CHRONIC

INFLAMMATION
Inflammation of Prolonged duration in which Active Inflammation /
Tissue Injury / Healing Proceeds Simultaneously

CAUSES OF CHRONIC
INFLAMMATION
• Persistent Infection
• Immune-Mediated Inflammatory Diseases
• Toxic Agents (Foreign Bodies)
• Fungal Infection / T.B are time taking factor which cause Chronic
Inflammation
ACUTE INFLAMMATION: Progressive (Osteo-Myelitis) /
Recurrent (Choly-Cystitis / Gastritis)
Cholycystitis is Inflammation of Gall Bladder

Chronic Inflammation causes Tissue Damage in common Human

Disabling Diseases such as,
• Rheumatoid Arthritis / Athero-Sclerosis / Tuberculosis / Pulmonary
Fibrosis
• Involved in Progression of Cancer
• Also Involved in Alzheimer’s Disease (Disease once thought to be
Purely Degenerative)
 MORPHOLOGIC
FEATURES OF CHRONIC
INFLAMMATION
INFILTRATION: Infiltration with Mononuclear cells (Macrophages
/ Lymphocytes / Plasma cells)
TISSUE DESTRUCTION: induced by the Persistent Offending
EAgent / Inflammatory Cells
REPLACEMENT OF DAMAGED TISSUE: Connective Tissue
Replacement of Damaged Tissue to Heal, by Proliferation
Angiogenesis (proliferation of new Blood Vessels) / Fibrosis

ROLE OF MACROPHAGES
Dominant cells in most Chronic Inflammation Reactions
• Contribute to the reaction by Secreting Cytokines / Growth Factor
that act on various Cells, by Activating Other Cells (T-Lymphocytes) /
Destroying Foreign Invaders / Tissues
• Professional Phagocytes that act as filter for particulate Matter /
Microbes / Other Cells
• Act as Effector Cells that Eliminate Microbes in Cellular / Humoral
Immune Responses
Macrophages are the Tissue Cells Derived from Hemato-Poietic
Stem Cells of Bone Marrow / Progenitors in Embryonic Yolk Sac /
Fetal Liver during Early Development
• Macrophages are Normally Scattered in most Connective Tissues
Macrophages in blood Stream (Circulating Cells of this Lineage) are
called Monocytes
Organs in which Macrophages are found are:
• Liver (Kupffer Cells)
• Spleen / Lymph Nodes (Sinus Histio-Cytes)
• Central Nervous System (Microglial Cells)
• Lungs (Alveolar Macrophages)

MONONUCLEAR
PHAGOCYTE SYSTEM
• In Inflammatory Reactions, Progenitors in the Bone Marrow give rise
to Monocytes
• Monocytes Migrate in blood to Various Tissues / Differentiate into
Macrophages
• Entry of blood monocytes into Tissues is governed by the same
factors that are involved in neutrophils emigration such as Adhesion
Molecules / Chemokines
There are two main pathways of macrophages activation:

CLASSICAL MACROPHAGE
ACTIVATION (M1)
• May be induced by Microbial Products (Endotoxins)
• Endotoxins contain TLRs / Other Sensors which causes T cell-derived
Signals importantly, the Cytokine IFN-(Gama) in Immune Responses
• Macrophages enhance the Phagocytosis as, they Produce Reactive
Oxygen Specie (ROS) / Nitrogen Oxide (NO)
• Macrophages Secrete Cytokines to Regulate Inflammation

ALTERNATIVE MACROPHAGES
ACTIVATION (M2)
Principle Function of is to Repair Tissue
• Growth Factor is Released that Enhances Tissue Repair / Fibrosis
• IL-10 is Released which Terminates Inflammation (this pathway is
Anti-Inflammatory)
• TH-17 cells Release Inter-Leukin 17 (IL-17) which causes Recruitment
of Neutrophils / Monocytes
 ROLE OF LYMPHOCYTES
Microbes / Other Environmental Antigens activate T & B
lymphocytes, which amplify chronic inflammation
TH1: Produce Cytokine (IFN-γ), which Activates Macrophages in
Classical Pathway
TH2: Secrete IL-4 / IL-5 / IL-13 which Recruit / Activate Eosinophils
• Activates Macrophages in Alternative Pathway
• Important in Defense against Parasites / Allergic Inflammation
TH17: Secrete IL-17 / Other Cytokines that Induce Secretion of
Chemokines which are Responsible for Recruiting Neutrophils /
Monocytes into the Reaction
Both TH1 & TH17 are involved in defense against many types of
Bacteria / Viruses / Autoimmune Diseases

OTHER CELLS IN CHRONIC

INFLAMMATION
EOSINOPHILS: Abundant in Immune Reactions Mediated by (IgE)
in Parasitic Infections
• Have Granules that contain major Basic Protein / Highly Cationic
Protein that is Toxic to Parasites but also Injures Host Epithelial Cells
MAST CELLS: Originate from Bone Marrow
• They have Similarities with Circulating Basophils
• This type of response occurs during Allergic Reactions
NEUTROPHILS: Acute as well as Chronic Inflammation
 MEDIATORS OF
INFLAMMATION
Substances that Initiate / Regulate Inflammatory Reactions
They can be: Cell Derived / Plasma Protein Derived
• Vasoactive Amines
• Lipid Products
• Cytokines
• Products of Complement Activation
Active Mediators are Produced only in Response to Various Stimuli
like Microbial Products
• Life Span of Mediators is very Short
One Mediator can Stimulate the Release of another Mediator
(Complement Activation causes release of Histamine / Cytokines)

VASOACTIVE AMINES
HISTAMINE & SEROTONIN
First Mediators and act upon Blood Vessels

HISTAMINE
Mast cells are richest Source of Histamine
• Stored as Granules / Released by Degranulation
Releases in response to following stimuli: Physical Injuries
• Antibodies Mediated (Hypersensitivity Reaction)
• Complement Products (Anaphyl-Toxin C3a / C5a)
• Neuropeptides (Substance-P) / Cytokines (IL1, IL8)

FUNCTIONS
Dilation of Arterioles / Increases Permeability of Venules
• Principal Mediator of Immediate Transient Phase
• Increased Vascular Permeability which Produces Inter-Endothelial
Gaps in Venules.
• Act via H1 Receptors Present on Microvascular of Endothelial Cells

SEROTONIN
(5-HYDROXYTRYPTAMINE)
It is a Performed Mediator
• Present in Platelets (Released during Platelet Aggregation) / Certain
Neuro-Endocrinal Cells (G.I.T)
• Primarily acts as a Neuro-Transmitter
• Induce Vaso-Constriction during Clotting

ARACHIDONIC ACID
METABOLITES
 Prostaglandins / Leukotrienes are Lipid Mediators, produced from
Arachidonic Acid (AA) Present in Membrane Phospholipids
• Stimulate Vascular / Cellular Reactions
• Arachidonic acid derived from Dietary Linoleic Acid
Mechanical / Chemical / Physical stimuli / Other Mediators (C5a)
Release AA from Membrane Phospholipids through the Action of
Cellular Phospholipases (Mainly Phospholipase A2)
 PROSTAGLANDINS
Produced by Mast Cells / Macrophages of Endothelial Cells
• Involved in Vascular / Systemic Reactions of Inflammation
• COX-1 / COX-2 is Involved in Synthesis of Prostaglandins
• COX -1 is Produced in Response to Inflammatory Stimuli and is also
constitutively expressed in most Tissues where they may serve as
Homeostatic Function
• COX2 is induced by Inflammatory Stimuli

PGD2
Major Prostaglandin / made by mast cell
• Causes Vasodilation / Increases Permeability of Post Capillary
Venules and thus Potentiating Exudation / Resultant Edema

THROMBOXANE A2 (TXA2)
Derived by action of Thromboxane Synthase present in Platelets
• Platelets Aggregation (Promote Thrombosis)
• Causes Vaso-Constrictions
• Unstable / Converted to Inactive forms TxB2

PROSTA-CYCLIN( PGI2)
Formed by Action of Prosta-Cyclin Synthase (Present in Vascular
Endothelium)
• Increases Vascular Permeability
• Inhibits Platelets Aggregation
PGF2: Stimulates contraction of uterine and bronchial smooth
muscles and small arterioles
• Prostaglandins involved in the pathogenesis of pain and fever in
inflammation
PGE2: Hyper-Algesic, makes Skin Hypersensitive to Painful Stimuli

LEUKOTRIENE
Produced by the action of 5-Lipoxygenase(Major AA-Metabolizing
Enzyme in Neutrophils)

SYNTHESIS OF LEUKOTRIENE
• Generation of Leukotriene A4 (LTA4), which in turn gives rise to LTB4
/ LTC4
LTB4: is Produced by Neutrophils & some Macrophages
• Chemotactic / Neutrophil Activator
LTC4: and its subsequent Metabolites (LTD4 / LTE4) are Produced
mainly in Mast Cells and cause Broncho-Constriction / Increased
Vascular Permeability
• Leads to Aggregation / Adhesion of cells to Venular Endothelium
• Generation of ROS
LTC4 / LTD4 / LTE4 Causes:
• Vaso-Constrictions
• Broncho-Spasm
• Increased Permeability of Venules
• Leukotrienes are more Potent than Histamine in Increasing Vascular
Permeability
 LIPOXINS
Generated from AA by Lipoxygenase Pathway
• Suppresses Inflammation by Inhibiting Recruitment of Leukocytes
• Inhibits Neutrophil Chemotaxis / Adhesion to Endothelium

PHARMACOLOGIC INHIBITORS OF
PROSTAGLANDINS / LEUKOTRIENES
Cyclo-Oxygenase Inhibitors-Aspirin /Other Non-Steroidal Anti-
Inflammatory drugs (NSAIDs)
• Inhibit both COX-1 / COX-2
• COX1 is responsible for Production of Prostaglandins Involved in
Inflammation / Homeostasis (Fluid / Electrolyte Balance in Kidney /
Cyto-Protection in G.I.T)
• COX2 generates Prosta-Glandins that are Involved only in
Inflammatory Reactions
LIPOXYGENASE INHIBITORS: Zileuton
CORTICOSTEROIDS: Broad spectrum Anti-Inflammatory
• Reduces Transcription of Genes which Encodes COX2 /
Phospholipase A2 / Pro-I0nflammatory Cytokines (IL1 / TNF)
LEUKOTRIENE RECEPTOR ANTAGONISTS: Blocks
Receptor (Montelukast)

CYTOKINES
 Proteins Produced by many cell types (Activated Lymphocytes /
Macrophages / Dendritic Cells)
• Mediate / Regulate Immune / Inflammatory Reactions

TNF / INTERLEUKIN- 1
Participates in Leukocyte Recruitment
• Promotes Adhesion of Leukocytes to Endothelium / Their Migration
through Vessels
• Produced by Macrophages / Dendritic Cells
• TNF is also Produced via T-Lymphocytes / Mast Cells
Stimulus for secretion: Microbial Products
• Immune Complexes
• Foreign Bodies
• Physical Injury
• Other inflammatory Stimuli
TNF production is induced by TLRs and other Microbial sensors

ROLES OF CYTOKINES IN INFLAMMATION

ENDOTHELIAL ACTIVATION
by TNF / IL-1
• Increased Expression of Adhesion Molecules (P / E-selectins /
Ligands for Leukocytes)
• Increased Production of Various Mediators
• Increased Pro-Coagulant Activity
ACTIVATION OF LEUKOCYTES & OTHER CELLS
• Stimulates Microbicidal activity of Macrophages
• IL1 Activates Fibroblasts to Synthesize Collagen / Stimulate
Proliferation of Synovial / other Mesenchymal cells
• Stimulates TH17 responses (Induce Acute Inflammation)
SYSTEMIC ACUTE-PHASE RESPONSE
Induced by IL-1 / TNF / IL-6
• TNF Antagonists have been remarkably Effective in the Treatment of
Chronic Inflammatory Diseases (Rheumatoid Arthritis / Psoriasis)

CHEMOKINES
 Family of small (8-10 kD) Proteins that act Primarily as Chemo-
Attractants for Specific types of Leukocytes
• About 40 different Chemokines & 20 different Receptors for
Chemokines have been Identified

CLASSIFICATION OF CHEMOKINES
Consists four Major Groups

C-X-C CHEMOKINES
Have one Amino Acid residue, which Separates the First Two of the
Four Conserved Cysteine Residues
• Act Primarily on Neutrophils
• Secreted by Macrophages / Endothelial Cells
FUNCTION: Activation / Chemotaxis of Neutrophils
EXAMPLE: IL-8

C-C-CHEMOKINES
have the first two Conserved Cysteine residues adjacently
• Includes Monocyte Chemo-Attractant Protein (MCP1)
• Eotaxin Selectively Recruits Eosinophils

C CHEMOKINES
Lack the First / Third of the Four Conserved Cysteines
• Specific for lymphocytes
EXAMPLE: Lymphotactin
 CX3C CHEMOKINES
Contains Three Amino Acids between Two Cysteines
EXAMPLE: Fract-Alkine (Exists in two forms)
Cell Surface Bound Protein Form: Promotes Strong Adhesion of
Monocytes / T cells
Soluble Form: Derived by Proteolysis of the Membrane Bound Protein
and is Potent Chemo-Attractant

FUNCTIONS OF CHEMOKINES
• In Acute Inflammation, Stimulates Leukocyte attachment to
Endothelium by acting on Leukocytes to Increase the Affinity of
Integrins
• Chemotaxis
• Maintains of Tissue Architecture
• Homeostatic Chemokines Produced Constitutively in Tissues

OTHER CYTOKINES IN ACUTE

INFLAMMATION
IL-6: Secreted by Macrophages involved in Local / Systemic Reactions
IL-17: Produced by T-Lymphocytes, Promotes Neutrophil Recruitment
Type I Interferons: Some Systemic Manifestations
 OTHER MEDIATORS OF
INFLAMMATION
PLATELET-ACTIVATING FACTOR (PAF)
A Phospholipid derived Mediator
• Secreted by Platelets / Basophils / Mast Cells / Neutrophils /
Macrophages / Endothelial cells
Causes: Platelets Aggregation
• vaso-Constriction
• Broncho-Constiction
• At Low Concentrations, Induces Vaso-Dilation / Increased Venular
Permeability

PRODUCTS OF
COAGULATION
KININS
Vasoactive Peptides
• Derived from Plasma Proteins (Kininogens) by the action of Specific
Proteases called kalli-Kreins

BRADYKININ
 Increases Vascular Permeability / Smooth Muscles Contractions
• Dilatates of Blood Vessels / Causes Pain

NEUROPEPTIDES
Secreted by Sensory Nerves / Various Leukocytes
• Substance-P / Neurokinin-A

SUBSTANCE-P
Prominent in Nerve Fibers / Lungs / GIT
FUNCTIONS: Transmits Pain Signals
• Regulates B.P
• Stimulates Hormone Secretion by Endocrine Cells
• Increases Vascular Permeability