Acute Inflammation (PART ONE)
1) Inflammation (General)
a) Cardinal Signs – First listed by Celsus
i) Rubor (Redness) / Tumor (Swelling) / Calor (Heat) / Dolor (Pain)  Typically more prominent in A. Inflam.
ii) 5th Sign – Loss of Function (Added by Virchow – 19th Century)
2) Definitions
a) Exudate
i) Inflammatory extravascular fluid, high protein
concentraction
ii) Specific Gravity > 1.020
iii) Usually due to Increased Permeability
b) Transudate
i) Fluid with LOW protein concentration (albumin)
ii) Specific Gravity < 1.012
iii) Permeability usually NOT increased (due to a
pressure response)
c) Edema
i) Excess Interstitial Fluid (either exudate or
transudate)
d) Pus
i) Purulent exudate
ii) Leukocytes (Neutrophils), Debris of Dead Cells, Microbes
3) Types (of Inflammation)
a) Acute vs. Chronic
i) Depends on nature of the stimulus / Effectiveness of the initial reaction in eliminating the stimulus or the
damaged tissues
b) Acute
i) Rapid Onset (Min.) / Short Duration (Hours or Days) / Exudation of Fluid & Plasma Proteins (Edema) / Emigration
of Leukocytes (Neutrophils) **Delivers Leukocytes/Plasma Proteins to Infection/Site of Injury**
ii) Leukocyte Types
(1) Neutrophils – Predominate inflammatory infiltrate (6-24 hours)
(2) Monocytes – Replace neutrophils in 24-48 hours (Survive Longer, may proliferate
in tissues)
c) Chronic
i) May follow acute inflammation / May be insidious in onset / Longer Duration /
Presence of Lymphocytes & Macrophages / Proliferation of BV’s & Fibrosis / Tissue
Destruction
ii) Monocytes – replace neutrophils @ 24-48 hours (survive longer, may proliferate in
tissues, dominant population in chronic inflammatory response)
4) Steps/Process of Inflammation
a) Three Major Components
i) Alterations in vascular caliber
ii) Structural changes in the Microvasculature
iii) Emigration of Leukocytes
b) Stimuli for Inflammation
i) Infections (Bacteria, Viral, Fungal, Parasitic), Microbial Toxins – most common and
medically important causes
ii) Tissue Necrosis (Ischemia, Trauma, Physical/Chemical Injury)
iii) Foreign Bodies
iv) Immune Reactions
c) Actions of Inflammation
i) Vascular Changes – Vasodilation
(1) Earliest Manifestation, follows transient constriction of arterioles
(2) Last a few seconds, first involves the arterioles
(3) Leads to opening of new capillary beds  Increased blood flow (cause heat and redness (erythema) at site of
inflammation)
(4) Induced by Histamine and NO
ii) Vascular Changes – Increased permeability of microvasculature (follows vasodilation) – HALLMARK of
Inflammation
(1) Outpouring of protein rich fluid into extravascular tissues  CAUSES EDEMA
(2) Mechanisms
(a) Contraction of endothelial cells
(i) Increased interendothelial spaces, common mechanism of vascular leakage
(ii) Elicited by histamine, bradykinin, leuotrienes, the neuropeptide substance P and other mediators
(iii) Immediate transient response (occurs rapidly after exposure to mediator, usually short-lived ~15-30
min)
(b) Endothelial Injury
(i) Results in endothelial cell necrosis/detachment
(ii) Direct damage to the endothelium
(c) Transcytosis
(i) Increased transport of fluids and proteins through the endothelial cell
iii) Vascular Changes – Loss of Fluid / Increased Vessel Diameter
(1) Leads to slower blood flow, conc. of RBC’s in small vessels, increased viscosity  Dilation of small vessels
(packed with slowly moving red cells)  Stasis
iv) Stasis progresses
(1) Neutrophils accumulate along the vascular endothelium
(2) Endothelial cells  activated by mediators produced at site of infection/tissue damage
(3) Neutrophils adhere to the endothelium (migrate through vascular wall into interstitial tissue)
v) Lymph Flow
(1) Increased, helps drain edema fluid, accumulates due to increased vascular permeability
(2) Lymph vessels proliferate during inflammatory reactions
(3) Lymphatics may become inflamed due to inflammation (Lymphangitis), Draining Lymph nodes may become
inflamed (lymphadenitis)
(a) Hyperplasia of lymphoid follicles, increased numbers of lymphocytes and macrophages
vi) Leukocytes
(1) Recruited from blood into extravascular tissue, recognize microbes and necrotic tissue, REMOVE offending
agent
(2) Recruitment: Extravasation (Journey of Leukocytes – lumen  Tissue)
(a) Margination
(i) Blood Flow slows early in inflammation (stasis)
(ii) Hemodynamic conditions change (wall shear stress decreases)
(iii) More White Cells assume peripheral position on endothelial surface
(b) Rolling on Vessel Wall
(i) Individual, then rows of leukocytes adhere transiently to endothelium, detach then bind again
(c) Adhere
(i) Cells finally come to rest, firmly attach (“pebbles which a stream runs over w.o disturbing”)
(d) Migration through Endothelium
(i) Diapedesis, mainly in post-capillary venules
(ii) Chemokines act on adherent leukocytes (Stim. cells to migrate through interendothelial spaces, pierce
the basement membrane  Toward site of injury/infection where chemokines are being produced)
(3) Chemotaxis of Leukocytes
(a) Movement: Extend Filopodia (Pull back of cell in direction of extension) – migrate toward inflammatory
stimulus **Emigrate toward site via CHEMOTAXIS – locomotion oriented along a chem. gradient)
(b) Chemoattractants
(i) Exogenous Substances (Bacterial Products/Lipids)
(ii) Endogenous Substances (Chem Mediators- Cytokines, Components of Complement, Arachidonic Acid)
(4) Leukocytic Infiltrate
(a) Nature of Infiltrate depends on age of inflammatory response and type of stimulus
(b) Generally
(i) Acute Inflammation – Neutrophils predominate (6-24 hours), replaced by monocytes (24-48 hours),
survive longer, may proliferate in tissues, become dominant population in chronic inflammatory
reaction
(c) Exceptions
(i) Pseudomonas Bacteria – Infiltrate dominated by recruited Neutrophils for several days
(ii) Viral Infections – Lymphocytes may be first cells to arrive
(iii) Hypersensitivity Reactions – Eosinophils may be main cell type
(5) Recognition of Microbes/Dead Tissue
(a) Leukocyte – must be activated to perform function (Recognition of offending agents – activated to
ingest/destroy offending agents and amplify the inflammatory response)
(6) Phagocytosis (Three Steps)
(a) Leukocyte recognizes/attaches particle to be ingested
(b) Engulfment and formation of a phagocytic vacuole
(i) Particle bound to phagocyte receptors – extensions of cytoplasm (pseudopods) pull it in, plasma
membrane pinches off to form vesicle (phagosome) which fuses with lysosomal granule, degrading it
(c) Kill or degrade ingested material
(i) Final step of elimination of infectious agents/necrotic cells (happens within neutrophils/macrophages)
(ii) Microbial killing (Reactive Oxygen Species / Reactive Nitrogen Species)
1. Also occurs through substances in leukocyte granules
a. Elastase, Defensins (toxic to microbes), Cathelicidins (anti-microbial proteins), Lysozyme
(Hydrolyzes bond in glycopeptide coat of bacteria), Lactoferrin (Iron-binding protein), Major
basic protein (Protein of eosinophils – Limited bactericidal activity, Cytotoxic to many
parasites), Bactericidal Increasing protein (binds bacterial endotoxin)
(7) Functional Response of Activated Leukocytes
(a) Produce Growth Factors
(i) Stim. proliferation of endothelial cells / fibroblasts, Stim. synthesis of collagen, Stim. enzymes that
remodel connective tissues, Drive process of repair after tissue injury
vii) Defects in Leukocyte Function
(1) Cause
(a) Increased Vulnerability to Infections, Impaired Leukocyte Function, Inherited Defects in Leukocyte
Adhesion, Inherited Defects in phagolysosome function
(2) Chediak-Higashi Syndrome
(a) AR condition, defective fusion of phagosomes with lysosomes (susceptible to infection)
(b) Abnormal: Melanocytes (albinism), Cells of Nervous System (Nerve Defects), Platelets (Bleeding
Disorders), Leukocytes (Neutropenia, Defective Degranulation, Delayed microbial killing)
(3) Inherited Defects in Microbicidial Acitivity
(a) Chronic Granulomatous disease – defect in bacterial killing (susceptible to recurrent bacterial infections)
(b) Inherited Defect in gene encoding components of phagocyte oxidase
(c) Initial neutrophil defense = inadequate (collection of activated macrophage  Wall off Microbes –
granulomas)
(4) Acquired Deficiency
(a) Bone Marrow Suppression
(i) Decreased Production of Leukocytes
(ii) Seen following therapy for cancer (radiation, chemotherapy)
(iii) Marrow Space compromised by tumors (leukemias, metastatic from other sites)
Acute and Chronic Inflammation (PART TWO)
1) Mediators of Inflammation
a) Generated from cells or plasma proteins
b) Types (Derived From)
i) Cell-Derived Mediators
(1) Generally
(a) Normally sequestered in intracellular granules
(b) Can be rapidly secreted by granule exocytosis (Histamine in mast cell granules)
(c) Synthesized de novo in response to stimulus (Prostaglandins, Cytokines)
(2) Cells producing Mediators
(a) Platelets, Neutrophils, Monocytes/Macrophages, Mast Cells
(b) Mesenchymal Cells (Endothelium, SM, Fibroblasts)
(c) Most Epithelia
ii) Plasma derived Mediators
(1) Generally
(a) Produced in the Liver
(b) Complement proteins, Kinins
(c) Present in circulation as inactive precursors (must be activated to acquire biological properties)
c) Characteristics
i) Active Mediators
(1) Produced in response to various stimuli
(a) Microbial Products, Substances released from necrotic cells
(b) Proteins of complement, kinin and coagulation systems – activated by microbes and damaged tissues
(ensures inflammation is normally triggered only when/where needed
(2) Short Lived (once activated/released)
(a) Quickly Decay (Arachidonic Acid Metabolites)
(b) Inactivated by enzymes (Kininase inactivates bradykinin)
(c) Scavenged or Inhibited
(i) Antioxidants scavenge toxic oxygen metabolites
(ii) Inhibited: Complement regulatory proteins break up and degrade activated complement components
d) Cell-Derived Mediators
Cell-Derived Mediators – Vasoactive Amines (stored pre-formed, among 1st released during inflammation)
Histamine
Serotonin
MAST CELLS (CT adjacent to BV’s), Basophils &
Platelets
Physical Injury (Trauma, Cold, Hot)
Ab’s to Mast Cells (Allergic Reaction)
Complement (Anaphylatoxins- C3a/C5a)
Hist.-releasing proteins (leukocyte)
Neuropeptide (Substance P)
Cytokines (IL-1, IL-8)
Platlets, Neuroendocrine Cells (GI Tract)
Actions
Dilation of Arterioles, Inc. Permeability (Venules)
Dilation of Arterioles, Inc. Permeability (Venules)
Key
Principal Mediator of Immediate transient phase of
increased vascular permeability (make
interendnothelial gaps in venules)
Found In
Released in
Reponse To
Platelets Aggregate (After contact w. collagen,
thrombin, adenosine diphosphate and Ag-Ab
complexes)
Arachidonic Acid (AA) Metabolites (From dietary source – linoleic acid)
**Not free in cell, esterified in membrane phospholipids (damaged mem. = release) – Mechanical, Chemical, Physical
Stimuli (Release through action of cellular phospholipases)**
Eicosanoids: Prostaglandins
Leukotrienes
Lipoxin
Class
Cycloocygenases
Lipoxygenases
Lipoxygenases
Produced By
Mast Cells,
Macrophages,
Endothelial Cells,
Others
Secreted mainly by
leukocytes
Generated from AA by lipoxygenase pathway
Actions
Key
Action of Two
Cyclooxgenases
(Expressed COX-1,
inducible enzyme COX2)
Bind to G protein
coupled receptors
(mediate virtually
every step of
inflammation)
Involved in vascular
and systemic reactions
of inflammation
Leukocytes (esp Neutrophils) – produce
intermediates in lipoxin syntehesis (converted to
lipoxins by platelets interacting with leukocytes
Lipoxygenase enzymes
Bind to G protein coupled
receptors (mediate
virtually every step of
inflammation)
Bind to G protein coupled receptors (mediate
virtually every step of inflammation)
Chemo-attractants for
Leukkocytes, Vascular
Effects
Inhibitors of Inflammation
Inhibit leukocyte recruitment & other cellular
components of inflammation
Inhibit Neutrophil Chemotaxis & adhesion to
endothelium
Inverse relationship (lipoxin/leukotrienes) –
negative regulators of leukotrienes (resolution of
inflammation)
Prostaglandins (Divided based on structural features – subscript = # of double bonds)
PGI2 (Prostacyclin) Vasodilator, Potent inhibitor of Platelet Aggregation, Markedly potentiates permeability-increasing
and chemotactic effects of other mediators
PGD2
Major Prostaglandin (Prod. by Mast Cells)
Vasodilation, Inc. Permeability of post-capillary venules  EDEMA
PGE2
Major Prostaglandin (Prod. by Mast Cells)- More widely distributed than PGD2
Hyperalgesic, Makes skin hypersensitive to PAIN, Involved in cytokine-induced fever (infections)
PGF2α
Stim. Contraction of Uterine/Bronchial SM & Small Arterioles
Leukotrienes
5- Lipoxygenase
LTB4
LTC4, LTD4, LTE4
Predominant in NEUTROPHILS
Converts AA  5-hydrocyeicosatetraenoic acid (chemotactic for neutrophils, precursor for
Leukotrienes)
Potent Chemotactic Agent and Activator of Neutrophils, Cause aggregation & adhesion (venular
endothelium), Generate ROS (damaging in large amounts), Releases Lysosomal Enzymes
Cysteinyl-containing leukotrienes
Intense Vasoconstriction, Bronchospasm and Increased Vascular Permeability
i)
Inhibition of Eicosanoid Synthesis
(1) Anti-inflammatory drugs work by inhibiting synthesis of eicosanoids!
(a) Cyclooxygenase Inhibitors
(i) Ex: Aspirin, Non-steroidal anti-inflammatory drugs (Indomethacin)
1. Inhibit both COX-1/COX-2 (Prostaglandin Synthesis)
(b) Lipoxygenase Inhibitors (5-lipoxygenase – not affected by NSADIs)
(i) Ex: Zileuton: Inhibit leukotriene production
(ii) Ex: Montelukast: Block leukotriene receptors (helpful for asthma)
(c) Broad-Spectrum Inhibitors
(i) Corticosteroids
1. Powerful anti-inflammatory agents
2. Reduce transcription of genes encoding COX-2, Phospholipase A2, Pro-inflammatory cytokines
(IL-1, TNF)
(d) Modify Dietary Lipid Intake
(i) Increase consumption of Fish Oil
1. Poly unsaturated FA’s – poor substrate for conversion to active metabolites, excellent for
production of anti-inflammatory lipid products (Resolvins, Protectins)
2) Platelet-Activating Factor (PAF)
a) Phospholipid-derived
b) Actions
i) Platelet Aggregation, Vasoconstriction, Bronchoconstriction
ii) Increased leukocyte adhesion, chemotaxis, degranulation, and oxidative burst
iii) Boost synthesis of other mediators (Eicosanoids)
iv) Low Concentrations: Induces Vasodilation, Increased Venular Permeability
c) Elaborated By: Platelets, Basophils, Mast Cells, Neutrophils, Macrophages, Endothelial
Cells
3) Nitric Oxide
a) Soluble Gas, released from Endothelial Cells, Macrophages, some neurons
b) Microbicidal – mediator of host defense against infection
c) Actions
i) Vasodilation
ii) Paracrine manner on target cells (relaxation of vascular SM cells)
iii) Inhibits cellular component of inflammatory response- inhibits several features of
mast cell induced inflammation, inhibits leukocyte recruitment
d) In vivo – half life is only SECONDS, gas acts only on cells in close proximity to where its
produced)
4) Cytokines and Chemokines
a) Cytokines
i) Proteins produced by many cell types (Principally activated lymphocytes and macrophages), also endothelial,
epithelial and CT’s
ii) Involved in Cell IR
iii) Major Cytokines Mediating Inflammation
(1) TNF and IL-1
(a) Secretion stimulated by endotoxin, microbial products, immune complexes, physical injury and other
inflammatory stimuli
(b) Actions
(i) Endothelial Activation, Induce expression of endothelial adhesion molecules
(ii) Synthesize chemical mediators (Cytokines, Chemokines, Growth Factors, Eicosanoids and NO)
(iii) Produce Enzymes associated with matrix remodeling
(iv) Augments response of neutrophils to other stimuli (bacterial endotoxin)
(v) Induce systemic acute-phase response (associated with infection/injury)
(vi) Regulates energy balance – promote lipid/protein mobilization and suppress appetite
1. Sustained production  Cachexia (Weight Loss/Anorexia) – accompanies some chronic infections
and neoplastic diseases
4
b) Chemokines
i) General
(1) Chemo-attractants for specific types of leukocytes
ii) Groups (Four Major) – According to arrangement of cysteine residues in mature proteins
(1) C-X-C (α- chemokines)
(a) Act primarily on Neutrophils – IL-8 is typical
(b) Induced by: Microbial Products, other cytokines (mainly IL-1/TNF)
(c) Secreted by: Activated Macrophages, Endothelial Cells
(d) Causes: Activation/Chemotaxis of Neutrophils, limited activity on Monocytes and Eosinophils
(2) C-C (β-chemokines)
(a) Attract monocytes, eosinophils, basophils, lymphocytes (NOT NEUTROPHILS)
(3) C (γ-chemokines)
(a) Lymphotacin (relatively specific for lymphocytes)
(4) CX3C chemokines
(a) Fractalkine (Cell Surface bound protein OR Soluble Form)
iii) Actions
(1) Stim. Leukocyte recruitment in inflammation
(2) Control normal migration of cells through various tissues
5) Neuropeptides
a) Secreted by: Sensory nerves and Various Leukocytes
b) Actions: Role in initiation and propogation of inflammation
c) Substance P / Neurokinin A
i) Produced in CNS/PNS
ii) Functions
(1) Transmit Pain Signals / Regulate BP / Stim. Secretion by Endocrine Cells / Increase Vascular Permeability
6) Lysosomal Constituents of Leukocytes
a) Neutrophils/Monocytes : Lysosomal Granules
b) Neutrophils
i) Primary (Azurophil) Granules
(1) Myeloperoxidase, Bactericidal Factors, Acid Hydrolases, Neutral Proteases
ii) Secondary (Specific) Granules
(1) Lysozyme, Collagenase, Gelatinase, Lactoferrin, Plasminogen activator, Histaminase, Alkaline phosphatase
7) Reactive Oxygen Species
a) Oxygen derived free radicals (may be released extracellulary from leukocytes) – after exposure to microbes,
chemokines, and immune complexes
b) Production – dep. on activation of NADPH oxidase system
c) Superoxide anion, hydrogen peroxide, hydroxyl radical
i) Major species prod. within cells (combine with NO to form reactive nitrogen species)
d) Implicated in response in inflammation
i) Endothelial cell damage, resulting in increased vascular permeability
ii) Injury to other cell types (parenchymal cells, RBC’s), Inactivation of antiproteases (α1-antitrypsin)
8) Antioxidants
a) Superoxide dismutase: Found or activated in variety of cell types
b) Catalase: Detoxifies H202
c) Glutathione peroxidase: Powerful H202 detoxifier
d) Ceruloplasmin: Copper-containing serum protein
e) Serum Transferrin: Iron-free ffraction
9) Plasma Protein-Derived Mediators
a) THREE INTERRELATED sytems!
i) Complement, Kinin, Clotting Systems
Inflammation
Functional Categories of COMPLEMENT
C3a, C5a – Stim. Histamine release (mast cells), Inc. Vascular Permeability, Cause
Vasodilation **Anaphylatoxins**
Phagocytosis
C5a – Powerful Chemotactic Factor (Neurtophils, Monocytes, Eosinophils,
Basophils) – Activate lipoxygenase pathway of AA metabolism in
neutrophils/monocytes (Inc. Inflamm. Response)
C3b, iC3b (inactive) –
Fixed to Microbial act as opsonins
Promote phagocytosis by neutrophils/macrophages
Deposition of MAC on cells (Cells permeable to water and ions  Cell Death by lysis
Cell Lysis
ii) C3a/C5a
(1) Most important inflammatory mediators (cleaved by several enzymes present in inflammatory exudate)
(a) Plasmin, Lysosomal enzymes released from neutrophils (Self-perpetuating cycle of neutrophil recruitment)
b) Coagulation/Kinin Systems
i) Culminate in activation of THROMBIN and Formation of FIBRIN
ii) Intrinsic Clotting Pathway
(1) Series of Plasma Proteins
(2) Activated by Hageman Factor (Factor XII) – synthesized in liver, circulates in inactive form (activated upon
contact with negatively charged surface)
iii) Kinin Casacade
(1) Active form of Factor XII (Factor XIIA)
(a) Converts plasma pre-kallikrein into active form (kallikrein)
(b) Kallikrein then cleaves kininogen to produce BRADYKININ
(2) Bradykinin
(a) Increase Vascular Permeability, Contracts SM’s, Dilates BV’s, Causes Pain when injected into Skin
(b) SHORT lived – quickly inactivated by kininase
1) Activated Hageman factor (factor XIIa)
a) Initiates four systems (inflammatory response)
i) Kinin system
(1) Produces Bradykinin
ii) Clotting system
(1) Induces formation of thrombin
iii) Fibrinolytic system
(1) Produces plasmin (Lyse Fibrin Clots, Cleave C3  C3 fragments, Degrade Fibrin to Fibrin Split Products)
(2) Degrades fibrin to produce fibrinopeptides
iv) Complement system
(1) Produces anaphylatoxins and other mediators
Inflammation
1) Outcomes of Acute Inflammation
a) Complete Resolution (Usual Outcome – Injury limited/short-lived, little tissue destruction, parenchymal cells can
regenerate)
i) Restoration of site to normal: Removal of cellular debris/microbes by macrophage, resorption of edema fluid by
lymphatic
b) CT Replacement (Fibrosis)
i) Substantial Tissue Destruction (Inflamm. of Tissues incapable of Regeneration, Abundant fibrin exudation in
tissues or serous cavities that can’t be adequately cleared)
ii) CT grows in damaged area – converts it into a mass of fibrous tissue
c) Progression to Chronic Inflammation
i) May follow acute, may be chronic from onset
ii) Acute  Chronic
(1) Acute Inflamm. Response can’t be resolved
(a) Persistance of Injury, Interference with normal healing (Bacterial infection in lung – Acute inflamm.
(pneumonia)  Extensive Tissue destruction & formation of cavity = Chronic Lung Abscess) \
Serous Inflammation
Outpouring of Thin Fluid (From
plasma/secretions of mesothelial cells) –
Peritoneal, pleural, and pericardial cavities
(accumulation of fluid in these cavities =
effusion)
Skin Blister – Burn or Viral Infection
Serosanginous
Effusion of
Bilateral
Pleural Cavities
Chylous inflammation of peritoneal
cavity
Serous Effustion of R Pleural Cavity
Vascular Leaks are large, Pro-coagulant
Stimulus (Cancer Cells), Lining Body Cavities
(meninges, pericardium, pleura)
Fibrinous Inflammation
Fibrinous Exudate (Eosinophilic meshwork of
threads, amorphous coagulum), removed by
fibrinolysis and clearing of other drbeis by
macrophages
Fibrin not removed – Stimulates ingrowth of
fibroblast/BV’s (scarring)
Suppurative Inflammation
“Bread & Butter” – Fibrin Strands
Fibrinous Pericarditis
Large amounts of purulent exudate
(Neutrophils, Liquefactive Necrosis, Edema
Fluid, Bacteria produces localized suppuration“pyogenic-pus producing”
Ex: Acute Appendicitis
Suppurative
Inflammation of
the alveolar space
Suppurative Inflammation of the
Meningal Space
Suppurative Inflammation of
Pericardial Cavity
Abscesses
Suppurative Inflammation
Localized Collection of purulent
inflammatory tissue (buried deep in a
tissues, organ or confined space),
produced by deep seeding pyogenic
bacteria
Central Region – mass of necrotic
leukocytes and tissue cells
High Power of Slide to the Right:
Marked Acute Inflammation within
Abscess Cavity
Ulcers
Necrotic Focus – Around it (zone of
preserved neutrophils) Outside it
(vascular dilation and
parenchymal/fibroblast proliferation)
Local Defect or Excavation of the surface
of an organ or tissue (produced by
sloughing of inflamed necrotic tissue)
Most Common: Mouth, Stomach,
Intestines, Genitourinary Tract, Skin of
Lower Extremities
Stomach Ulcer
Chronic Duodenal Ulcer
Chronic Inflammation
1) Prolonged Inflammation (weeks or months) – may follow acute or begin insidiously
a) Causes
i) Persistent Infections by micro-organisms (Mycobacteria, certain viruses, fungi, and parasites, Delayed Type
Hypersensitivity)
ii) Immune Mediated Inflammatory Disease
iii) Autoimmune Diseases
iv) Artherosclerosis (Chronic Inflammatory process of arterial wall – induced by endogenous toxic plasma lipid
components)
b) Morphology
i) Infiltration with mononuclear cells (macrophages, lymphocytes,
plasma cells – think CHRONIC (“clock face” with eccentric
nucleus))
ii) Proliferation of small blood vessels (angiogenesis)
iii) Fibrosis
The * = collection of chronic inflammatory cells, Triangles indicate
destruction of parenchyma (normal alveoli replace by spaces), Arrows
indicate replacement by connective tissue (fibrosis)
c) Cells in Chronic Inflammation
i) Mononuclear Phagocyte System (AKA Reticuloendothelial System)
(1) Closely related Cells of Bone Marrow Origin
(a) Mononuclear Phagocytes
(i) Arise from common prescursor in the BM – give rise to BLOOD Monocytes
1. Monocytes migrate from blood  Tissues (half-life ~1 day)
a. Emigrate into tissues during early acute inflammation (predominate cell type within 48 hours)
2. Differentiate into macrophages (life span of tissue macrophage
several months to years)
a. Transformation activated by microbial products, cytokines,
other chemical mediators
(b) Tissue Macrophages
(i) Scattered through CT, Liver (Kupffer Cells), Spleen, Lymph Nodes,
Lungs, CNS (Microglia)
(2) THE MACROPHAGES
(a) Activation of Macrophages
(i) Increased levels of lysosomal enzymes and reactive oxygen/nitrogen
species
(ii) Production of cytokines, growth factors and other mediators of
inflammation
(b) Products of Activated Macrophages
(i) Eliminate injurious agents, initiate repair, responsible for TISSUE
injury in chronic inflammation
(c) TISSUE DESTRUCTION = HALLMARK OF CHRONIC INFECTION!!
ii) Lymphocytes
iii) Plasma Cells
(1) Develop from activated B lymphocytes (produce Ab’s) - against persistent foreign or self Ag’s
iv) Eosinophils
(1) Abundant in Immune reactions (mediated by IgE), parasitic infections
(2) Eotaxin: Chemokine that recruits Eosinophils
(3) Granules (Major Basic Protein)
(a) Toxic to Parasites, lysis of mammalian epithelial cells
(b) Contribute to tissue damage in immune reactions (allergies)
v) Mast Cells
(1) Widely distributed in CT’s (In Acute & Chronic Inflammatory Responses)
(2) Degranulation/Release of Mediators
(a) Histamine, Prostaglandins
(b) Allergic Reaction to foods, insects, venom or drugs – catastrophic results (anaphylactic shock)
2) Granulomatous Inflammation
a) Distinctive pattern of chronic inflammation – attempt to contain an offending agent that is difficult to eradicate
i) Strong activation of T-lymphocytes  Macrophage activation (injury to normal tissues)
b) Most Commonly Seen In
i) Tuberculosis, Sarcoidosis, Cat-scratch disease, Lymphogranuloma inguinale, Leprosy, Brucellosis, Syphilis, Mycotic
infections, Berylliosis
c) Morphology
i) Microscopic aggregation of macrophages – transformed into epithelium like cells, surrounded by a collar of
mononuclear leukocytes (lymphocytes, occasionally plasma cells)
d) Granuloma
i) Epitheliod Cells
(1) Pale Pink Granular Cytoplasm, indistinct cell boundaries
(2) Fuse to Form Giant Cells – periphery or center of granulomas
ii) Types
(1) Foreign Body Granuloma
(a) Incited by relatively inert foreign bodies (sutures, talc-IV drug users)
(b) Foreign Body can be identified in center of granuloma – refractile
(2) Immune Granulomas
(a) Caused by a variety of agents capable of inducing cell-mediated immune response
(i) Granuloma produces when inciting agent is poorly degradable or particulate
(b) Prototype – caused by infection with Mycobacterium tuberculosis
(i) Granuloma referred to as tubercle
(ii) Presence of central caseous necrosis (RARE in other granulomatous diseases)
Caseous Granuloma
(Cells dying, becoming degraded)
Non-caseous Granuloma
(Cells present)
3) Systemic Effects of Inflammation
a) Acute-Phase Response
i) **AKA systemic inflammatory response syndrome**
ii) Reactions to cytokines whose prod. is stimulated by bacterial products
iii) Clinical/Pathological changes
(1) Fever (Elevated 1-4 degrees) – One of MOST prominent manifestations (response to pyrogens)
(2) “Symptoms”: Increased Pulse/BP, Decreased Sweating (blood flow directed to deep vascular beds), Rigor
(Shivers), Chills, Anorexia, Somnolence
(3) Acute Phase Proteins
(a) Plasma Proteins, Synthesized in the Liver, Concentrate in plasma in response to inflammatory stimuli
(b) Three best known proteins
(i) C-reactive protein (CRP)
(ii) Fibrinogen
(iii) Serum amyloid A (SAA Protein)
(4) Leukocytosis
(a) Esp. common to inflammatory reactions induced by bacterial infections (Leukocyte count usually climbs to
15000 – 20000 cell/microliter)
(b) May reach crazy high levels (40000 – 100000 cells/microliter)
(i) Leukemoid Reaction – similar to WBC counts observed in leukemia
(c) Accelerated Release of cells from BM (Rise in number of immature neutrophils in blood)
(5) Bacterial Infections : Increase in Blood Neutrophil Count
(6) Viral Infections (Infectious Mono, Mumps, and German Measles) : Absolute increase in number of
lymphocytes
(7) Bronchial Asthma, Allergy, Parasitic Infestations (Absolute increase in eosinophils)
(8) Infections (Typhoid fever and viruses, Rickettsiae, and certain protozoa: Decrease in circulating WBC’s
b) Consequence of Defective or Excessive Inflammation
i) Defective
(1) Increased susceptibility to infections
(2) Delayed wound healing
ii) Excessive
(1) Basis of many types of human disease
(2) Allergies (disorders in which fundamental cause of tissue injury is inflammation)