INFLAMMATION

Created by,

Sam Aaseer Thamby

Lecturer, Faculty of Pharmacy

AIMST University

Malaysia

INTRODUCTION First described by Cornelius Celsus 2000 years ago.

It is an important non-specific defensive reaction to tissue injury (by pathogen invasion or wound injury etc.)

It is the response by which the body not only destroys the invading pathogens, but also the healthy cells (in the host)

E.g., Anaphylaxis and RA are due to uncontrolled inflammatory response.

Caused by various agents like pathogen infection, burns, physical injury, chemical injury (acid or alkalies).

Triggered by a complex set of events induced by pathogen invasion or tissue injury

Ruptured cells in infected areas release their cytoplasmic contents

Increased acidity in the surrounding ECF (↓ed pH)

These changes lead to the 5 Classical Symptoms of Inflammation:

• Rubor (Redness due to vasodilation and hyperemia)

• Calor (Heat; area becomes hot due to excessive blood flow)

• Dolor (Pain due to bradykinins and PGs at the inflamed site)

• Tumor (Swelling due to excess fluid at the site)

• Functio Laesa (loss / reduction of body functions)

THE INFLAMMATORY PROCESS (briefly)

Breach in the skin ; Bacteria (pathogens) invade the body

I – VASODILATION ( capillaries enlarged; blood vessels’ diameter enlarged, causing increased volume of blood flow with decreased velocity; microcirculation is affected)

II – Circulation slows down; Margination (blood cells mostly WBCs adhere to the vascular endothelium); Emigration (neutrophils get out of the capillaries and enter the inflamed site)

• First 24 hrs – neutrophils are the most predominant;

• Later, monocytes also are present;

III – PHAGOCYTOSIS ( pathogen is engulfed and degraded or digested within the phagocyte)

• Removal of the necrotic or damaged tissue as well as infective organisms.

• Large nos. of WBCs also die (the fluid in inflamed site becomes white and is the main component of Pus)

• Host (our body) cell damage occurs by the inflammatory process.

LOCAL VASODILATATION

• Due to histamine (H1) and serotonin (5HT) release. H1 from the mast cells and basophils; serotonin from platelets.

• H1 relaxes arteriolar and venular smooth muscles →vasodilatation;

• Vasodilation → increased vol. of blood flow with decreased velocity; increased capillary permeability → emigration of WBCs

LEUCOCYTE EMIGRATION

• Normally, most WBCs and RBCs occupy the central axis of flowing blood in a blood vessel.

• If the flow velocity is ↓ed, the WBCs and RBCs occupy the

periphery of the flow and would come very close to the vessel walls (MARGINATION)

• Post-Margination: WBCs stick to the capillary walls (by C5a and AAMs)

• WBCs emigrate (neutrophils go first and release Chemotactic factor, which draws out the monocytes); later RBCs also emigrate

• The emigrated WBCs are drawn towards the invading pathogen (+ Chemotaxis)

WHAT IS CHEMOTAXIS?????

PATHOGEN DIGESTION

• Metabolic activity within the neutrophils → H2O2 forms in the neutrophils → H2O2 + MPO in the ‘azurophilic granules’

kill the pathogen. (MPO increases the lethal activity of H2O2)

• MPO = Myeloperoxidase

• Azurophilic granules (1° granules): are lysosomal granules located within the neutrophils; they contain proteo or amylo-lytic granules + MPO granules + lysozyme enyme granules

• Metabolic activity within the neutrophils also ↑es the lactic acid levels in the neutrophil → fall in intracellular pH of

neutrophil and death of the ingested pathogen

• Monocytes don’t have MPO. So, monocytes have to kill the pathogen with H2O2 only.

• Sometimes, the defense mechanisms of the human body aren’t strong enough as the pathogens are stronger →

infection and inflammation spreads rapidly

• During phagocytosis and pathogen digestion, some destructive agents like ROIs are released from the neutrophils → damage and destruction of the host cells.

• After inflammation, the process of repair is initiated (Wound Healing)

HOW DO PATHOGENS SURVIVE???• M.tuberculosis, M.leprae, L.pneumophila, T.gondii: inhibit

phagosome fusion with lysosomes, preventing exposure to toxic lysosomal contents

• Trypanosoma cruzi, Listeria monocytogenes, Shigella flexneri: lyse phagosomal membrane and escape into the cytoplasm

• Leishmania spp., M.lepramurium, S.typhimurium: resist inactivation by lysosomal factors

• Coxiella spp.: reproduce inside the phagolysosome

BRADYKININS

• Vasoactive amine involved in vasodilatation

• Factor XII (Hageman factor) [present normally in plasma]

• Active Factor XII (β XIIa)

• βXIIa + prekallikrein Kallikrein

• Kallikrein + HMW Kininogen BRADYKININ

COMPLEMENTS

• Proteins by nature; Produced by the liver

• C1, C2, C3 on activation form C1a, C2a, C3a

• Roles: Helps in ….

• Neutrophil (or monocyte)-mediated immunity against the pathogens (Non-specific immunity)

• Phagocytosis; ↑ing capillary permeability; chemotaxis; Ag-Ab reaction in lymphocyte-mediated immunity

ARACHIDONIC ACID METABOLITES (AAMs)

• Arachidonic acid + polyunsaturared fatty acids

• Belong to the class Eicosanoids

• Can’t be synthesized in the body (essential fatty acids)

• E.g., Classical PGs (PGF2 , PGE2 etc..)

• TXs (TXA2)

• Prostacyclins (PGI2)

• Leukotrienes (LTS) Lipo Oxygenase (LOX)pathway

• PGF2 , PGE2 are powerful vasodilators (local vasodialatation in inflammation)

• TXA2 is a vasoconstrictor causing platelet aggregation (hemostasis)

• PGI2 opposes vasoconstriction

Cyclo Oxygenase

(COX) PATHWAY

FOR YOUR INFO….

• Chemotaxis: the cellular movement of WBCs initiated by chemokines; may be mediated by exogenous (bacterial products) or endogenous chemoattractants (cytokines; complement systems; LOX pathway products)

• Chemokines: are a family of small cytokines that induce chemotaxis.

• Cytokines: are cell signalling molecules that aid cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection and trauma.

• Chemotactic agents (CA): also called chemoattractants; e.g., C5a, Platelet Factor (PF4); They combine with the receptors on WBCs; cause + Chemotaxis

• Marginal Pool: Even in the absence of inflammation, some WBCs marginate. They constitute the Margin Pool

• AAMs: Arachidonic Acid Metabolites; aka Eicosanoids; e.g., PGs, Leukotrienes (LTs), Thromboxane (TX), Prostacyclins

• Receptor + CA → ↑ed Ca2+ entry into the cells → ↑ed contraction within the WBCs → ↑ed WBCs locomotion toward the pathogen → Invasion of the pathogen; Phagocytosis

and digestion of the pathogen.

• Complement: Substance normally present in serum; it combines with Ag-Ab complex to destroy the pathogens

• Bradykinin: Is a peptide formed from protein degradation by enzymes; is a powerful vasodilator;

• PGs: Hormones produced in many body tissues (brain, lungs, uterus etc..)

• Reactive Oxygen Intermediates (ROIs): Macrophage lysosomes contain oxygen-dependent enzymes that produce ROIs like superoxide radical, H2O2 singlet oxygen and hypohalite ions. These ROIs are toxic products that cause damage to the normal cells of the host tissue.

• Prekallikrein: It is cleaved by β XIIa to form plasma kallikrein.

• Kallikrein: serine protease that activates kinins

• HMW Kininogen: is a circulating plasma protein that is involved in the initiation of blood coagulation.

TO BE CONTINUED …