Acute inflammation / dental implant courses by Indian dental academy

INDIAN DENTAL ACADEMY
Leader in continuing Dental Education
www.indiandentalacdemy.com

ACUTE INFLAMMATION
INDIAN DENTAL ACADEMY
Leader in continuing Dental Education

• DEFINATION
• HISTORICAL HIGHLIGHTS
• STIMULI
• CELLS
• CARDINAL SIGNS
• VASCULAR EVENTS
• CHEMICAL MEDIATORS
• CELLULAR EVENTS
• PHAGOCYTOSIS
• REGULATION,SYSTEMIC EFFECTS.
• OUTCOMES
• MORPHOLOGIC PATTERN
• REFERENCES

• DEFINATION: ACUTE INFLAMMATION IS A
COMPLEX REACTION TO INJURIOUS AGENTS
SUCH AS MICROBES & DAMAGED, USUALLY
NECROTIC CELLS THAT CONSIST OF VASCULAR
RESPONSES,MIGRATION & ACTIVATION OF
LEUCOCYTES & SYSTEMIC REACTIONS IN A
VASCULARISED TISSUE.

• Without inflammation, infections would go
unchecked,wounds would never heal & injured
organs might remain permanent fostering
sores.
• Inflammation is fundamentally a protective
response, the ultimate goal of which is to rid
the organism of both the initial cause of cell
injury eg, microbes,toxins & the consequences
of such injury eg necrotic cells & tissues.
• Is closely interwined with the process of
repair.,inflammation & repair may be
potentially harmful however.

• Historically,inflammation has been referred to
as either ACUTE OR CHRONIC, depending on
the persistence of the injury,the nature of the
inflammatory response.
• ACUTE: is rapid in onset-seconds or minutes &
is of relatively short duration lasting for several
minutes, hours or few days with
exudation,predominant presence of
neutrophils.
• chronic ?

• Historical highlights:the clinical signs of
inflammation termed PHLOGOSIS by the
Greeks & INFLAMMATION in Latin were
described in classic times.
• In the 2nd
centuryAD, AULUS CELSUS
• described the four cardinal signs of
inflammaton,namely, RUBOR,CALOR,TUMOR,
& DOLOR.
• fifth sign,FUNCTIOLAESA was later added by
VIRCHOW.
• According to medieval concepts, inflammation
represented an imbalance of various humors
including mucus,bile and blood.

• The modern understanding of the vascular
basis of inflammation began in 18th
century with
the observation of JOHN HUNTER who noted
dialatation of blood vessels and appreciated
that pus represents an accumulation of
material derived from the blood.
• That inflammation is usually a reaction to prior
tissue injury was described by RUDOLF
VIRCHOW, whose Pupils JULIUS CONHEIM was
the first to associate inflammation with
emigration of leucocytes through the walls of
microvasculature.

• At the turn of 19th
century,the role of
phagocytosis in the inflammatory process
was emphasized by the great Russian
zoologist ELI METCHINKOFF
• The importance of chemical mediators in
the inflammatory process was described in
1927 by THOMAS LEWIS, who
demonstrated that HISTAMINE & other
substances produced an increase in
vascular permeability & elicited the
migration of leucocytes into the
extravascular spaces.

• Acute inflammation has 3 major
components:
• 1-alteration in vascular caliber that lead to
an increase in blood flow
• 2-structural changes in the microvasculatue
that permit plasma proteins & leucocytes
to leave the circulation.
• 3-emigration of the leucocytes from the
microcirculation, their accumulation in the
focus of injury,& their activation to
eliminate the offending agent.

• STIMULI:
• INFECTIONS & MICROBIAL TOXINS
• TRAUMA
• PHYSICAL & CHEMICAL AGENTS- thermal
injury; burns or frostbite, irradiation, some
environmental chemicals.
• TISSUE NECROSIS from any cause
• FOREIGN BODIES; splinters,dirt ,sutures.
• IMMUNE REACTIONS

• CELLS OF INFLAMMATION
• Leucocytes are the major cellular
components of
inflammation:NEUTROPHILS,T &B
lymphocytes, mast cells
,eosinophils,basophils etc.
• NEUTROPHILS are the hallmark of acute
inflammation.-accumulate at the site of
injury, -are activated in response to
phagocytic stimuli,cytokines ,
chemokines,chemoattractant mediators, ag
–ab complexes that bind specific receptors
on their cell membrane.www.indiandentalacdemy.com

• Eosinophils;characteristic of Ig E mediated
reactions_hypersensitivity,asthama
• contain leukotreins,PAF, as well as acid
phosphatase, peroxidase. ,contain large granules
with eosinophilic major basic protein involved in
defense against parasites.
• Platelets source of inflammatory mediators,
dense granules rich in
serotonin,histamine,calcium,ADP; degranulation
causes increase in vascular permiability,also
secrete cationic proteins that neutralize the
negative charges on the endothelium & promote
increased permeability.

• Endothelial cells:are flattened cells that
form a monolayer lining theblood
vessels.they maintain patency & blood flow
through the production of
antiplatelet,antithrombin agents & regulate
vascular tone through the production of
vasodialators & vasoconstrictors.
• an intact endothelial cell lining inhibits
platelet adheion and blood clotting,
whereas injury to blood vessel alters the
endothelial barrier & expose local
procoagulant signal.
•

• Endothelial cells function as gatekeepers in
inflammatory cell recruitment, presenting
adhesion molecules to anchor flowing
leucocytes.
• Respond rapidly to inflammatory agents
such as bradykinin,
histamine,endotoxins,cytokines.

• VASCULAR EVENTS:
• VASODIALATATION;earliest.
• follows transient vasoconstriction of
arterioles lasting few seconds.
• increased blood flow-heat,
redness
• histamine,nitric oxide.
• INCREASED PERMEABILITY OF THE
MICROVASCULATURE.:VASCULAR LEAKAGE.

• CARDINAL SIGNSOF INFLAMMATION
:redness & heat
• :swelling-accumulation of excess interstitial
fluid which contains solutes,proteins
derived from the plasma in the
extavascular compaetment.
• :pain-less well understood than the other
cardinal signs. The local increase in the
tissue turgor is one of the factor
involved,and denser the tissue effected
greater the degree of pain some
endogenous chemical copmpounds-

EDEMA: THE HALLMARK OF ACUTE INFLAMMATION IS
INCREASED VASCULAR PERMIABILITY LEADING TO
ESCAPE OF EXUDATE INTO EXTAVACULAR SPACE,
RESULTING IN EDEMA.
About one sixth of the total volume of the body
consists of spaces between the cells which is collectively
caled the INTERSTITIUM.& the fluid is, interstitial fluid.
Hydrostratic pressure in the capillaries tend to force the
fluid and its dissolved substances through the capillary
pores into the interstitial space.

• Conversely osmoic pressure caused nu the
plasma proteins-colloid osmotic pressure
tends to cause fluid movement
• by osmosis from interstitial space into
blood. This normally prevents significant
loss of fluid volume into the interstital
space.
• Lympatic sysyem- returns to the
circulation the small amount of excess
protein& fluid that leaks from the blood
unto interstitial; space.

• The average capillary pressure at the
arterial ends of the capillaries is 15-20
mmHg greter than at the venoc end.
• FORCES TENDING TO MOVE FLID
OUTWARD:
• Capillary pressure-A 30mmHg
• Negative interstitaial
• fluid pressure 3mmHg
• Interstitial fluiid osmotic
• pressure 8mmHg
• = 41mmHg.

• FORCES TENDING TO MOVE FLUID INWARD
• Plasma colloid osmotic
• pressure 28mmHg
• total inward force 28mmHg
• SUMMATION OF FORCES
• OUTWARD 41mmHg
• INWARD 28mmHg
• NET OUTWARD FORCE AT
• ARTERIAL END =13mmHg
• TENDING TO MOVE FLUID OUTWARD
THROUGH THE CAPILLARY PORE.

FORCES TENDING TO MOVE THE FLUID INWARDS
Plasma colloid oncotic pressure 28mmH
total inward force 28mmHg
FORCES TENDING TO MOVE FLUID OUTWARD
Capillary pressure at venous end 10mmHg
Negative interstitial fluid pressure 3mmHg
Interstitial fluid colloid osmotic p 8mmHg
total outward force =21mmHg

• SUMMATION OF FORCES
• INWARD 28mmHg
• OUTWARD 21mmHg
• NET INWARD FORCE = 7mmHg
• causes fluid to move into the capillaries.
• E .H . STARLING pointed out that under
normal conditions a state of near
equilibrium exists at the capillary
membrane i.e,

• Normal fluid exchange & microvascular permiability are
critically dependent on an intact endothelium
endothelium leaky in inflammation?
• 1 Formation of ENDOTHELIAL GAPS in venules.-
histamine,bradykinin,leukotreins,neuropeptide substance
P,IL-1,TNF,interferon-gamma
• reversible,short lived;immediate transient response.
• affects venules 20 – 60 micrometer in diameters
• Intracellular signalling pathways—PHOSPHORYLATION OF
CONTARCTILE & CYTOSKELETAL PROTEINS---contraction of
endothelial cells & seperation of intercellular junctions.

• DIRECT ENDOTHELIAL INJURY—endothelial cell
necrosis & detachment: necrotizing injuries-
immediate sustained response.
• venules,capillaries,arterioles
• DELAYED PROLONGED LEAKAGE–
• after a delay of 2 – 12hrs,lasts for several hrs
or days
• thermal injury,x radiation, UV radiation
• LEUCOCYTE MEDIATED ENDOTHELIAL INJURY
• venules,pulmonary & glomerular capillaries

• INCREASED
TRANCYTOSIS ACROSS
THE ENDOTHELIAL
CYTOPLASM—VEGF
•
• LEAKAGE FROM NEW
BLLOD VESSELS

CHEMICAL MEDIATORS.

• CHEMICAL MEDIATORS:
• Many are responsible for the events of
inflammation.
• Plasma derived 3 major enzyme cascades
each of which is composed of series of
sequentially activated proteases. These
interrelated systems include
• coagulation cascade
• kinin system
• complement system

• Clotting system & inflammation are
intimately connected process
• the protease thrombin provides the main
link
• binds to receptors that are called
PROTEASE ACTIVATED RECEPTORS,
EXPRESSED ON PLATELETS,ENDOTHELIAL
CELLS,SMOOTH MUCLE CELLS & MANY
OTHER
•

• Engagement of PAR-1 by thrombin triggers
• mobilization of P selectin
• production of chemokines
• Expression of endothelial adhesion molecules
for ;eucocyte integrins
• Induction of COX 2---PRODUCTION OF
PROSTAGLANDINS
• Production of PAF & NO
• Changes in endothelial shape

Factor 12A ACTIVATE FIBRINOLYTIC SYSTEM,
contributes to the vascular phenomenon
• Plasminogen--------plasmin
• cleaves C3 to produce C3 fragments
• degrades fibrin to form fibrin split
products, have permiability inducing
properties.

• KININ SYSTEM
• generates vasoactive peptides,
nonapeptide-BRADYKININ
• INCREASES VASCULAR PERMIABILITY,
CONTRACTION OF SMOOTH MUCLE CELLS,
DILATATION OF BLOOD VESSELS, & PAIN
WHEN INJECTTED INTO SKIN.
• SIMILAR TO HISTAMINE
• Kallikrein has chemotactic activity, directly
converts C5 to C5 a.

• COMPLEMENT SYSTEM
• Vascular phenomenon:C3a,C5a,C4a—
histamine release from mast cells----increase
vascular permiability & vasodilatation.
• anaphylactins
• C5a –activates lipoxygenase pathway of AA
metabolism---furter release of inflammatory
mediators.
• leucocyte adhesion, chemotaxix &
activation. Ic3 B---OPSONIN.

• CELLULAR DERIVED:
• VASOACTIVE AMINES:
• histamine.—widely distributed, richest being MAST
CELLS.,also found in basophils,platelets.
• mast cell degranulation—physical injuries,immune
reactions,C3a,C5a,,HRProtiens by leucocytes,substance
P, IL-1, IL-8.
• dialatation of arterioles,increased permeability of
venules
• principal mediator of immediate transient phase.
• SEROTONIN.---HISATAMINE.

• ARACHIDONIC ACID METABOLITES.
• AA—20 carbon PUFA derived from leonoleic
acid.
• esterified in membrane phospholipids,
• relesed from the action of PHOSHOLIPASE
A2.,brought about by increase cytosolic calcium,
varios kinases.
• Cyclooyygenase & lipoxygenase pathway.

• COX pathway:
• prostacyclin-PGI2:vasodilatation,increase
platelet aggretation
• TXA2:vasoconstriction,promote platelet
aggregation.
• PGD2,PGE2,PGF2-alpha: vasodilatation—
potential oedema.
• LOX pathway;
• 5HETE-hydroxyeicosatetraenoic acid—
chemotaxis.
•

• LEUKOTRIEN A4,B4 –CHEMOTAXIS
• LEUKOTRIEN
C4,D4,E4:vasoconstriction,increase
permiability.
• LIPOXIN A4,B4:vasodilatation,inhibit
neutrophil chemotaxis,stimulate monocyte
adhesion.
• Resolvins;have been identified in
experimental animals treted with aspirin---
inhibit leucocyte recruitment & activation.

• PAF: bioactive phospholipid derived
mediator.
•
platelets,basophils,neutrophils,monocytes,
macrophages,endothelial cells can
elaborate PAF in both secreted & cell
bound form.
•
vasoconstriction,bronchoonstriction,extem
ely low concentration—vasodilatation &
increased venular permeability.
• increses L adhesion to endothelial
cells,chemotaxis,degranulation & oxidative
burst. www.indiandentalacdemy.com

• CYTOKINES:proteins produced by many cell
types that modulate the function of other
cell types.
• TNF-alpha & IL-1
• activated macrophages
• bacterial products,immnne complexes,
toxins,physical injuries,other cytokines
• ---acute phase reactions
---endothelial effects:increase L
adherence,PG synthesis,procoagulant
activity,IL1.IL8.IL6,PGDF.
----IL1,IL 6 www.indiandentalacdemy.com

• CHEMOKINES:are a family of small protiens
that act primarily as chemoattractants for
specific types if leucocytes.
• 40 different C , 20 different receptors
have been identified.
• 4 major groups according to the
arrangement of conserved cysteine-C
residues in the mature proteins.
• C-X-C:1L-8—ACTIVATION & CHEMOTAXIS
OF NEUTROPHILS.

• C-C:BETA ,:mcp-Monocyte
Chemoattracatant Protein,
eotaxin,Macrophage Inflammatory
Protein,RANTES:attract
monocytes,eosinophils,basophils,lymphooc
ytes
• C:LYMPHOTACTIN—SPECIFIC FOR
LYMPHOCYTES.
• CX3C:fractalkinepromote strong adhesion
of monocytes & Tcells.

• NO:NITRIC OXIDE:soluble gas produced by
endothelial cells,macrpohages & some neurones
in the brain.
• Vasodilatation,reduce platelet aggregation,inhibit
several features of mast cell induced
inflammation—endogenous regulator of
leucocyte recruitment.----reduce the
inflammatory response.
• LYSOSOMAL CONSTITUENTS OF LEUCOCYTES.
• destructive effects—tissue damage
• ROI--
• NEUROPEPTIDES—substance P ,neurokinin A;
INCREASE VASCULAR PERMIABILITY.

• CELLULER EVENTS:LEUCOCYTE
EXTRAVASATION & TRANSMIGRATION.
• requires a complex series ofinteractions
between endothelium &
leucocyte;receptor—conterreceptor
interactions.
• Adhesion receptors invilved belong to 4
molecular families.
• SELECTINS
• IMMUNOGLOBULIN FAMILY
MOLECULES.ICAM, VCAM.
• INTEGRINS.
• MUCIN LIKE GPs.

• Selectins:family of three closely related proteins
• function in adhesion of L toendothelial cells.
• single chain transmembrane GPs with an amino
terminus related to cho-binding proteins known
as C type lectins.
• has a fast on rate & fast off rate.—rolling .
• L selectin:CD62L—lymphocytes& other
leucocytes.—located on the tips of microvillous
projections of L.
• ENDOTHELIAL CELL LIGANDS:
• GlyCAM 1—HEVs of lymph node.
• MadCAM 1—ENDOTHELIAL CELLS IN GALT. &
CD34.

• E selectinCD62 E –ELAM 1:cytokine
activated endothelial cells.
• important in homing if effector &
memory T cells to some peripheral sites of
inflammation
• P selectin.CD62P:secretory granules of
platelets
• endothelialcells—Weibel Palade bodies.
• mediates binding ofneutrophils,T cells &
monocytes.

• INTEGRINS—30 structurally homologus proteins
that promote cell—cell, cell—matrix interactions.
• they coordinate the signals from extacellular
ligands with cytoskeleyon– dependent
motility,shape change& phagocytic response.
• alpha & beta polypeptide chains.
• subfamilies—3 beta subunits,now additional 5
have been identified.
• Beta1—VLA
molecules;CD49ahCD29:ATTACHMENT OF CELLS
TO ECM MOLECULES

• VLA 4:ONLY ON L, mediate attachment of
these cells toendothelium byinteracting
with VCAM.
• BETA 2 itnegrins:
• CD11a-CD18—LFA1: adhesion of
lymphocytes & other L with APC,vascular
endothelium.
• CD11b-CD18—Mac 1:
• CD11c-CD18 : mediate L
attachment to endothelial cells &
subsequent extravasation.

• CELLULAR EVENTS:
• in the lumen
• MARGINATION
• ROLLING
• PAVEMENTING
• FIRM ADHESION
• INDUCTION OA ADHESION
MOL;histamine,PAF,TNF,IL1,Chemokines.
• TNF,IL1:endothelial expression of VCAM,ICAM.
• CHEMOKINES;BIND TO proteoglycans,activate
L,stimulate diapedisis.

• In the ECM ,L adhere by virtue of beta 1
integrins,CD44.
• CHEMOTAXIS:
• CHEMOATTRACTANTS:
• exogenous:bacterial products
• endogenous:C5a,LTB4,IL8.
• G PROTEIN COUPLED RECEPTORS ON THE
L
• activation of several effector
molecules:phosholipase c, phpsphinositol 3
kinase,protien tyrisine kinase.

• Activation of oxidative burst., secretion of
cytokines,modulation of L adhesion
molecules.
• L surface receptors.
• Toll like receptors—bacterial
LPS,PROTEOGLYCANS..FOUND ONLY IN
BACTERIA.
• Different seven transmembrane G
protein coupled receptors—recognise short
peptides containingN-formylmethionyl
residues,chemokines,PAF,LTB4,C5a.

• generate lipid second mrssangers—increase
cytosolic calcium& GTPases
• increased polymerised actin, actin organization
• cross linking of the filaments.
• LEUCOCYTE ACTIVATION:
• microbes,products of necrotic cells,ag-ab
complexes,cytokines.chemofactors--- induce a no
of responses in the L.
• FUNCTIONAL RESPONSES: production of AA
metabolites,degranulation & secretion of
enzymes

• PHAGOCYTOSIS:
• opsonins
• RECOGNITION & ATTACHMENT
• Mannose, Scavenger receptors.
• ENGULFEMENT
• KILLING AND DEGRADATION.
• oxygen dependent & independent
mechanisms.
• RELEASE OF L PRODUCTS –tissue injury?

• TERMINATION
• mediators have short half life.
• proinflammatory leukotreins
• anti inflammatorylipoxins
• cytokineTGF-beta—macrophages & other
cells.
• neural impulses—cholinergic—inhibit the
production of TNF in macrophages.
• Glucocorticoids.
• Shed receptor & receptor antagonists
• Suppressor cells & cross regulatory
cytokines.

OUTCOMES OF INFLAMMATION

• SYSTEMIC EFFECTS:the sysemic changes
assocuated with infection especially who have
infection is called ACUTE PHASE RESPONSE.
• REACTION TO THE CYTOKINES
• FEVER:PYROGENS—PG synthesis in vascular &
perivascular cells of hypothalamus
• LPS—IL1,TNF-aplha—increase AA metabolism—
PGs .
• PGE2—Increase Cyclic –AMP—RESET the
temperature set point at higher level
• APP—synthesised in the liver: CRP,Fibrinogen

• Leucocytosi—15000—
20000cells/cubicmilimeter.
• increased pulse,BP,rigors,chills,malaise
• sepsis
• TNF-alpha,IL1:DIC,SHOCK, LUNGS—
ARDS.

Morphologic patterns:
1 serous—effusion—outporing of thin fluid.
2 fibrinous—vascular leakages are kerge
enough or there is a procoagulant
stimulation the interstitium.
meninges,pericardium. Pleura
suppurative or purulent;appendicitis.
Abcesses
.

• REFERENCES
• ROBBINS & COTRAN PATHOLOGIC
BASIS OF DISEASE 7TH
EDITION,2004
• WOOLF PATHOLOGY BASIC &
SYSTEMIC 1998
• RUBIN’S PATHOLOGY 4TH
EDITION
• ANDERSON’S PATHOLOGY 8TH
EDITION

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