inflamation ppt
TRANSCRIPT
INFLAMMATION&
It’s TREATMENT
By SROTA DAWN
M.PHARM(PHARMACOLOGY)1ST YEAR ,2ND SEM
VELS SCHOOL OF PHARMACEUTICAL SCIENCES
What is inflammation?
• Inflammation – Protective response intended to eliminate the initial
cause of cell injury and the necrotic cells and tissues arising from the injury.
• Inflammation is intimately associated with the repair process which includes parenchymal cell regeneration and scarring
TYPES OF INFLAMATION
ACUTE CHRONIC
Acute Inflammation• Acute - minutes to days
• Characterized by fluid and protein exudation
• PMN’s
• Exudate SG > 1.020
Chronic Inflammation
• Chronic - weeks to years
• Lymphocytes and macrophages
• ACUTE Inf - PMN’s (Polymorphonuclear Cells)
• CHRONIC Inf - Mononuclear Cells
Acute inflammation“The immediate and early response to an injurious agent”
Chronic inflammation “Inflammation of prolonged duration (weeks or months) in which active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously“
Aims• Eliminate pathologic insult• Remove injured tissue components• Protective response• Hand in hand with repair• Steps:
– Initiation-stimulus– Amplification: activation of cellular
inflammation– Termination: Elimination
Five classic local signs of acute inflammation
– Heat– Redness– Swelling– Pain– Loss of
function
– Calor – vasodilatation– Rubor – vasodilatation– Tumor – vascular permeability– Dolor – mediator
release/PMNs– Functio laesa – loss of
function
Vascular changes happens during inflammation:
1. Transient vasoconstriction2. Vasodilation 3. Exudation of protein rich fluid4. Blood stasis5. Margination6. Emigration/Transmigration
Cellular events-Aims
• Delivery of leucocytes to the site of injury
• Ingest & kill bacteria & microbes• Degrade necrotic tissues & foreign
antigens• May prolong inflammation• Rarely induce tissue damage by
releasing enzymes & chemical mediators, toxic radicals
Normal environment a
Inflammatory mediators
Vascular events Increased vascular
permeability› Escape of protein rich fluid into
interstitium› Oedema-excess of fluid in interstitium or
serous cavities› Imbalance of hydrostatic pressure
Transudate-low protein, sp gr-< 1.012› Permeability not altered
Exudate-high protein, sp gr > 1.020› Permeability altered
Pus –rich in polymorphs
Vascular events
Protein exits vessels :
intravascular osmotic pressure
intravascular hydrostatic pressure
Endothelial gaps at intercellular junctions:
* immediate transient response
*histamine, bradykinin, leukotrienes, substanceP
Blood pressure and plasma colloid osmotic forces in normal and
inflamed microcirculation..
hydrostatic pressure (red arrows) is about
32 mm Hg
12 mm Hg osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure
Arteriole pressure is increased to 50 mm Hg 30 mm Hg.
osmotic pressure is reduced (averaging 20 mm Hg) because of protein leakage across the venule. The net result is an excess of extravasated fluid
Increased vascular permeability Endothelial cell contraction- Immediate transient
response- only venules-chem mediators Cytoskeletal & junctional re-organization Direct endothelial injury-Immediate sustained
response-cell necrosis & detachment-All levels Leucocyte mediated injury Leakage from regenerating capillaries-Angiogenesis
• Extravasation-Journey of the leucocytes from lumen to interstitial tissue– Margination, Rolling – Adhesion
• Transmigration/ Diapedesis• Chemotaxis - Migration in interstitial tissue towards a
chemical stimulus• Leucocyte activation• Phagocytosis• Release of Leucocyte products
Cellular events-Steps
Leukocyte Cellular Events
• Margination and Rolling• Adhesion and Transmigration• Migration into interstitial tissue
Inflammation
Chemotaxis
• Movement toward the site of injury along a chemical gradient– Chemotactic factors include
• Complement components (20 serum proteins)• Arachadonic acid (AA) metabolites• Soluble bacterial products• Chemokines, cytokines
Leucocyte activation
• Production of Arachidonic acid metabolites by DAG & increased Ca
• De-granulation & secretion of lyso enzymes & activation of oxidative burst
• Modulation of leucocyte adhesion molecules• Priming-Increased rate & extent of leucocyte
activation
Phagocytosis & Degranulation
• Phagocytosis (engulf and destroy)• Degranulation and the oxidative burst
destroy the engulfed particle• Recognition & attachment
– Opsonins coat target and bind to leukocytes• Engulfment• Killing/degradation
– O2 dep: Reactive O2 species in lysosomes & EC– O2 indep: Bactericidal permeability agents,
lysozyme, MBP, lactoferrin
Chemotacticfactors (eg. c5a)
Tissue injury
Vasoactivemediators(eg. histamine)
Increased vascularpermeability
Recruitment of inflammatory cells
Edema PMNs Monos
Production of inflammatory
mediators
Acute inflammation
Chronic inflammation
Plasma Mediator Systems - Interaction
1. Kinin
2. Clotting
3. Complement
4. Fibrinolytic
C5
C5a
Plasminogen Plasmin
C3
C3a
Fibrin FSPs
Prothrombin Thrombin
Fibrinogen
XII
Kinin
Complement
Clotting
Fibrinolytic
Fibrinopeptides
Prekallikrein XIIa Kallikrein
High Mol. Wt. Kininogen Bradykinin
Plasma Mediator Systems - Interaction
Kinin cascade
• Leads to formation of bradykinin• Bradykinin causes
– Increased vascular permeability– Arteriolar dilatation – Smooth muscle contraction
• Bradykinin is short lived (kininases)• Vascular actions similar to histamine
Complement system
• Role in immunity (C5-9 complex)– Membrane Attack Complex (MAC C5-9)– Punches a hole in the membrane
Complement system
• Role in inflammation (c3a and c5a)– Vascular effects
• Increase vascular permeability and vasodilation• Similar to histamine
– Activates lipoxygenase pathway of arachidonic acid metabolism (c5a)
Complement system
– Leukocyte activation, adhesion and chemotaxis (c5a)– Phagocytosis
• c3b acts as opsonin and promotes phagocytosis by cells bearing receptors for c3b
Inflammatory Mediators from Complement
Anaphylatoxins:
C3a, C5a, & C4a trigger mast cells to release histamine and cause vasodilatation
C5a also activates the lipoxygenase system in PMNs and monocytes release of inflammatory mediators
Leukocyte activation, adhesion, & chemotaxis:C5a activates leukocytes, promotes leukocyte
binding to endothelium via integrins and is chemotactic for PMNs, monos, eos, & basos
Inflammatory Mediators from Complement
Phagocytosis:
C3b and C3bi are opsonins
Control:
Convertases are destabilized by "decay accelerating factor" (DAF)
Inability to express DAF causes paroxysmal nocturnal hemoglobinuria
C1 inhibitor (C1INH) deficiency causes hereditary angioneurotic edema
Vasoactive amines• Histamine
– Found in mast cells, basophils and platelets– Released in response to stimuli – Promotes arteriolar dilation and venular
endothelial contraction • results in widening of interendothelial cell junctions
with increased vascular permeability
• Serotonin– Vasoactive effects similar to histamine– Found in platelets – Released when platelets aggregate
Bradykinin: Potent biomolecule
1. Vasodilatation2. Increased vascular permeability3. Contraction of smooth muscle4. Pain on injection5. Short life, kininase degrades
Factor XII activated by:
1. Plasmin2. Kallikrein3. Collagen & basement membrane4. Activated platelets5. Co-factor = HMWK
Vascular Permeability:
- Bradykinin
- Fibrionopeptides
- Fibrin Split Prod.
- Factor Xa
- Leukotrienes
Arachidonic Acid (AA)
• Where is it located?– AA is a component of cell membrane phospholipids
• The breakdown of AA into its metabolites produces a variety of biologic effects
Arachidonic acid metabolites
• Metabolites of AA - short-range hormones• AA metabolites act locally at site of generation• Rapidly decay or are destroyed
Arachidonic Acid
• AA is released from the cell membrane by phospholipases which have themselves been activated by various stimuli and/or inflammatory mediators
• AA metabolism occurs via two major pathways named for the enzymes that initiate the reactions; lipoxygenase and cyclooxygenase
AA metabolites (eicosanoids)Cyclooxygenases synthesize
Prostaglandins
Thromboxanes
Lipoxygenases synthesize
Leukotrienes
Lipoxins
PGG2
PGH2
PGI2
ProstacyclinTXA2
Thromboxane
PGD2 ; PGE2 PGF2
Vasodilatation
Inhibits Platelet Aggregation
Vasoconstriction
Promotes Platelet Aggregation
Vasodilatation Edema
PGI2
TXA2
Arachidonic Acid Pathways you need to know this
• Lipoxygenase– 5-HETE
• Chemotaxis
– 5-HPETE• Leukotriene generation
– Leukotrienes• Vasoconstriciton• Bronchospasm• Increased vascular
permeability
• Cyclooxygenase– Prostaglandins
• Vasodilatation• Increased vascular
permeability– Prostacyclin
• Vasodilatation• Inhibits platlelet aggregation
– Thromboxane A2• Vasoconstriction• Promotes platlelet
aggregation
Arachidonic Acid Pathways you need to know this
• Lipoxygenase– 5-HETE, 5-HPETE,
Leukotrienes• Spasm (Vaso, Broncho)
• Cyclooxygenase– Prostaglandins - EDEMA– Prostacyclin vs TXA2
• Vasodilatation vs. Vasoconstriction
• Platelet aggregationInhibits vs. promotes
Platelet-Activating Factor (PAF)• Another phospholipid-derived mediator released
by phospholipases• Induces aggregation of platelets• Causes vasoconstriction and bronchoconstriction• 100 to 1,000 times more potent than histamine in
inducing vasodilation and vascular permeability• Enhances leukocyte adhesion, chemotaxis,
degranulation and the oxidative burst• It does everything!
Cytokines
• Polypeptides that are secreted by cells• Act to regulate cell behaviors• Autocrine, paracrine or endocrine effects• These “biological response modifiers” are
being actively investigated for therapeutic use in controlling the inflammatory response.
1. Macrophages make IL-1 & TNF-
2. T-cells make TNF- (lymphotoxin)
3. Can be autocrine, paracrine, endocrine
4. IL-1, TNF, IL-6 acute phase responses, fever, (appetite, slow wave sleep, circ. pmn, ACTH, corticosteroids)
5. TNF notable for role in septic shock and maintenance of body mass (cachexia in cancer from TNF- )
Lymphocyte function
Nitric Oxide
• NO is a soluble free radical gas• Made by nitric oxide synthetase (NOS) in
endothelium (eNOS), macrophages (iNOS), and specific neurons in the brain (nNOS)
• Broad range of functions and effects that are short range
– Vasodilatation by relaxing smooth muscle.– platelet aggregation– Inhibits mast cells– Regulates leukocyte recruitment