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