Transcript Inflammation

Inflammation
Dr.ROOPA
Premed 3
Pathophysiology
Introduction:
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“Inflame” – to set fire.
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“Inflammation is a reaction of a tissue and
its microcirculation to a pathogenic insult.
It is characterized by the generation of
inflammatory mediators and movement of
fluid & leukocytes from the blood into
extravascular tissues.”
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“dynamic response of vascularised tissue to
injury.”
Is a protective response.
Serves to bring defense & healing
mechanisms to the site of injury.
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Naming of inflammatory
diseases:
[prefix] + ‘itis’
(exceptions exist)
crohn’s disease
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Types of Inflammation
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Acute
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Chronic
Acute Inflammation
Acute inflammation is a rapid response to an
injurious agent that serves to deliver mediators of
host defense—leukocytes and plasma proteins—to
the site of injury. Acute inflammation has three
major components: (1) alterations in vascular
caliber that lead to an increase in blood
flow; (2) structural changes in the
microvasculature that permit plasma
proteins and leukocytes to leave the
circulation; and (3) emigration of the
leukocytes from the microcirculation, their
accumulation in the focus of injury, and their
activation to eliminate the offending agent
Acute inflammatory reactions are triggered
by a variety of stimuli:
• 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 Vs Chronic
Flush, Flare &
Wheal
 Acute inflammatory
cells - Neutrophils
 Vascular damage
 More exudation
 Little or no fibrosis
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Little signs Fibrosis,
 Chronic
inflammatory cells
– Lymphocytes
 Neo-vascularisation
 No/less exudation
 Prominent fibrosis
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Table 5–1. Differences between Acute and Chronic Inflammation.
Acute
Chronic
Duration
Short (days)
Long (weeks to months)
Onset
Acute
Insidious
Specificity
Nonspecific
Specific (where immune response is activated)
Inflammatory cells
Neutrophils, macrophages
Lymphocytes, plasma cells, macrophages,
fibroblasts
Vascular changes
Active vasodilation, increased permeability
New vessel formation (granulation tissue)
Fluid exudation and edema
+
–
Cardinal clinical signs
(redness, heat, swelling, pain)
+
–
Tissue necrosis
+ (ongoing)
– (Usually)
+ (Suppurative and necrotizing inflammation)
Fibrosis (collagen deposition)
–
+
Operative host responses
Plasma factors: complement, immunoglobulins, properdin, etc;
neutrophils, nonimmune phagocytosis
Immune response, phagocytosis, repair
Systemic manifestations
Fever, often high
Low–grade fever, weight loss, anemia
Changes in peripheral blood
Neutrophil leukocytosis; lymphocytosis (in viral infections)
Frequently none; variable leukocyte changes,
increased plasma immunoglobulin
Cardinal Signs of Inflammation
Rubor : Redness –
Hyperaemia.
 Calor : Warm –
Hyperaemia.
 Dolor : Pain – Nerve,
Chemical med.
 Tumor: Swelling –
Exudation
 Loss of Function: Eg.
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The 5 Cardinal Signs of
Heat
Redness Swelling
Pain Loss Of Func.
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Inflammation - Mechanism
1. Vaso dilatation
2. Exudation - Edema
3. Emigration of cells
4. Chemotaxis
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Mechanism of Inflammation:
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Leukocyte cellular events
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Leukocytes leave the vasculature routinely
through the following sequence of events:
– Margination and rolling
– Adhesion and transmigration
– Chemotaxis and activation
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They are then free to participate in:
– Phagocytosis and degranulation
– Leukocyte-induced tissue injury
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PRINCIPAL CELL EFFECTORS
 1st
24 hours: NEUTROPHILS
 Bacterial infections, infarction
 Come from the bone marrow reserve pool
 Band neutrophils: less mature cells
Neutrophils
-- the key cell
type of the
acute
inflammatory
response
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 2nd-3rd
day: neutrophils are replaced by
monocytes-macrophages
 Tuberculosis, salmonellosis
Eosinophils
Allergic reactions
 Parasitic infections
 Hodgkin lymphoma
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Mast cells and basophils
Chronic myelogenous leukemia
 Myeloproliferative diseases
 histamine
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Cellular response of leukocytes
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Emigration
Margination
Pavementing
Rolling/Tumbling
Adhesion
Transmigration
Chemotaxis
Phagocytosis
Opsonization
Intracellular microbial killing
Oxygen-dependent
Oxygen-independent
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MARGINATION
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THE ENDOTHELIAL CELLS ARE
ACTIVATED, ATTRACT THE SURFACE
GLYCOPROTEINS ON NEUTROPHILS
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DIAPEDESIS
INSINUATION OF THE NEUTROPHILS
THRU THE ENDOTHELIAL CELLS
BASEMENT MEMBRANE
EXTRAVASCULAR TISSUES
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CHEMOTAXIS
NEUTROPHIL DIRECT ITS
MIGRATION TOWARDS THE
CHEMOATTRACTANT
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PHAGOCYTOSIS
FORMATION OF PHAGOSOME
LYSOSOME
PHAGOLYSOSOME
Intracellular microbial killing:
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Oxygen-dependent killing is the MOST
important microbial process
Phagocytosis activates HMP shunt
oxidative burst
suppplies electrons to NADPH oxidase
superoxide anion
Hydrogen peroxide
Hydrogen peroxide
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Oxides microbial proteins and disrupts cell
walls
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Myeloperoxidase-halide system of
bacterial killing
After killing and eliminating the microbes,
the activated leukocytes play other
functions
 1.Macrophages produce GF(growth factor)
that stimulate endothelial cell proliferation
and fibroblasts.
 2.Synthesis of collagen
 3,Aids in the process of repair.
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DEGRANULATION
 THE TOXIC SUBSTANCES MAY CAUSE
LOSS OF FUNCTION (FUNCTIO LAESA)
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INCREASED BLOOD FLOW DUE TO
RELAXATION OF THE TERMINAL
ARTERIOLES
 RUBOR AND CALOR
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CONTRACTION OF CAPILLARY
ENDOTHELIAL CELLS
 INCREASED VASCULAR PERMEABILITY
 SWELLING
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TUMOR
MILDEST: EXTRAVASATION OF WATER,
LOW MOLECULAR WEIGHT PROTEINS
 MODERATE: + HMW(high molecular
weight) PROTEINS
 SEVERE: + BLOOD CELLS
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MEDIATORS OF ACUTE
INFLAMMATION
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Exogenous:
microbial products
Endogenous:
1. vasoactive amines
histamine
serotonin
2. Arachidonic acid metabolites
cyclooxygenase pathway
lipooxygenase pathway
3. Cytokines
4. Kinin system
5. Complement system
Histamine
increase capillary permeability
contracts postcapillary venules
 Source: basophils, mast cells,platelets
 Stimuli:
binding of IgE
binding of C3a and C5a:”anaphylotoxins”
heat, cold
Interleukin-1
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Serotonin
5-hydroxytryptamine
 Action: similar to histamine
 Source: platelets
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Arachidonic acid metabolites
Cyclooxygenase
pathway
 Enzymes:COX-1,COX-2
 Products:
1. Platelet TxA2
-vasoconstrictor,platelet
aggregator
2. Endothelial prostacyclin
-vasodilator,inhibits
platelet aggregation
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Lipooxygenase pathway
Products:
hydroperoxyeicosatetraen
oic acid (HPETE)
5-HPETE
-leukotrienes
Important leukotrienes
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LTB4: chemotactic for neutrophils
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LTC4,LTD4,LTE4
“slow reacting substance of anaphylaxis”
vasocontriction
bronchospasm (bronchcontriction)
increase capillary permeability
Cytokines
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Soluble proteins
Secreted by numerous cells(monocytes-macrphages)
Act as “effector molecules”
IL-1 and TNF
“acute phase response”
Fever, increase WBC: systemic
Synthesis of C-reactive proteins, complement
components, fibrinogen, prothrombin
Synthesis of adhesion molecules
Neutrophil degranulation
Kinin system
Formed during active secretion in sweat
glands, salivary glands, pancreas, kidneys
 End product: bradykinin
 Actions: vascular permeability
arteriolar dilation
pain
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Complement system
20 Plasma proteins
 HEPATOCYTES,MACROPHAGES, GIT
CELLS
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Action: cell lysis
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COMPLEMENT CASCADE
classical pathway
alternative pathway
OPSONIZE BACTERIA
 ACTIVATE PMN, MACROPHAGES
 REGULATES AB RESPONSE
 CLEARS AWAY IMMUNE COMPLEXES
 INFLAMMATION, TISSUE DAMAGE
 ANAPHYLAXIS
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MAC
Classical pathway vs alternative
pathway
Starts with C1 + antigen-antibody
 Bacterial surface
activates
the pathway
 Ends with the membrane attack
complex
 Works in the absence
of antibodies
 Less efficient
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C3b: opsonin
 C3a and C5a: anaphylotoxins
 C5b-C9: “MAC”
membrane attack complex
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Inflammation Outcome
Fibrosis/Scar
Resolution
Injury
Acute
Inflammation
Chronic
Inflammation
Abscess
Ulcer
Fistula
Sinus
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ABSCESS
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Cavity filled with pus
Pus: neutrophils,
monocytes and
cellular debris
Fibrous wall
Inaccessible to
circulation
Bacterial infections,
especially
staphylococci
Ulcer
Involves epithelial surfaces
 Loss of surface epithelium
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Fistula
Abnormal communication between 2 organs
or
between an organ and a surface
Scar
Final result of tissue destruction
 Distortion of structure
 Altered function
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Patterns of chronic inflammation
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Chronic nonspecific inflammation
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Granulomatous inflammation
Chronic nonspecific inflammation
Proliferation of fibroblasts and new vessels
 Increased macrophages, lymphocytes,
plasma cells
 Macrophage+antigen
B lymphocyte
activation
antibody-producing plasma
cells
 Scarring and distortion of tissue
architecture
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Most characteristic: CASEOUS NECROSIS
 Multinucleated giant cells
TB, fungal infections, Syphyllis, cat-scratch
fever, foreign bodies
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