3. • INFLAMMATION IS FUNDAMENTALLY A
PROTECTIVE RESPONSE
• GOALS ARE ….
• TO GET RID OF THE MICROBES
• TOXINS,NECROTIC CELLS
• BY DESTROYING ,DILUTING AND WALLING
OFF THE INJURIOUS AGENTS
• INFLAMATION IS CLOSELY INTERWINED WITH
THE PROCESS OF REPAIR
4. • DESIRED RESULT OF INFLAMMATION IS …
• REGENERATION (HYPERPLASIA )
• FIBROSIS (SCARRING )
• INFLAMMATION& REPAIR CAN BE POTENTIALLY
HARMFUL
• EXAMPLES ..RHEUMATOID ARTHRITIS
,ATHEROSCLEROSIS ,LUNF FIBROSIS , LIFE
THREATENING HYPERSENSITIVITY
• DISFIGURING SCARS ,INTESTINAL OBSTRUCTION
‘LIMITATION OF THE MOBILITY OF JOINTS .
5. INFLAMMATION IS DIVIDED INTO
ACUTE AND CHRONIC PATTERNS
ACUTE INFLAMMATION
RAPID IN ONSET
LAST FOR MINUTES TO FEW DAYS
CHARECTERISED BY EDEMA & EMIGRATION OF
LEUCOCYTES
CHRONIC INFLAMMATION
LONGER DURATION
HISTOLOGICALLY ASSOCIATED WITH
PRESENCE OF …
6. • LYMPHOCYTES ,MACROPHAGES
,PROLIFERATION OF BLOOD
VESSELS,FIBROSIS,TISSUE NECROSIS
• HISTORICALLY
• ANCIENT ROMAN WRITER CELSUS LISTED 4
CARDINAL SIGNS OF INFLAMMATION
• RUBOR = REDNESS
• TUMOR =SWELLING
• CALOR=HEAT
• DOLAR =PAIN
• VIRHOW GAVE “LOSS OF FUNCTION “.
7. ACUTE INFLAMMATION
• MAJOR COMPONENTS ARE
• ALTERATION IN VASCULAR CALIBER
• STRUCTURAL CHANGES OF THE VESSELS
• EMIGRATION OF THE LEUCOCYTES
& THEIR ACTIVATION
8. • EXUDATE INFLAMMATORY , EXTRAVASCULAR
FLUID WHICH HAS HIGH OROTEIN
CONC.,CELLULAR DEBRIS & A SPECIFIC GRAVITY
ABOVE 1.020
• IT IMPLIES SIGNIFICANT ALTERATION IN THE
NORMAL PERMEABILITY OF SMALL BLOOD
VESSELS IN THE AREA OF INJURY.
• TRANSUDATE FLUID WITH LOW PROTEIN
[ALBUMIN] & A SPECIFIC GRAVITY OF LESS THAN
1.012 .
• IMPLIES ULTRAFITERATE OF BLOOD PLASMA ,
RESULTS FROM OSMOTIC OR HYDROSTATIC
IMBALANCE ACROSS THE BLOOD VESSEL .
9. • PUS , A PURULENT EXUDATE RICH IN
NEUTROPHILLS , DEBRIS OGF DEAD CELLS,
MICROBES .
11. VASCULAR CHANGES
• VASODILATION INVOLVES ARTERIOLES FIRST
FOLLOWED BY OPENING OF NEW CAPILLARY
BEDS , INDUCED BY HISTAMINE & NITRIC
OXIDE .
• FOLLOWED BY INCREASED PERMEABILITY
WITH OUTPOURING OF PROTEIN RICH FLUID
• STASIS , WITH STASIS CELLS ACCUMULATE
ALONG THE ENDOTHELIUM & MIGRATE OUT
OF THE BLOOD VESSELS .
13. • DECREASED INTRAVASCULAR OSMOTIC
PRESSURE & INCREASED OSMOTIC PRESSURE
IN THE INTERSTITIAL TISSUE ( BECAUSE OF
LOSS OF PROTEINS FROM VESSELS TO
OUTSIDE ) WITH INCREASED HYDROSTATIC
PRESSURE IN THE VESSELS (BECAUSE OF
DILATED ARTERIOLES ) , THERE IS NET
OUTWARD FLOW OF FLUID LEADING TO
EDEMA
14. VASCULAR LEAKAGE
• ENDOTHELIAL GAP
• DIRECT INJURY
• LEUCOCYTE DEPENDENT INJURY
• INCREASED TRANSCYTOSIS
• NEW BLOOD VESSEL FORMATION
15. ENDOTHELIAL GAP FORMATION
• MOST COMMON MECHANISM
• IMMEDIATE & TRANSIENT
• AFFECTS VENULES
• ELICITED BY HISTAMINE ,BRADYKININ
,LEUCOTRIENES,SUBSTANCE P,ETC
• PHOSPHORYLATION OF THE CONTRACTILE PROTEINS
SUCH AS MYOSIN
• CYTOKINES SUCH AS IL-I,TNF ,IFN-Y CAUSE
STRUCTURAL REORGANISATION OF CYTOSKELETON
AND CELLS RETRACT FROM EACH OTHER (DELAYED &
LONG LIVED )
16. DIRECT INJURY
• SEVERE BURNS ,LYTIC BACTERIAL INFECTIONS
• RESULTS FROM NECROSIS & DETACHMENT
• VENULES,CAPILLARIES,ARTERIOLES
• IMMEDIATE & SUSTAINED RESPONSE
17. LEUCOCYTE DEPENDENT INJURY
• IN THE EARLY INFLAMMATION LEUCOCYTES
AFER ACTIVATION RELEASE PROTEOLYTIC
ENZYMES & TOXIC OXYGEN SPECIES
• LARGELY RESTRICTED TO VASCULAR SITES
SUCH AS VENULES & PULMONARY AND
GLOMERULAR CAPILLARIES WHERE
LEUCOCYTES ADHERE FOR PROLONGED
PERIOD .
21. • MARGINATION ….IN EARLY INFLAMMATION
• THERE IS STASIS IN THE FLOW OF BLOOD AND
MORE OF THE WBCs OCCUPY A PERIPHERAL
POSITION
• ROLLING…ROWS OF WBCs TUMBLE SLOWLY
ALONG THE ENDOTHELIUM & ADHERE ONLY
TRASIENTLY TO THE ENDOTHELIUM
• ADHESION …AFTER ROLLING WBCs FINALLY STICK
WITH THE ENDOTHELIUM
• AFTER ADHESION LEUCOCYTES INSERT
PSEUDOPODS INTO THE JUNCTIONS BETWEEN
THE ENDOTHELIAL CELLS & SQUEEZE OUT
THEMSELVES TO OUT SIDE BLOOD VESSELS
22. • LEUCOCYTE ADHESION & TRANS MIGRATION
ARE LARGELY REGULATED BY BINDING OF
COMPLIMENTARY ADHESION MOLECULES ON
THE RESPECTIVE RECEPTORS
• AND CHEMOATTRACTANTS & CERTAIN
CYTOKINES AFFECT THESE PROCESSES BY
MODULATING AVIDITY OF SUCH ADHESION
MOLECULES & SURFACE EXPRESSION OF THE
RECEPTORS
23. • ADHESION RECEPTORS BELONG TO 4
MOLECULAR FAMILIES
• SELECTINS
• IMMUNOGLOBULIN SUPER FAMILY
• INTEGRINS
• MUCIN LIKE GLYCOPROTEINS
24. SELECTINS THEY ARE SO CALLED BECAUSE
THEY CARRY AN EXTACELLULAR N-TERMINAL
DOMAIN RELATED TO SUGAR BINDING
MAMMALIAN LECTINS
• E-SELECTIN ……..ENDOTHELIUM
• P-SELECTIN………ENDOTHELIUM & PLATELETS
• L-SELECTIN……….LEUCOCYTES
• SELECTINS BIND THROUGH LECTIN DOMAIN
TO SIALYLATED FORM OF OLIGOSACCHARIDES
(SIALYLATED LEWIS X ) WHICH THEMSELVES
ARE BOUND TO MUCIN LIKE GLYCOPROTEINS
25. IMMUNPOGLOBULIN SUPER FAMILY
MOLECULES
1)ICAM -1(INTERCELLULAR ADHESION
MOLECULE 1)
2)VCAM -1(VASCULAR CELL ADHESION
MOLECULE 1)
• BOTH SERVE AS LIGANDS FOR INTEGRINS
FOUND ON LEUCOCYTES
27. MUCIN LIKE GLYCOPROTEINS
• HEPARAN SULFATE
• FOUND IN EXTRACELLULAR MATRIX & ON CELL
SURFACES
• SERVE AS LIGAND FOR LEUCOCYTE ADHESION
MOLECULE CD 44
28. • MEDIATORS SUCH AS HISTAMINE ,THROMBIN
& PAF STIMULATE DISTRIBUTION OF P
SELECTIN WHICH ARE STORED IN WEIBEL
PALADE BODIES
29. TNF & IL-1 ACT ON ENDOTHELIAL CELLS
INDUCE EXPRESSION OF LIGANDS
• PSELECTIN (ENDOTHELIUM )……SIALYL LEWIS X
(OF WBC)
• E SELECTIN (ENDOTHELIUM )…..SIALYL LEWIS
X(WBC )
• ICAM -1(ENDOTHELIUM )……INTEGRINS (WBC
)
30. CHEMOKINES THAT ARE PRODUCED AT THE
SITE OF INJURY ENTER THE BLOOD STREAM
AND ACT ON THE ROLLING WBCs AND
ACTIVATE THEM AND INCREASE THE AFFINITY
OF THE INTEGRINS (WBCs ) FOR THE
ENDOTHELIAL CELL RECPTORS
31. • LEUCOCYTE DIAPEDESIS PREDOMINANTLY
OCCURS IN VENULES
• WBCs SECRETE COLLAGENASES AND PIERCE
THE BASEMENT MEMBRANE
• IN THE EXTRAVASCULAR CONNECTIVE TISSUE
WITH THE HELP OF BETA 1 INTEGRIN & CD 44
ADHERE TO MATRIX PROTEINS
32. • LAD 1( LECOCYTE ADHESION DEFICIENCY
THERE IS DEFECT IN THE SYNTHESIS OF BETA 2
CHAIN SHARED BY LFA1& Mac 1 INTEGRINS
• LAD 2 THERE IS ABSENCE OF SIALYL LEWIS X ,
LIGAND FOR E SELECTIN ,DUE TO DEFECT IN
FUCOSYL TRANSFERASE WHICH BINDS
FUCOSE MOIETY TO PROTEIN BACKBONE
33.
34. • NEUTROPHILLS PREDOMINATE DURING 6 TO 24
HOURS
• MONOCYTES IN 24 TO 48 HOURS
• NEUTROPHILLS AFTER ENTERING TISSUES ARE
SHORT LIVED THEY DISSAPPEAR AFTER 48 HOURS
• PSEUDOMONAS ….NEUTOPHILLS REMAIN 2 TO 4
DAYS
• VIRAL INFECTION …..LYMPHOCYTES ARE FIRST
CELLS TO ARRIVE
• HYPERSENSITIVITY REACTIONS …..EOSINOPHILLIC
GRANULOCYTES ARE THE MAIN TYPE
35. CHEMOTAXIS
IT IS THE EMIGRATRION OF THE WBCs IN
TISSUE TOWARDS THE SITE OF INJURY ALONG
A CHEMICAL GRADIENT
• EXOGENOUS AGENT…..BACTERIAL PRODUCTS
• ENDOGENOUS AGENTS……C5a,PRODUCTS OF
LIPOXYGENASE PATHWAY LTB4,CYTOKINE IL-8
36. • ALL THESE CHEMOTACTIC AGENTS BIND TO
GPCRs ( G PROTEIN COUPLED RECEPTOR ) ON
WBCs
• THERE IS RECRUITMENT OF G PROTEIN AND
ACTIVATION OF PHOSPHOLIPASE C PHOSPHO
INOSITOL 3 KINASE & TYROSINE KINASE
• PHOSPHOLIPASE C & PHOSPHO INOSITOL 3
KINASE ACT ON MEMBRANE INOSITOL
PHOSPHOLIPIDS TO GENERATE LIPID SECOND
MESSENGERS WHICH INCREASE CYTOSOLIC
CALCIUM & ACTIVATE GTPases …INDUCE
POLYMERISATION OF ACTIN AT THE LEADING
END OF THE CELL
37. LEUCOCYTE ACTIVATION
• MICROBES ,PRODUCTS OF NECROTIC
CELLS,AG-AB COMPLEXES,CYTOKINES INDUCE
A NUMBER OF RESPONSES IN LEUCOCYTES …
1)PRODUCTION OF ARACHIDONIC ACID
METABOLITES
2)SECRETION OF CYTOKINES
3)MODULATION OF LEUCOCYTE ADHESION
MOLECULE
38. • LEUCOCYTES EXPRESS FOLLOWING
RECEPTORS WHICH ARE INVOLVED IN ITS
ACTIVATION
• TOLL LIKE RECEPTOR
• SEVEN ALPHA HELICAL TRANSMEMBRANE
RECEPTOR , ETC
39. TOLL LIKE RECEPTOR (TLR)
• PLAY ESSENTIAL ROLES IN CELLULAR
RESPONSE TO LIPOPOLYSACCRIDES ,OTHER
BACTERIAL PRPOTEOGLYCANS
• RESULTS IN PRODUCTION OF CYTOKINES AND
REACTIVE OXYGEN INTERMEDIATES
40. SEVEN ALPHA HELICAL
TRANSMEMBRANE RECEPTOR GPCRs
• RECOGNISE N-FORMYL METHIONYL RESIDUES,
• CHEMOKINES (C5a,LTB4,IL-8)
• THERE IS EXCHANGE OF GTP FOR GDP , GTP
BOUND FORM ACTIVATES MANY ENZYMES
,,PHOSPHOLIPASE C WHICH DEGRADES
MEMBRANE PHOSPHOLIPD AND INCREASE
CYTOSOLIC CA ++ IONS , ULTIMATELY CELL
LOCOMOTION.
41. C1Q BINDS MICROBES OPSONISED WITH
PLASMA MBL(MANNOSE BINDING LECTIN ),
INTEGRINS BIND FIBRINOGEN COATED
PARTICLES
ACTIVATION THROUGH THESE RECEPTORS
RESULTS IN ENHANCEMENT OF
PHAGOCYTOSIS
42.
43. PHAGOCYTOSIS
• THREE DISTINCT STEPS
• RECOGNITION & ATTACHMENT OF THE
PARTICLE
• ENGULFMENT..PHAGOCYTIC VACUOLE
FORMATION
• KILLING & DEGRADATION
44. MANNOSE RECEPTORS & SCAVENGER RECEPTOR
• INVOLVED IN RECOGNITON & ATTACHMENT
• MANNOSE RECEPTOR IS A LECTIN WHICH BINDS
WITH THE MANNOSE,FUCOSE RESIDUES OF
GLYCOLIPID AND GLYCOPROTEINS FOUND ON THE
CELL WALLS OF MICROBES
• SCAVENGER RECEPTOR
• DEFINED AS MOLECULES THAT BIND AND
MEDIATE ENDOCYTOSIS OF OXIDISED AND
ACETYLATED LDL PARTICLES THAT CAN NO
LONGER INTERACT WITH LDL RECEPTOR
45. ENGUFMENT
• EXTENSIONS OF CYTOPLASM OF THE
MACROPHAGE COMPLETELY SURROUND THE
PARTICLE AND ENCLOSE IT WITHIN A
PHAGOSOME
• MEMBRANE OF THIS PHAGOSOME THEN
FUSES WITH THE MEMBRANE OF THE
LYSOSOME
• RELEASE OF THE LYSOSOMAL GRANULES INTO
THIS PHAGOLYSOSOME
46. KILLING & DEGRADATION
• ACCOMPLISHED BY OXYGEN DEPENDENT
MECHANISMS LARGELY
THERE IS RAPID ACTIVATION OF NAPDH
OXIDASE WHICH REDUCES OXYGEN TO SUPER
OXIDE ANION
• NAPDH OXIDASE IS A COMPLEX OF SEVEN
PROTEIN, LOCATED AT THE PLASMA
MEMBRANE OF THE PHAGOSOME
• SUPER OXIDE IS THEN CONVERTED TO
HYDROGEN PER OXIDE
47. • AZUROPHILLIC GRANULES OF NEUTROPHILLS
CONTAIN MYELOPEROXIDASE ENZYME
WHICH IN PRESENCE OF HALIDE CONVERTS
IT INTO HOCL…HYPOCHLORITE
• H2O2-MPO –HALIDE SYSTEM IS THE MOST
EFFICIENT BACTERICIDAL SYSTEM
48. • OXYGEN INDEPENDENT MECHANISMS
• ARE THOSE THROUGH THE ACTION OF
SUBSTANCES IN LEUCOCYTE GRANULES
BPI….BACTERICIDAL PERMEABILITY INCREASING
CAUSES PHOSPHOLIPASE
ACTIVATION,PHOSPHOLIPID
DEGRADATION,INCREASED MEMBRANE
PERMEABILITY
LACTOFERRIN …FOUND IN EOSINOPHILLS
DEFENSINS….
LYSOZYME…..HYDROLYSES MURAMIC ACID –N-
ACETYL -GLUCOSAMINE
51. Inflammation
• “Inflame” – to set fire.
• Inflammation is “dynamic response of
vascularised tissue to injury.”
• Is a protective response.
• Serves to bring defense & healing
mechanisms to the site of injury.
52. Inflammation
• Inflammation is the process in which healthy
tissue responds to an injury.
• Purpose of inflammation
– to destroy and remove substances recognized as
being foreign to the body;
– to prevent minor infections from becoming
overwhelming;
– To prepare any damaged tissue for repair.
53. • Defn: Complex reaction to injurious agents
like-Microbes, Physical, chemical; Leading to
Damage & Necrosis of Cells; which shows
vascular Response, WBC response & other
Systemic reactions.
• Reaction of Blood Vessels, leading to
accumulation of Fluid & WBCs in Extra
vascular tissues.
55. Historically
• Celcus in 1st century AD listed the cardinal
Signs of Inflammation.
-Rubor, Calor, Tumor, Dolor.
• Virchow later added 5th sign- Functio laesa.
• Metchnikoff & Paul Ehrlich- WBCs & Serum
factors are critical in defense against the
microbes. (Nobel Prize in 1908)
• Sir Thomas Lewis- Chemical mediators in
Inflammation.
63. Classic Signs of Inflammation
• Rubor -- erythema due to capillary
dilation
• Calor -- warmth due to increased blood
flow
• Tumor -- edema
• Dolor -- pain due to local pressure and
stimulation of nerve endings
• Functio laesa -- alteration in function
74. • Vasodilatation induced by Chemical
mediators: Histamine & Nitric oxide
• Initially starts in the Arterioles later in the
Capillaries.
• Followed by Increased vascular
permeability.
• Stasis of blood, Loss of Plasma, Proteins
and later the WBCs.
75. Phases of Fluid Loss & Permeability
• Immediate Transient Response: 30 min.
Mediated by Histamine & leukotrienes.
• Delayed response: 2 Hrs. Mediated by Kinins,
complements.
• Prolonged response: Mediated by direct
endothelial Injury.
77. PHASES OF CELLULAR EVENTS
• WBC Margination, Rolling &
Adhesion.
• Transmigration across Endothelium
• Chemotaxis
• Leukocyte activation
• Phagocytosis
78.
79. WBC Adhesion & Transmigration
• Regulated by the binding of complimentary
Adhesion molecules on WBC & Endothelial
surface.
• Surface expression is modified by Chemical
mediators like cytokines which causes
Chemoattraction.
• There are Four classes of Cell Adhesion
Molecules
80. CEL ADHESION MOLECULES
1. Selectins:: L, E, P types
2. Immunoglobulin family:: ICAM,
VCAM
3. Integrins:: Beta-1 & Beta- 2 types.
4. Mucin like Glycoproteins:: CD 44
81. Functions of cell Adhesion Molecules
• Rolling of WBCs in Lumen
• Adhesion to Endothelium
• Arrest of motion
• Activation
• WBC migration
• Leukocyte Homing.
82.
83. CHEMOTAXIS
• Is Migration of WBCs in tissue towards the site
of Injury
• LOCOMOTION oriented along the CHEMICAL
GRADIENT.
• Chemoattractants can be Exogenous or
Endogenous.
• Bacterial products, Complements, leukotriens,
Cytokines are Chemoattractants.
84. • WBCs move by extending the filopodia.
• Rapid assembly of Actin monomers into
Actin polymers occurs
• Actin regulating proteins are ::
-Filamin
-Gelsolin
-Profilin
-Calmodulin.
85. LEUKOCYTE ACTIVATION
• Activated by Microbes, Necrotic cells, Ag-Ab
complexes, Chemotactic factors, Cytokines.
• Activation leads to::
-Production of Arachidonic acid metabolites
-Secretion of Lysosomal enzymes
-Degranulation
-Secretion of cytokines
-Modulation of CAM
86.
87. Cellular Response - Margination
• Movement of neutrophils toward the
endothelial lining
• Causes of margination
– electrical charge on the endothelial cells changes
– blood viscosity increases
– chemical mediators
88. Cellular Response - Diapedesis
• Diapedesis means “cell-walking”
• When activated, neutrophils squeeze
through the endothelial gaps into the tissues
by a process known as Diapedesis
93. Cellular Response - Chemotaxis
• Chemotaxis is the directional and purposeful
movement of cells by amoeboid movement
toward an area of injury in response to a
chemical mediator.
95. Acute/Chronic Inflammation
• Acute
• Short term
inflammatory
process that
complete resolves
– mostly Neutrophils,
Eosinophils,
Macrophages etc.
• Chronic
• long term that may
or may not
completely resolve
– mostly Lymphocytes,
Plasma cells,
Macrophages, etc.
