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Overview

Introduction

 Inflammation is a protective response intended to


eliminate the initial cause of cell injury as well as
necrotic cells and tissues resulting from the original
insult.

 It sets into motion the events that eventually heal and


reconstitute the sites of injury.
Inflammation
 Definition
Inflammation (Latin, inflamatio, to set
on fire) is a localized protective response
elicited by injury or destruction of tissues,
which serves to destroy, dilute or wall off
(sequester) both the injurious agent and
the injured tissue.

(Dorland’s medical dictionary; 30th ed)


Inflammation
 Definition
Inflammation is a complex reaction to
injurious agents such as microbes and
damaged, usually necrotic, cells that consists
of vascular responses, migration and activation
of leukocytes and systemic reactions.

(Robins and Cotran; 7th ed.)


History
 Egyptian papyrus (3000 BC)
 Celsus (1st century AD) – 4 cardinal signs of
inflammation
 Virchow – fifth clinical sign i.e. functio laesa
 John Hunter (1973)– inflammation is not a
disease but a non-specific response that has a
salutary effect on its host.
History
 Julius Cohnheim (1839-1884) – described
the process of inflammation
 Ellie Metchnikoff – Phagocytosis
 Sir Thomas Lewis – chemical substances,
such as histamine locally induced by injury,
mediate the vascular changes of
inflammation
Inflammation
 Inflammation is divided into two basic patterns:
Acute Inflammation : It is the immediate and early
response to injury, designed to deliver leukocytes to
the site of injury.
(Robbins 7th ed.)

 Also defined as inflammation usually of sudden


onset characterized by classical signs, with
predominance of vascular and exudative processes.
(Dorlands Dic.)
Inflammation
 Chronic Inflammation : It is considered to be
inflammation of prolonged duration (weeks to
months to years) in which active inflammation,
tissue injury and healing proceed simultaneously.
(Robbins 7th ed.)

 Inflammation of slow progress and marked chiefly


by the formation of new connective tissue.

(Dorlands Dic.)
Inflammation
 The inflammatory
response has many
players
 These include:
 Circulating cells
 Neutrophils
 Eosinophils and
Basophils
 Lymphocytes and
Monocytes
 Platelets
Inflammation
 Circulating Proteins :
 Clotting Factors
 Kininogens
 Complement
components

 Vascular wall cells :


 Endothelial cells in
direct contact with
blood
 Smooth muscle cells
that impart tone to
vessels
Inflammation
 Connective tissue cells
 Mast cells
 Macrophages
 Lymphocytes
 Fibroblast

 Extra cellular Matrix :


 Fibrous Structural
Proteins (e.g. Collagen &
Elastin)
 Gel forming
proteoglycans
 Adhesive glycoprotein
(e.g. Fibronectin)
Acute Inflammation
STIMULI FOR ACUTE INFLAMMATION
Infections (bacterial, viral, parasitic) and microbial toxins
 Trauma (blunt and penetrating)
 Physical and chemical agents (thermal injury, e.g., burns or
frostbite; irradiation; some environmental chemicals)
Tissue necrosis (from any cause)
Foreign bodies (splinters, dirt, sutures)
Immune reactions (also called hypersensitivity reactions)
Acute Inflammation
 Lewis experiment. Lewis induced the changes in
the skin of inner aspect of forearm by firm stroking
with the blunt point eliciting the triple response

 Red line appears in a few seconds due to local


vasodilation.
 Flare is the bright reddish appearance also due
to vasodilation of the adjacent arterioles.
 Wheal is the swelling or edema due to
transudation of fluid into extravascular space.
Acute Inflammation
Flare – indirect vasodilating effect
of histamine by stimulating axon
Red line – direct reflex
vasodilating effect of
histamine Wheal – Histamine induced
increased permeability
Acute Inflammation
 Classical signs of inflammation (Celsus)

1. Heat (Calor)

2. Redness (Rubor)

3. Swelling (Tumor)

4. Pain (Dolor)

5. Loss of function (Functio laesa) (Virchow)


Acute Inflammation
 Acute inflammation has two main components:

 Vascular Changes : Alteration in the vessel caliber


resulting in increased blood flow (vasodilation) and
structural changes that permits plasma proteins to
leave circulation (increased vascular permeability).

 Cellular Events : Emigration of leukocytes from the


microcirculation and accumulation in the focus of
injury (cell recruitment and activation).
Vascular Changes
Vascular Changes
Starling’s Law:
Movement of fluid in and out of arterioles, capillaries and
venules is regulated by the balance between
1.Intravascular hydrostatic pressure – tends to force fluid
out of vessels
2.Osmotic pressure of the plasma proteins – tends to retain
fluid within the vessels
Vascular Changes
Transudate Vs Exudate
Transudate Exudate
Filtrate of blood plasma without
changes in endothelial Oedema of inflamed tissue with
permeability increased vascular permeability
Non-Inflammatory Oedema Inflammatory Oedema
Protein < 1g/dl Protein -- High 2.5-3.5 g/dl
Glucose – same as plasma Glucose – Low (<60 mg/dl)
Specific Gravity < 1.015 Specific Gravity > 1.018
pH > 7.3 pH < 7.3
Few Cells, mainly mesothelial Inflammatory as well as
cells and cellular debris parenchymal cells
eg. Oedema in congestive
cardiac failure Purulent exudate such as pus
Increased vascular permeability
 Endothelial cell contraction leads to intercellular
gaps in venules.
Increased vascular permeability

 Endothelial cell retraction :

 Reversible mechanism
 Induced by cytokine mediators (TNF & IL-1)
 Cause structural reorganization
 Cells retract
 Takes 4 to 6 hrs to develop and persists for 24hrs
or more
Increased vascular permeability
 Direct endothelial injury :
 Seen in severe injuries (burns, infections etc.)
 Leakage begins immediately after surgery and persists for
several hours. (immediate sustained response)
Increased vascular permeability
 Leukocyte dependent endothelial injury :
 Leukocytes may accumulate during inflammatory response.
 These leukocytes may release toxic oxygen species and
proteolytic enzymes causing injury.
Increased vascular permeability
 Leakage from new blood vessels :
Cellular Events
Cellular Events
Transendothelial Migration
 E-selectins are expressed at low levels or are not present at
all on normal cells. They are upregulated after stimulation by
specific mediators. eg.IL-1 and TNF.

 P-selectins are found intracellularly in Weibel-Palade bodies,


which once stimulated by mediators such as histamine are
distributed over the cell surface.

 L-selectins interact with carbohydrate molecules known as


vascular addresins (eg.sialomucin) on the luminal surface of
endothelial cells. This brief interaction manifests itself as
rolling of the leukocyte along the luminal surface of
endothelium.
Transendothelial Migration
Chemotaxis and Activation
 After extravasating from the blood, leukocytes
migrate toward sites of injury along a chemical
gradient in a process called chemotaxis.

 Both exogenous and endogenous substances can


be chemotactic for leukocytes.
 Soluble bacterial products : N-formylmethionine termini.
 Components of complement system : C5a
 Products of lipoxygenase pathway : leukotriene B4
 Cytokines : IL-1, IL-8
Chemotaxis and Activation
Biochemical Events In Leukocyte Activation
Phagocytosis and Degranulation
 Phagocytosis and the elaboration of degradative
enzyme are two major benefits of having recruited
leukocytes at the site of inflammation.

 Phagocytosis consists of three distinct but


interrelated steps:
 Recognition and attachment of the particle to the
ingesting leukocyte.
 Engulfment with subsequent formation of a
phagocytic vacuole
 Killing and degradation of the ingested material.
Phagocytosis and Degranulation
Phagocytosis and Degranulation
Phagocytosis and Degranulation
 2O2 +NADPH NADPH oxidase 2O2 - + NADP+ + H+

 Superoxide is then converted by spontaneous


dismutation to hydrogen peroxide.

 O2 - + 2H+ H2O 2

Cl -
 H2O 2 Myeloperoxidase HOCl + H2O
Chemical Mediators Of
Inflammation
Vasoactive Amines
 Histamine – widely distributed in mast cells; also
present in circulating basophils and platelets.
 Preformed histamine is stored in mast cell granules and
released in response to a variety of stimuli :
 Physical injury
 Immune reactions involving binding of IgE antibodies to Fc
receptors on mast cells.
 Anaphylatoxins; C3a and C5a
 Leukocyte derived histamine releasing proteins.
 Neuropeptides
 Certain cytokines (IL-1; IL-8)
Vasoactive Amines
 Histamine causes arteriolar dilatation and is the
principal mediator of immediate phase of
increased vascular permeability.

 Soon after its release it is inactivated by


histaminase.

 Serotonin is also a preformed vasoactive mediator


with effects similar to those of histamine.

 Found in platelets and released during platelet


aggregation.
Neuropeptides
 Like vasoactive amines neuropeptides can initiate
inflammatory responses

 Nerve fibers that secrete neuropeptides are


prominent in lungs and GIT

 They are small proteins, such as substance P, that


transmit pain signals, regulate vascular tone and
modulate vascular permeability.
Plasma Proteases
 Many effects of inflammation are mediated by
three interrelated plasma derived factors :
 The Kinins all linked by initial
activation of
 The clotting system Hageman Factor( factor XII)
 The complement system

 Hageman factor is a protein synthesized by liver


that circulates in an inactive form until it
encounters collagen, basement membrane or
activated platelets.
Plasma Proteases
Complement system
Arachidonic acid metabolites
Platelet-Activating Factor
(PAF)

 Platelets, basophils, mast cells, neutrophils,

monocytes/macrophages and endothelial cells

 Vasoconstriction and bronchoconstriction

 Increased leucocyte adhesion to endothelium

 Chemotaxis, degranulation and oxidative burst


Cytokines
Nitric Oxide
Summary
References
 Robbins & Cotran. Pathologic basis of
disease; 7th ed.
 Dorland’s medical dictionary; 30th ed
 Harsh Mohan. Essential Pathology for Dental
Students.; 3rd ed.
 Henry Trowbridge. Inflammation A review of
the process; 4th ed.
Contents
 Fate of Acute Inflammation
 Morphologic patterns of Acute
Inflammation
 Chronic Inflammation
 SIRS & Sepsis
 Anti-Inflammatory agents
Fate of Acute Inflammation
Fate of Acute Inflammation
Abscess
A localized collection of pus (suppurative inflammation)
appearing in an acute or chronic infection, and associated
with tissue destruction, and swelling.
Pathogenesis: the necrotic tissue is surrounded by
pyogenic membrane, which is formed by fibrin and help in
localize the infection.
Abscess
Fate of Acute Inflammation
Abscess
Pathogenesis: the necrotic tissue is surrounded by
pyogenic membrane, which is formed by fibrin and help in
localize the infection.
Morphologic Patterns
Serous Inflammation
Inflammation of serous membrane
characterized by clear fluid in serous cavity
(pleural, peritoneal pericardial & synovial
cavities)

E.g. skin Blisters caused by Burns OR viral


infection
Morphologic Patterns
Morphologic Patterns
Fibrinous Inflammation
Severe injury with excessive deposition of Fibrin in serous
cavity
Exudate and Fluid is removed by lymphatic
Fibrinous exudate may be degraded by Fibrinolysis and
removed by macrophage resulting in Resolution.
Incomplete Removal of fibrin resulting in organization and
scarring with
Fibrous Adhesion of pleura OR pericardium.
Morphologic Patterns
Morphologic Patterns
Suppuration (purulent ) Inflammation
Large amount of Purulent exudates (pus) caused by
pyogenic Bacteria staph aureus and Streptococcus
pyogenes
E.g Boil = Furuncle = Abscess of Hair follicles .
Morphologic Patterns
Pseudomembraneous Inflammation
Very severe ulcerative inflammation of mucous membranes
Extensive Necrosis of surface epithelium
Severe acute Inflammation of underlying tissue
Pseudo membrane, consisting of exudate, fibrin,
neutrophils RBC, Bacteria and tissue debris
e.g. Diphtheria – Larynx . pseudomembraneous Colitis –
clostridium difficile
Morphologic Patterns
Pseudomembraneous Inflammation
Morphologic Patterns
Ulceration
An ulcer is a local defect, or excavation, of the surface of an
organ or tissue that is produced by the sloughing of
inflammatory necrotic tissue
Tissue necrosis and resultant inflammation exist on or near
a surface
e.g Gastric (peptic) ulcer
Chronic Inflammation
 Inflammation of prolonged duration (weeks or
months) in which active inflammation, tissue
destruction, and attempts at repair are proceeding
simultaneously

(Robbins 7th ed.)


Chronic Inflammation
 Characterized by the following:
Chronic inflammatory cell infiltration lymphocytes,

plasma cells and macrophage


Tissue destruction by Inflammatory cells

Healing and Repair – involving New Blood Vesel

proliferation (Angiogenesis) and Fibrosis


Chronic Inflammation
Causes:
Persistent infections
Prolonged exposure to potentially toxic agents
 Silica  silicosis

 Toxic plasma lipid components  atherosclerosis

Autoimmunity

 Rheumatoid arthritis & LE


SIRS & Sepsis
 Systemic inflammatory response syndrome
(SIRS) is the clinical expression of the
action of complex intrinsic mediators of the
acute phase reaction.
 SIRS can be precipitated by events such
as infection, trauma, pancreatitis, and
surgery.
SIRS & Sepsis
SIRS & Sepsis
SIRS & Sepsis
 SIRS can compromise the function of various
organ systems resulting in Multiple Organ
Dysfunction Syndrome (MODS).
 Clinicians should learn to identify SIRS in their
patients at an early stage to determine the
underlying cause and treatment before the
SIRS progresses to a more severe form.
H1 Anti-histaminics
 Blocks histamine induced
bronchoconstriction, contraction of
intestinal and other smooth muscle
 Blocks triple response
 Suppresses manifestations of type I
hypersensitivity reactions
Corticosteroids
 Corticosteroids have an anti-inflammatory
action – Hench et al (1949)
 Average rate of cortisol secretion–15-20
mg/day
 Increase in response to stress
Corticosteroids
Corticosteroids
 Blocking the cleavage of arachidonic
acid  inhibit PG synthesis

 Stabilizes intracellular lysosome


membranes  decreased release of
mediators
Corticosteroids
 Decreases permeability of capillary
membranes & reduces amount of
plasma lost  reduced amount of
edema

 Decreased migration of WBC in


inflamed tissues  diminished
phagocytosis
Corticosteroids
 Primary effect – marked reduction in post-
operative edema

Therapeutic uses in OMFS:


 Removal of impacted teeth (Beirne &
Hollander)
 Multiple extractions with alveoloplasty
 Removal of tori
 Apicoectomy
Corticosteroids
 Orthognathic surgeries (Schaberg et al)
 Rhinoplasty (Koopmann)
 Management of TMJ disorders – intraarticular
injection of corticosteroid provides relief of
symptoms in acute osteoarthritis of TMJ
 No more than 3 injections at a minimal interval of
1-3 months are recommended
NSAIDs
 Peripheral acting analgesics
 Anti-inflammatory, antipyretic and anti-thrombotic
activity
 Most effective when administered preoperatively
or immediately postoperatively, before the effects
of anesthesia have been reversed completely
NSAIDs
 COX1 – present in platelets, stomach, kidney
(cytoprotective to GIT)
 COX 2– induced by cytokines & endotoxins at
the site of inflammation
 Newer NSAIDs safer because they are selective
for COX-2
NSAIDs
 NSAIDs – control postoperative pain
 Corticosteroids – control postoperative edema
 Combination provides best results, since
NSAIDs potentiate the anti-inflammatory action of

steroids
Steroids add to the analgesic effect of NSAID
Leukotriene antagonists
 Montelukast & Zafirlukast
 Antagonize cysLT1 mediated
bronchoconstriction, increased vascular
permeability and recruitment of eosinophils
 Indicated for prophylactic therapy of mild to
moderate asthma
Omalizumab
Omalizumab
 Does not bind to cell-bound IgE
 Therefore, does not trigger cell activation
by crosslinking of the IgE molecules on cell
membranes.
Omalizumab
Omalizumab
 Omalizumab reduces the allergen induced
late asthmatic response, airway
hyperresponsiveness and sputum
eosinophilia
 Reduces both asthma exacerbations and
corticosteroid requirement
 Agent may have a long-term anti-
inflammatory effect
Enzymes as anti-
inflammatory agents
 Cleave the antigenic surface protein of organisms
and digest their outer coat
 Reduce number and activity of receptors for
pathogen on host cells
 Detoxify blood and remove viruses from circulation
 Cause enhancement of immune cells to kill
bacteria, viruses, molds and fungi
Enzymes as anti-
inflammatory agents
 Break down immune complexes which block the
immune cells
 Accelerate the volume and fluidity of blood flow
 Bromelain modulate arachidonate pathway in
such a way that thromboxane production is
decreased with no effect on cyclooxygenase
Enzymes as anti-
inflammatory agents
 Powerful anti-oxidants and effectively combat the
harmful free radicals such as nitric oxide
 Block pro-inflammatory metabolites that
propagate the inflammation
 Possess anti-secretory and mucolytic qualities
and decrease acute phase reactions
Serratiopeptidase
 Proteolytic enzyme isolated from the
non-pathogenic enterobacteria Serratia
E15 found in silkworms
 Acts upon inflammation by thinning the
fluids in the body that collect around
injured areas and increases fluid
drainage
Serratiopeptidase
 Enhances tissue repair and reduces pain
 Ability to block the release of pain-inducing
amines from inflamed tissues
 Ability to dissolve dead and damaged
tissue
 Modifies cell-surface adhesion molecules
References
 Robbins & Cotran. Pathologic basis of disease; 7th ed.
 Harsh Mohan. Essential Pathology for Dental Students.; 3rd ed.
 Henry Trowbridge. Inflammation A review of the process; 4 th ed.
 Goodman & Gilman's The Pharmacologic Basis of Therapeutics -
11th Ed. (2006)
 Laskin DM, Giglio JA. The use of steroids and NSAID in Oral and
Maxillofacial Surgery. Oral and Maxillofacial Surgery Clinics of
North America. 2001 Feb; 13(1): 31-41.
References
 M. Soler et al. The anti-IgE antibody omalizumab reduces
exacerbations and steroid requirement in allergic asthmatics Eur
Respir J 2001; 18: 254–261
 G. Hanf et al. Omalizumab inhibits allergen challenge-induced nasal
response. Eur Respir J 2004; 23: 414–418.
 Shahid S . Role of Systemic Enzymes in Infections . WebmedCentral
COMPLEMENTARY MEDICINE 2012;3(1):WMC002504
 Chopra et al. A randomized, double-blind, placebo-controlled study
comparing the efficacy and safety of paracetamol, serratiopeptidase,
ibuprofen and betamethasone using the dental impaction pain
model. Int. J. Oral Maxillofac. Surg. 2009; 38: 350–355