This is the normal appearance of the appendix against the background of the cecum.

The colonoscopic view of the appendiceal orifice between the fork of two haustral folds in the cecum is seen below.

This appendix was removed surgically. The patient presented with abdominal pain that initially was generalized, but then localized to the right lower quadrant, and physical examination disclosed 4+ rebound tenderness in the right lower quadrant. The WBC count was elevated at 11,500. Seen here is acute appendicitis with yellow to tan exudate and hyperemia, including the periappendiceal fat superiorly, rather than a smooth, glistening pale tan serosal surface.

Microscopically, acute appendicitis is marked by mucosal inflammation and necrosis.

This is a normal esophagus with the usual white to tan smooth mucosa seen at the left. The gastroesophageal junction (not an anatomic sphincter) is at the center, and the stomach is at the right. The upper GI endoscopic view of the transition from tan squamous mucosa to pink columnar mucosa is seen below.

Acute esophagitis is manifested here by increased neutrophils in the submucosa as well as neutrophils infiltrating into the squamous mucosa at the right.

This is normal esophageal squamous mucosa at the left, with underlying submucosa containing mucus glands and a duct surrounded by lymphoid tissue. The muscularis is at the right.

One consequence of acute inflammation is ulceration. This occurs on epithelial surfaces. Here the gastric mucosa has been lost, or ulcerated. A larger ulcer and several adjacent smaller ones with surrounding erythema appear at the left of center.

This example of a fluid collection, a friction blister of the skin, is an almost trivial example of edema.

The cardinal signs of inflammation are rubor (redness), calor (heat), tumor (swelling), dolor (pain), and loss of function. Seen here is skin with erythema, compared to the more normal skin at the far right.

This yellow-green exudate on the surface of an inflamed, hyperemic (erythematous) bowel mucosa consists of many neutrophils along with fibrin and amorphous debris from dying cells.

Here is an example of the fibrin mesh in fluid with PMN's that has formed in the area of acute inflammation. It is this fluid collection that produces the "tumor" or swelling aspect of acute inflammation.

INFLAMMATION

INFLAMMATION
Reaction of cascularized conective tissue to injury or stimuli Protective mechanism If goes unchecked Tissue damage- scarring Hypersensitivity- increased response

COMPONENTS INVOLVED IN INFLAMMATION

Blood vessels: endothelium Blood: Cells: Neutrophils Monocytes Lymphocytes Eosinophils Basophils Platelets Plasma: Serum Clotting system

COMPONENTS INVOLVED IN INFLAMMATION Connective tissue Cells: Mast cells Fibroblasts Macrophages lymphocytes

COMPONENTS INVOLVED IN INFLAMMATION

Connective tissue Extracellular matrix Basement membrane Proteoglycans Adhesion glycoproteins Adhesion glycoproteins Fibronectin Laminin Collagen type IV Structural proteins Collagen Elastin Proteoglycans

INFLAMMATION
Acute Short duration Edema ( leakage of proteins & fluids) Leukocyte migration (PMNs mainly) Chronic Long duration Lymphocytes & macrophages Blood vessel proliferation Fibrosis Tissue necrosis

Terminate on removal of stimulus Stimulus sends signals via chemical mediators

Fig 3.1 (robins)

DEFINITIONS
Exudation Fluid rich in proteins and cells (exudate) Secondary to increased vascular permeability Specific gravity of 1.020 or more Pus Purulent exudate rich in PMN's and cell debris Transudation Fluid with very little protein (mostly albumin) From increased hydrostatic pressure in vessels There is no increase in permeability Specific gravity 1.012 or more Edema Excess extravascular (interstitial ) accumulation of fluid Could be either exudate or transudate

This example of a fluid collection, a friction blister of the skin, is an almost trivial example of edema.

The arm at the bottom is swollen (edematous) and reddened (erythematous) compared to the arm at the top.

This yellow-green exudate on the surface of an inflamed, hyperemic (erythematous) bowel mucosa consists of many neutrophils along with fibrin and amorphous debris from dying cells.

Exudation of a protein-rich fluid into a cavity leads to a transudate. The fibrin in this fluid can form a fibrinous exudate on the surfaces. Here, the pericardial cavity has been opened to reveal a fibrinous pericarditis with strands of stringy pale fibrin between visceral and parietal pericardium.

Here is an example of the fibrin mesh in fluid with PMN's that has formed in the area of acute inflammation. It is this fluid collection that produces the "tumor" or swelling aspect of acute inflammation.

Fig 3.2 Robins

Fig 3.3 Robins

Mechanism of vascular leakage in acute inflammation

Fig 3.4 Robins

CLINICAL SIGNS OF ACUTE INFLAMMATION

Redness Heat Swelling Pain Loss of function

CELLULAR EVENTS
Extravasation
Journey of leukocytes from lumen to interstitial tissue Lumen Margination Rolling Adhesion Wall Diapedesis (transmigration across endothelium) Interstitial tissue Migration towards stimuli

Fig 3.5 Robins

Fid 3.9 Robins

Fig 3.7 Robins

Fig 3.8 Robins

LEUKOCYTE ACTIVATION
Induced by Chemotactic agents Phagocytosis Ag-Ab complexes Includes Production of AA metabolites Degranulation & secretion of lysosomal enzymes & activation of oxidative burst Modulation of leukocyte adhesion molecule

CHEMOTAXIS
Emigration of leukocytes toward the site of injury along a chemical gradient Chemotactic agents Soluble bacterial products Components of the complement system Products of the lipoxygenae pathway of arachidonic acid Cytokines

Fig 3.11 Robins

Biochemical events in leukocyte activation

PHAGOCYTOSIS
Steps include Recognition & attachment Opsonins (opsonization of particles) Fc & IgG ______FcR C3b & C3bi______CR1,2,3 Lectins ( carbohydrate binding proteins) of plasma called collectins

PHAGOCYTOSIS contd.
Engulfment Triggered by binding of opsonized particle to FCR Markedly enhanced in presence of complement receptors Binding to CR alone: engulfment Results in phagosome Phagolysosome [ lysosome & phagosome] (degranulation) Killing or degradation Bacteria killed by O2 dependant mechanism

PHAGOCYTOSIS contd
Killing or degradation Phagocytosis causes Increased O2 consumption Glycogenolysis Increased glucose oxidation Production of reactive O2 metabolites

PHAGOCYTOSIS contd
Mechanisms of killing H2O2- MPO- Halide system: Most efficient bactericidal system in neutrophils Others: Bactericidal permeability increases protein (BPI) Lysozyme Lactoferrin Major basic protein (eosinophils); for parasites After killing : degradation by acid hydrolases in azurophilic granules

Phagocytosis of a particle

Fig 3.11 Robins

LEUKOCYTE INDUCED TISSUE INJURY

By Lysosomal enzymes O2 derived active metabolites Products of AA metabolism Ways which these chemicals are released Regurgitation during feeding Transient opening of phagosome before closure Frustrated phagocytosis ? Surface phagocytosis Cytotoxic release After phagocytosis of membranolytic substance e.g. urate crystals

DEFECTS IN LEUKOCYTE FUNCTIONS

IN ADHESION: Defect in adhesion molecules Recurrent bacterial infections Phagocytosis Chediak Higashi syndrome Decreased PMNs Defective degranulation Delayed killing Giant granules Microbicidal activity Chronic granulomatous disease Bacterial infections Defect in NADPH Oxidase

Acute inflammation

At medium power magnification, numerous neutrophils fill the alveoli in this case of acute bronchopneumonia. Note the dilated capillaries in the alveolar walls from vasodilation with the acute inflammatory process.

PMN's seen here are in alveoli, indicative of an acute bronchopneumonia of the lung. The PMN's form an exudate in the alveoli

PMN's that are marginated along the dilated venule wall (arrow) are squeezing through the basement membrane (the process of diapedesis) and spilling out into extravascular space.

The milky white fluid shown here in the peritoneal cavity represents a chylous ascites. This is an uncommon fluid accumulation that can be due to blockage of lymphatic drainage, in this case by a

This example of a fluid collection, a friction blister of the skin, is an almost trivial example of edema.

This example of edema with inflammation is not trivial at all: there is marked laryngeal edema such that the airway is narrowed. This is life-threatening. Thus, fluid collections can be serious depending upon their location.

Here is simple edema, or fluid collection within tissues. This is "pitting" edema because, on physical examination, you can press your finger into the skin and soft tissue and leave a depression.

The arm at the bottom is swollen (edematous) and reddened (erythematous) compared to the arm at the top. Click to determine which areas are painful to touch.

At medium power magnification, numerous neutrophils fill the alveoli in this case of acute bronchopneumonia in a patient with a high fever. Pseudomonas aeruginosa was cultured from sputum. Note the dilated capillaries in the alveolar walls from vasodilation with the acute inflammatory process.

Acute bronchopneumonia

The PMN's seen here are in alveoli, indicative of an acute bronchopneumonia of the lung. The PMN's form an exudate in the alveoli. This patient had a "productive" cough because large amounts of purulent sputum were produced. The source, the neutrophilic alveolar exudate, is seen here.

exudate

exudate

Fibrinous Exudate (pericardium)

Fibrinous exudation (pericardium)

At higher magnification, vasculitis with arterial wall necrosis is seen. Note the fragmented remains of neutrophilic nuclei (karyorrhexis). Acute inflammation is a non-selective process that can lead to tissue destruction.

necrosis

Inflammation with necrosis

The vasculitis shown here demonstrates the destruction that can accompany the acute inflammatory process and the interplay with the coagulation mechanism. The arterial wall is undergoing necrosis, and there is thrombus formation in the lumen.

Migration of neutrophils

As in the preceding diagram, here PMN's that are marginated along the dilated venule wall (arrow) are squeezing through the basement membrane (the process of diapedesis) and spilling out into extravascular space.

Pleural effusion

Here is an example of fluid collection into a body cavity, or an effusion. This is a right pleural effusion (in a baby). Note the clear, pale yellow appearance of the fluid. This is a serous effusion. Extravascular fluid collections can be classified as follows: Exudate: extravascular fluid collection that is rich in protein and/or cells. Fluid appears grossly cloudy. Transudate: extravascular fluid collection that is basically an ultrafiltrate of plasma with little protein and few or no cells. Fluid appears grossly clear.

Effusions into body cavities can be further described as follows: Serous: a transudate with mainly edema fluid and few cells. Serosanguinous: an effusion with red blood cells. Fibrinous (serofibrinous): fibrin strands are derived from a protein-rich exudate. Purulent: numerous PMN's are present. Also called "empyema" in the pleural space.

Purulent exudate meninges

A purulent exudate is seen beneath the meninges in the brain of this patient with acute meningitis from Streptococcus pneumoniae infection. The exudate obscures the sulci.

The abdominal cavity is opened at autopsy here to reveal an extensive purulent peritonitis that resulted from rupture of the colon. A thick yellow exudate coats the peritoneal surfaces. A paracentesis yielded fluid with the properties of an exudate: high protein content with many cells (mostly PMN's).

Here is a purulent exudate in which the exuded fluid also contains a large number of acute inflammatory cells. Thus, the yellowish fluid in this opened pericardial cavity is a purulent exudate.

INFLAMMATIONS
Definition A protective response of vascularized connective tissue to injurious stimuli, leading to the accumulation of fluid and leukocytes in the E/V tissues.

PURPOSE
1.destroy 2.dilute 3.wall off

What will happen without inflammation

1.Infections would go un-checked 2.wounds would never heal

OUTCOMES OF INFLAMMATION
1.REGENERATION 2.SCARRING 3.HARM DONE BY THE RESPONSE ITSELF

TYPES
1.ACUTE SHORT-LIVED (MIN. TO FEW DAYS) ASSOCIATED WITH EXUDATION AND NEUTROPHIL EMIGRATION

TYPES
2. CHRONIC: LONGER-DURATION ASSOCIATED WITH NECROSIS FIBROSIS,PROLIFERATION OF BLOOD-VESSELS AND ACCUMULATION OF LYMPHOS AND MACROPHAGES

COMPONENTS/AFFECTORS OF THE RESPONSE

1.PLASMA 2.CIRCULATING CELLS--NEUTRO

EOSINO BASO LYMPHOS MONOS AND PLATELETS

AFFECTORS CONTD
3.BLOOD VESSELS 4.CELLS/EXTRACELLULAR CONSTITUENTS OF CT: mast cells,histiocytes,fibroblasts and collagen,elastin,fibronectin,laminin etc.

MEDIATORS OF THE RESPONSE

CHEMICALS DERIVED FROM: 1.PLASMA 2.CELLS: BLOOD CT ENDOTH NECROTIC CELLS ALSO

TERMINATION OF THE RESPONSE

REMOVAL OF THE CAUSE OR INHIBITION/DISSIPATION OF THE MEDIATORS

CARDINAL SIGNS
1.RUBOR(redness) 2.TUMOR(swelling) 3.CALOR(heat) 4.DOLOR(pain) 5.FUNCTIO LAESA(loss of function)

Inflammation vs immunity
1.SPECIFICITY 2.MEMORY 3.AMPLIFICATION 4.TYPE OF STIMULUS physical/chemical:inflammation infectious:combined

HOST TISSUE RESPONSE TO INJURY

Injury inducing tissue injury inducing inflam.only damage inflam/immune eg.phy/chem eg.infectious degen or necrosis inflammation immune resp removal of cause chronic inflam resolution(normalcy) repair by scar

Acute inflammation------events
Vascular events a.changes in calibre b.changes in structure Cellular events occuring in the a.lumen b.wall and outside the wall

Vascular events
Changes in the calibre a.trasient VC (arterioles) b.VD (arterioles/capillaries) Outcome of calibre changes a.increased blood flow b.increased hydrostatic pressure

Structural changes (increased permeability,leakage)

Vessels involved:arterioles,capillaries and venules Outcome:exudation Mechanisms:1.endothelial contraction 2.endothelial retraction 3.transcytosis 4.endothelial injury

Mechanisms contd
5.WBC-mediated 6.new blood vessels

Mechanism 1-endothelial contraction

1.vessels involved:- venules 2.type of response:- immediate/trasient 3.cause:chemical mediators 4.mechanism:cells shrink,so I/C junctions open up

Mechanism 2-endothelial retraction(cytoskeletal reorganization)

1.vessels involved:-capillaries/venules 2.type of response:-delayed/prolonged 3.cause:-mediators and sublethal injury to endothelial cells 4.mechanism:-rearrangement of cytoskeleton such that cells retract from each other at I/c junctions

Mechanism 3-increased transcytosis

1.vessels involved:- venules 2.cause:- mediators 3.mechanism:- increased transport across the cell cytoplasm,through small, inter-connected vesicles

Mechanism 4direct endothelial injury

1.vessels involved:-all levels of microcirc 2.type of response:-immediate/sustained 3.cause:-moderate to severe injury 4.mechanism:-necrosis and detachment of cells

Mechanism 5leukocyte-mediated injury

1.vessels involved:-venules 2.cause:-wbc-adherence to endothelium 3.mechanism:-endothelial injury due to toxic factors released from wbc

Mechanism 6leaky new blood vessels

During the process of healing,new blood vessels are formed(angiogenesis);these are leaky due to poorly developed I/c junctions

Outcome of vascular events

EDEMA formation edema is defined as excess fluid in the interstitium or in the body cavities.It can either be: a transudate or an exudate

Exudate vs transudate
Feature 1.permeab 2.protein 3.prot.type 4.fibrin 5.sp.grav 6.cells exudate increased 1.5-6g/dl all yes 1.015-1.027 inflammatory transudate normal 0-1.5g/dl albumin no 1.010-1.015 none

Cellular events
1.margination 2.rolling 3.adhesion 4.transmigration 5.chemotaxis 6.activation 7.phagocytosis role of WBC in inflammation 1.ingest 2.kill 3.degrade 4.prolong inflam 5.tissue damage

Adhesion/transmigration
Two factors are important: 1.complementory adhesion molecules on endothelium and white cells eg a. selectins on endoth/glycoproteins on wbc b.ICAM/VCAM on endoth/integrins on wbc 2.modulation by chemical mediators

Adhesion molecules------role of chemical mediators

They cause: 1.redistribution on surface 2.induction of production 3.increase affinity

chemotaxis
Unidirectional movement of wbc towards a chemical gradient or locomotion oriented along a chemical gradient agents classified: 1.exogenous: bacterial peptides and lipids 2.endogenous:LT,cytokines,complement

mechanism
Chemotactic agent
cell p.lipase-c activated PIP-2 IP-3 + DAG Ca released stimulates contractile apparatus

Leukocyte activation
Chemical mediators DAG

phagocytosis
3 steps involved: 1.recognition/attachement of particle opsonization opsonins 2.engulfment into vacoule 1.Fc of IgG 3.killing/degradation: 2.C3b oxygen-dependant 3.collectins oxygen-independant

Oxygen dependant mechanisms

Non-specific:over-production of free radicals due to increased metabolism specific:hydrogen peroxide-MPO-halide system in the azurophil granules;HOCl produced is bactericidal

Oxygen-independant
BPI factor(bacterial permeability increasing) lysozyme lactoferrin MBP(major basic protein)

Wbc-mediated injury
Regurgitation during feeding frustrated phagocytosis clinical examp 1.ARDS FATE of Neutrophils: 2.asthma apoptosis 3.trasplant rejec 4.arthritis 5.atherosclerosis

Defects in WBC
In adhesion: recurrent infections/impaired healing in phagocytosis: Chediah-Higashi syndrome in bactericidal activity: repeated infections

Chemical mediators of inflammation

stimuli
plasma: cells: precursors activated released from gran 1.bind to receptors or syn 2.act as enzymes 3.oxidative damage 4.stimulate release of mediators from targets

Mediators contd
Such secondary mediators can amplify or counter-act the primary mediators 5.act differently on different target cells
action terminated by decay or inactivation by enzymes

Classification of mediators
Plasma-derived: 1.Hageman-factor related: a.kinin system b.coagulation-fibrinolysis system 2.complement system

Cell derived
Pre-formed in the granules: histamine/serotonin lysosomal enzymes newly synthesized: a. prostaglandins b. leukotrienes c. platelet-activating factor d. reactive oxygen e.cytokines f.NO

Cellular sources of mediators

1.Platelets 3.monocytes/ macrophages 6.smooth muscles 8.epithelia 2.neutrophils 4.mast cells 5.endothelium 7.fibroblasts

Plasma derived mediators

factor-xii activated kinin system clotting cascade fibrinolytic cascade
complement cascade

Complement system
20 proteins in plasma: stimulus activation: C1-C9 i. classic pathway: MAC(C5-9), AA reaction by-products: ii. alternate pathway: a.vascular: a.endotoxins C3a,C5a b.aggregated Ig b.cells: c.polysacch/venom C5a,C3b,

Kinin system
Kininogens in plasma kallikrein vaso-active pep 1.chemotactic esp.bradykinin 2.convert c5 a.VD/permeab to c5a b.pain c.SM contract action terminated by:kininase in plasma and ACE in lungs

Clotting system
Activation of thrombin: increases wbc adhesion, fibrpblast proliferation fibrin/fibrinopeptides: increase permeability, chemotactic

Fibrinolytic system

plasmin cleaves C3

Cell-derived
Pre-formed: 1.Vaso-active amines: serotonin/histamine: tissue distribution:mast cells,basophils,platelets(in the granules) actions: a.dilatation of arterioles b.increased permeability of venules

Amines contd
Stimuli for degranulation: 1.physical:trauma,heat,cold 2.immune reactions 3.complement components,c3a and c5a 4.cytokines /other mediators

Preformed---lysosomal enzymes
Neutrophils have: specific granules containing: lysozyme,collagenases,lactoferrin, plasminogen activator secrete extracellularly azurophil granules containing: MPO,acid hydrolases,neutral proteases

Contd.
Termination: decay or enzymatic check/balance: anti-proteases

Newly synthesized
Arachidonic acid metabolites: .AA is a polyunsaturated fatty acid .derived from diet or synthesized from linoleic acid .exists in esterified form in memb PL .released by phospholipases through: physical,chemical stimuli or mediators

Contd.
Products are also called Eicosanoids;they are: prostaglandins leukotrienes lipoxins thromboxanes

AA metabolism
membrane phospholipids p.lipases x steroids AA NSAIDs LOX COX LT PG (A4 toE4 ) ( D2 toI2) increase permeab pain,fever

PAF
PL-derived sources:mast cells,basophils,platelets,endoth actions:platelet and leukocyte activation increase in permeability chemotaxis smoking generates it

Nitric oxide
Nature:gas source:neurons,macrophages,endothelium actions:paracrine smooth muscle relaxation through GMP production,antimicrobial activity VD,neutrophil activation,plt.aggregation enzymes in synthesis:NO synthetase

Contd.
NO synthetase: .e excited by increased Ca .n .i(cytokine induced)

cytokines
Nature:proteins source:mainly lymphocytes and macrophages types:1.CSF 2.chemokines 3.IL actions:autocrine,paracrine,endocrine

Contd.
Prototypes IL-1 and TNF secrete in response to:endotoxins,AA comp. And physical injury actions:1.acute phase reactions 2.on endothelium TNF controls 3.on white cells body mass 4.on fibroblasts

Most likely mediators of inflammation

Vasodilatation:protaglandins,NO increased permeability:amines,c3a c5a,LT, and bradykinin chemotaxis:chemokines,c5a,LT fever:PG,cytokines(IL-1,IL-6,TNF) pain:PG,bradykinin tissue damage:NO,oxygen,lysosomal enzymes

Systemic effects of inflammation

Acute phase reaction:CRP,SAA,SAP are proteins released by liver that cause activation of complement,opsonization of bacteria and damage microbial cell walls:also there is increased release of glucocorticoids.these account for changes in sleep,appetite and general behavior

Contd.
Fever:IL-1 IL-6 TNF
hypothalamus PG VM centre sympathetic hyperactivity skin vc less heat loss FEVER

Contd.
Leukocytosis:count is beyond 15 to 20,000 neutrophilia:bacterial infections lymphocytosis:viral eosinophilia:allergic/helminthic conditions leukopenia:typhoid,overwhelming leukemoid reaction:very high counts that resemble leukemias can be seen in infections