfment

STEPS IN PHAGOCYTOSIS

– markedly enhance engulfment STEPS IN PHAGOCYTOSIS 1. Recognition and attachment   2. Engulfment

1.

Recognition and attachment

 

2.

Engulfment

 

3.

Killing

and

degradation

of

the

ingested

material

KILLING AND DEGRADATION O2 dependent mechanisms Burst in O2 consumption, glycogenolysis, increase glucose oxidation via the HMP shunt and production of reactive oxygen metabolites

GENERATION OF O2 METABOLITES Oxidase Superoxide

KILLING AND DEGRADATION Reactive oxygen species (ROS) NADPH oxidized by NADPH oxidase(a.k.a. phagocytic oxidase) In the process reduces O2 to superoxide anion Respiratory burst Reactive nitrogen species Derived from NO NO reacts with superoxide = peroxynitrite

lipids,

proteins and nucleic acids of microbes

Attacks

and

damage

H2O2 – MPO – Halide System

H2O2 (lysozomes) + Myeloperoxidase (azurophilic granules of neutrophils) in the presence of Cl- = hypochlorite Most efficient bactericidal system in neutrophils H2O2 may also be converted to hydroxyl radical Fungi,viruses, protozoa and helminths

BACTERICIDAL KILLING DUE TO NEUTROPHIL GRANULES Bactericidal permeability increasing protein Lysozyme Lactoferrin Major Basic Protein Defensins

recurrent bacterial infection & impaired wound healing. Deficiency in Beta2 integrins (CD 18)

LAD 2

Absence of Sialyl- Lewis X clinically milder than LAD 1 Recurrent bacterial infection

DEFECTS IN PHAGOCYTOSIS Chediak-Higashi Syndrome Defective fusion of phagosomes and lysosomes Neutrophils have giant granules Reduced transfer of lysosomal enzymes to phagocytic vacuoles Affects melanocytes, cells of the nervous system and platelets.

DEFECTS IN MICROBICIDAL ACTIVITY Chronic Granulomatous Disease

LEUKOCYTE-MEDIATED TISSUE INJURY Lysosomal enzymes, ROS and NO “collateral damage” Autoimmune disease Allergic diseases

Congenital

/

inherited

defects

in

genes encoding several components of NADPH

oxidase which generates superoxide.

ACQUIRED DEFICIENCIES

Bone Marrow suppression

CLINICAL

LEUKOCYTEINDUCED INJURY Acute

EXAMPLES

OF

Decreased

function

of

leukocytes

following radiation and chemotherapy, leukemia and bone metastases of tumors

ARDS Acute Transplant Rejection Asthma Glomerulonephritis Reperfusion injury Septic Shock Vasculitis Chronic

CHEMICAL

MEDIATORS

 

OF

INFLAMMATION

originate either from plasma or from cells.

 

Major

cell

types:

platelets,

neutrophils,

monocyte/macrophages, mast cells

 

Mesenchymal

cells

(endothelium,

smooth muscle, fibroblasts) can also be induced to produce

Plasma-derived protein, kinins)

(complements,

Arthritis Asthma Atherosclerosis Chronic Lung Disease Chronic rejection

 

Precursors

are

inactive

in

plasma

DEFECTS IN LEUKOCYTE FUNCTION Defects in leukocyte adhesions. Defects in Phagocytosis. Defects in microbicidal activity

DEFECTS IN LEUKOCYTE ADHESIONS Genetic deficiencies in leukocyte adhesion molecules (LAD 1 & 2). LAD 1

CHEMICAL

MEDIATORS

 

OF

INFLAMMATION can stimulate the release of mediators by target cells themselves. Once activated and released from the cells, most of these are short-lived.

Most have the potential to cause harmful effects. Sequestered in intracellular granules that need to be secreted – e.g. Histamine in mast cells Synthesized de novo – e.g. Prostaglandins & Cytokines

CHEMICAL MEDIATORS Vasoactive Amines Plasma Proteases Arachidonic Acid Metabolites Platelet activating factors Cytokines & Chemokines Nitric Oxide

VASOACTIVE AMINES Histamine Present in mast cells near connective tissues adjacent to blood vessels Stimuli for Release:

Physical injury, binding of antibodies to mast cells Fragments of complements – C3a & C5a Histamine releasing proteins derived from leukocytes Neuropeptides – Substance P Cytokines- IL1 & IL 8 Dilation of arterioles and increase vascular permeability mediated by binding to H1 receptors of microvascular endothelial cells

SEROTONIN 5- hydroxytryptamine Platelets and neuroendocrine cells Preformed vasoactive mediator actions similar to histamine

PLASMA PROTEASES Complement System Kinin system Clotting system

System Kinin system Clotting system BIOLOGIC EFFECT OF COMPLEMENT FRAGMENTS: C3 & C5 –
System Kinin system Clotting system BIOLOGIC EFFECT OF COMPLEMENT FRAGMENTS: C3 & C5 –

BIOLOGIC EFFECT OF COMPLEMENT FRAGMENTS:

C3 & C5 – most important inflammatory mediators Vascular phenomena (release of histamine, increased vascular permeability&vasodilation) – C3a, C5a, C4a (anaphylotoxins) Leukocyte adhesion, chemotaxis & activation – C5a Phagocytosis – C3b & C3bi(inactive) Cell lysis MAC

THE KININ SYSTEM Generate vasoactive peptides from plasma proteins called Kininogens by kallikriens. Bradykinins vasoactive nonapeptide Increased vascular permeability Contraction of smooth muscle, dilatation of blood vessels & pain Activation of Hageman factor of the Intrinsic clotting Pathway

of Hageman factor of the Intrinsic clotting Pathway KALLIKRIENS Potent activator of Hageman factor

KALLIKRIENS Potent activator of Hageman factor Chemotactic activity: direct conversion of C5 to C5a

Chemotactic activity: direct conversion of C5 to C5a FIBRINOLYTIC SYSTEM Counter balances clotting by

FIBRINOLYTIC SYSTEM Counter balances clotting by cleaving fibrin – solubilizing the fibrin clot Plasmin important in lyzing clot Cleaves C3 to produce C3 fragments, and it degrades fibrin to form fibrin split products, which may have permeability- inducing properties

ARACHIDONIC ACID METABOLITES

which may have permeability- inducing properties ARACHIDONIC ACID METABOLITES 20 carbon polyunsaturated fatty acid 6

20 carbon polyunsaturated fatty acid

ANTI-INFLAMMATORY THERAPY Aspirin & NSAIDS (indomethacin or ibuprofen) – inhibit cyclooxygenase

ANTI-INFLAMMATORY THERAPY Aspirin & NSAIDS (indomethacin or ibuprofen) – inhibit cyclooxygenase Glucocorticoids - down-regulating the expression of specific target agents including COX2 Fish Oil – poor substrate for conversion to active metabolites of the cyclooxygenase & lipooxygenase series

PLATELET ACTIVATING FACTORS Phospholipid derived mediator Cells that elaborate PAF Platelets Basophils (Mast cells) Neutrophils Monocyte/Macrophage Endothelial cells

PLATELET ACTIVATING FACTOR Vasoconstriction Bronchoconstriction Vasodilation Increased vascular permeability Increase leukocyte adhesion to endothelium Chemotaxis Degranulation Oxidative burst

Chemotaxis Degranulation Oxidative burst CYTOKINES & CHEMOKINES Cytokines – proteins

CYTOKINES & CHEMOKINES Cytokines – proteins produced by many cell types, endothelium & connective tissues that modulate the function of other cell types. Chemokines – cytokines that share the ability to stimulate leukocyte movement ( chemokinesis) and directed movement (chemotaxis) Monokines – monocyte Lymphokines – activated lymphocytes Interleukins – broad family of cytokines that are produced by hematopoeitic cells & act primarily on leukocytes Growth factors – growth promoting properties

GENERAL PROPERTIES & FUNCTIONAL CLASSES OF CYTOKINES:

Secretion is transient & closely regulated Many cells produce multiple cytokines Proteins are pleotrophic Redundant effects Produce +/- regulatory effects

5 CLASSES OF CYTOKINES Cytokines that regulate lymphocyte growth Cytokines that are involved in Natural Immunity Cytokines that activate inflammatory response Chemokines Cytokines that stimulate hematopoiesis

REGULATE LYMPHOCYTE FUNCTIONS:

IL2 & IL 4 – promotes lymphocyte growth IL10 & TGF Beta – Negative regulators of Immune Response

NATURAL IMMUNITY TNF alpha IL 1 B Type I interferons (IFNa & IFN b) IL6

ACTIVATE INFLAMMATORY RESPONSE:

IFN gamma TNF alpha TNF beta IL5 IL10 IL12

STIMULATE HEMATOPOEISIS IL3, IL7 c kit ligand GSF MSF Stem cell factors

ACUTE PHASE REACTANTS Fever Increased sleep Decreased appetite Increased acute phase proteins Hemodynamic effects Neutrophilia

SYSTEMIC EFFECTS OF INFLAMMATION (ACUTE-PHASE RESPONSE) Fever Acute-phase proteins Leukocytosis Other manifestations Sepsis, in severe large amount or in debilitated patientsnts of organisms and LPS in the blood

SYSTEMIC EFFECTS OF INFLAMMATION (ACUTE-PHASE RESPONSE) Fever

Elevation 1 to 4 °C Most prominent Caused by pyrogens resulting to the resetting of the temperature set point

SYSTEMIC EFFECTS OF INFLAMMATION (ACUTE-PHASE RESPONSE) Acute-phase proteins CRP, fibrinogen, Serum Amyloid A (SAA) protein Acts as opsonins

SYSTEMIC EFFECTS OF INFLAMMATION (ACUTE-PHASE RESPONSE) Leukocytosis 15,000 to 20,000 cells/uL 40,000 - 100,000 cells/uL Leukemoid reaction

Accelerated release Shift to the left Neutrophilia, generally bacterial Lymphocytosis, generally viral Eiosinophilia, allergic reaction, asthma parasitic infections Leukopenia in some infections like typhoid fever

Other manifestations Increased pulse and blood pressure Decreased sweating Rigors (shivering) Chills Anorexia Somnolence malaise Sepsis, in severe large volume of infectious agent or in debilitated patients and LPS in the blood

ENDOTHELIAL EFFECTS Increased leukocyte adherence Increased PGI synthesis Increased procoagulant activity Decreased anticoagulant activity Increased IL1, IL6, PDGF

FIBROBLAST EFFECTS Increased proliferation Increase collagen synthesis Increased collagenase Increased proteases Increase PGE synthesis

LEUKOCYTE EFFECTS Increase cytokine secretion Priming

CHEMOKINES Superfamily of small (8-10kD) proteins that act primarily as activators & chemoattractants for specific types of leukocytes

4 MAJOR CLASSES OF CHEMOKINES C-X-C or alpha chemokines acts primarily on neutrophils IL8 – typical of this group IL1 & TNF a - inducers C-C or beta chemokines attract mononytes, eosinophils, basophils and lymphocytes C or Gamma chemokines – relatively specific for lymphocytes CX3C chemokines

NITRIC OXIDE Pleiotrophic mediator of inflammation Released by endothelial cells causing Vasodilation (EDRF) Soluble gas produced by macrophage & neurons of the brain

3 TYPES OF NO SYNTHASE Endothelial (eNOS) Neuronal (nNOS) Cytokine inducible (iNOS)

MORPHOLOGIC PATTERNS OF INFLAMMATION Morphologic hallmarks of all acute inflammatory reactions:

Dilation of small blood vessels, slowing of blood flow, accumulation of leukocytes and fluid in the extravascular tissue Serous inflammation Fibrinous inflammation Suppurative or Purulent inflammation Ulcers

SEROUS INFLAMMATION Marked by outpouring of a thin fluid from the plasma or secreted by mesothelial cells Effusion, accumulation of fluid in cavities Skin blisters from burns

FIBRINOUS INFLAMMATION Fibrin is formed and deposited in the extravascular space Fibrinous exudate is formed if the vascular leak is large or if there is procoagulant stimulus (cancer cells) Characteristic inflammation in the lining cavities: meninges, pericardium and pleura

Removed by fibrinolysis May undergo organization to form scar tissue

SUPPURATIVE/PURULENT INFLAMMATION Production of large amount of pus or purulent exudate consisting of neutrophils, liquefactive necrosis and edema fluid. Acute appendicitis, common example Abscess – localized collection of purulent inflammatory tissue Produced by deep seeding of a pyogenic bacteria into a tissue In time abscess may be walled off and replaced by connective tissue

ULCERS Local defect or excavation of the surface of an organ or tissue that is produced by the sloughing/shedding of inflamed necrotic tissue Occur only when tissue necrosis and inflammation exist on or near a surface Best exemplified by peptic ulcer

OUTCOMES OF ACUTE INFLAMMATION:

Complete resolution Fibrosis When there is substantial tissue destruction, incapable of regeneration fibrin exudation that cannot be adequately cleared Connective tissue grow into the area of damage Progression to Chronic Inflammation

CHRONIC INFLAMMATION

Causes:

1.

Persistent infections

Mycobacteria, fungi, parasites

2.

Immune-mediated inflammatory diseases

Autoimmune diseases

Ex. RA & MS

3. Prolonged exposure to toxic agents, either exogenous or endogenous

• Exogenous: silica

• Endogenous: atherosclerosis

Histologic features of Chronic Inflammation Infiltration with Mononuclear cells (Chronic Inflammatory Cells) Macrophages, lymphocytes & plasma cells Tissue Destruction Destruction of Parenchyma induced by persistent offending agent or by inflammatory cells Replacement by Connective tissue Accomplished by angiogenesis and fibrosis

MACROPHAGE Predominant cell in chronic inflammation Derived from blood monocyte Life span:

Monocyte – 1 day Macrophage – several weeks

MECHANISM OF MACROPHAGE ACCUMULATION:

Continued recruitment of monocyte from the circulation Local proliferation of macrophage Immobilization of macrophage

OTHER CELLS IN CHRONIC INFLAMMATION Lymphocytes Types:

T & B lymphocytes States: Activated or Memory Plasma cells Mast cells Eosinophils

GRANULOMATOUS INFLAMMATION Distinct pattern of chronic inflammatory reaction in which the predominant cell type is an activated macrophage with a modified epithelial appearance Cellular attempt to contain an offending agent Often there is strong activation of T lymphocytes leading to macrophage activation TB is the prototype

GRANULOMA Focal area of a granulomatous inflammation

Microscopic aggregation of macrophages that are transformed into epithelium like cells surrounded by collar of mononuclear leukocytes, lymphocytes and occasionally plasma cells. Rim of fibroblasts & connective tissue Giant cells

TYPES OF GRANULOMA Foreign body granuloma Incited by inert foreign body Immune granulomas Cell-mediated immune response Inciting agent is poorly degradable,

HALLMARK OF CHRONIC INFLAMMATION Tissue destruction

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F.R.2011