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Acute Inflammation

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Pathology

Response of Body to Injury & Infection

Pharm D 3rd Prof


Bahauddin Zakariya University Multan

Waseem Ashraf
Learning Objectives

After this lecture, students will be able to


• Describe Vascular and Cellular responses in Acute Inflammation

Recommended Books:
• Robbins and Cotran PATHOLOGIC BASIS OF DISEASE 1st South Asia Edition
Summary of Previous Lecture
Inflammation is a beneficial host response to foreign invaders and necrotic tissues; however, it may
also cause tissue damage.
There are two major components of inflammation Steps of Inflammatory Response (5Rs)
a) A vascular reaction 1. Recognition of the injurious agent
b) A cellular response 2. Recruitment of Leukocytes
mediated by mediators derived from plasma 3. Removal of agents
proteins or various cells. 4. Regulation (control) of response
5. Resolution (repair)
Causes of Inflammation Outcomes

• Infections • Trauma Elimination of noxious stimuli followed by decline

• Tissue necrosis • Immune responses in reaction and tissue repair OR

• Foreign bodies Persistent injury leading to chronic inflammation


Recognition of Microbes and Damaged Cells
1. Cellular Receptors e.g., Toll Like Receptors (TLRs) etc.
a. For Microbes there are Pathogen Associated Molecular Patterns (PAMPs)
lipopolysaccharides etc.
b. For cellular damages there are Damage Associated Molecular Patterns (DAMPs) DNA,
ATP, Uric Acid, low K+ etc.
2. Circulating proteins
a. Complementing system
b. Mannose-binding lectin
ACUTE INFLAMMATION
Three major steps in acute inflammation process
1. Dilution of small vessels, leading to an increase in blood flow
2. Increased permeability of the microvasculature enabling plasma proteins and Leukocyte to leave
the circulation
3. Emigration of Leukocytes from the microcirculation, accumulation and activation at site of injury
to eliminate the offending agents.

Reaction of Blood Vessels in Acute Inflammation


1. Changes in Vascular Flow and Caliber
2. Increased Vascular Permeability (Vascular Leakage)
3. Responses of Lymphatic Vessels and Lymph nodes
Changes in Vascular Flow and Caliber
• Vasodilation
• Caused by vasoactive amines (histamines),
• May be proceeded by temporary vasoconstriction
• Initially starts in arterioles and then proceeds to capillaries.
• Loss of fluid and slowness of blood flow leads to
concentration of blood cells (vascular congestion &
erythema)
Increased Vascular Permeability (Vascular Leakage)
• Retraction of endothelial cells caused by chemical
mediators (histamines, bradykinins etc.
Transient response short lived 15-30 mins
Mostly occurs at the postcapillary venules
• Endothelial Injury
• Can be because of traumatic injury (burn) or
infections (microbes) etc.
Permitting transport of fluids and proteins (transcytosis)
through endothelial cells
Responses of Lymphatic Vessels and Lymph Nodes
• Lymphatic system
• There may be secondarily inflammation (Lymphangitis /
Lymphadenitis)
Recruitment of Leukocytes to Sites of Inflammation
Major cells involved are
• Neutrophils – rapid but short-lived response
• Macrophages – slow but usually long-term response
1. Leukocyte Adhesion to Endothelium
Margination of white blood cells
‐ vasodilation & slow movement
Adherence to the endothelial cells
‐ Facilitated by complement system
‐ Selectins & Integrins
Selectin
Initial weak interactions between leukocytes and endothelium
• E-selectin – Endothelial cells
• P-selectin – Platelets
• L-selectin – Leukocytes
Normally low in concentration on membranes but increase with activation
Recruitment of Leukocytes to Sites of Inflammation
1. Leukocyte Adhesion to Endothelium
Integrin
Integrins are two chain glycoprotein expressed on leukocytes and mediate the interaction with endothelial cells.
Activated by chemokines and cytokines to bind the ligands on endothelial cells.
2. Leukocyte Migration through Endothelium
Transmigration of leukocytes through endothelium
Chemokines play a major role in this migration
Basement membrane is pierced by secreting collagenases and typically the vessel wall is not injured during
leukocyte transmigration.
3. Chemotaxis of Leukocytes
Exogenous & endogenous chemo-attractants Nature of Leukocyte to respond
Bacterial products Time Initial response – Neutrophils
Cytokines Late response – Macrophages
Components of the complement system (C5
Type of Bacterial infections – Neutrophils
Products of lipoxygenase of AA pathway (leukotrienes)
Response Viral infections – Lymphocytes
Hypersensitivity – Lymphocytes
Recruitment of Leukocytes to Sites of Inflammation
1. Leukocyte Adhesion to Endothelium
Integrin
Integrins are two chain glycoprotein expressed on leukocytes and mediate the interaction with endothelial cells.
Activated by chemokines and cytokines to bind the ligands on endothelial cells.
2. Leukocyte Migration through Endothelium
Transmigration of leukocytes through endothelium
Chemokines play a major role in this migration
Basement membrane is pierced by secreting collagenases and typically the vessel wall is not injured during
leukocyte transmigration.
3. Chemotaxis of Leukocytes
Exogenous & endogenous chemo-attractants Nature of Leukocyte to respond
Bacterial products Time Initial response – Neutrophils
Cytokines Late response – Macrophages
Components of the complement system (C5
Type of Bacterial infections – Neutrophils
Products of lipoxygenase of AA pathway (leukotrienes)
Response Viral infections – Lymphocytes
Hypersensitivity – Lymphocytes
Neutrophils Monocytes / Macrophages
Phagocytosis and Clearance of the Offending Agent
Leukocyte Activation
Phagocytosis and Clearance of the Offending Agent
Phagocytosis includes three sequential steps
1. Recognition and attachment of particle to be ingested by leukocytes
Mannose receptors
Scavenger receptors
Receptors for Opsonins
2. Engulfment with subsequent formation of phagocytic vacuole
3. Killing or degradation of ingested material (microbes / debris)
Reactive Oxygen Species (ROS)
Nitric Oxide NO
Granule enzymes and other proteins from leukocytes such as Neutrophils, Monocytes & Macrophages
Neutrophils – larger granules (Azurophil) contains myeloperoxidase, bactericidal factors (defensins), hydrolases
and neutral peptidases (elastase, cathepsin G, collagenases etc.)
Neutrophils – smaller “specific” granules (lysozymes, gelatinase, lactoferrin, plasminogen activator, histaminase
etc.)
Macrophages – acid hydrolases, collagenase, elastase, phospholipase and plasminogen activator.

To protect normal tissue from injury there are different preventive mechanisms such as anti-proteases.
Neutrophil extracellular traps are extracellular fibrillar network that concentrates anti-microbial substances at the
site of infection and prevent the spread of the microbes by trapping them in fibrils.
Leukocytes-Mediated Tissue Injury
1. Collateral damage of normal tissue in defense reaction against microbes e.g., Hepatitis,
Tuberculosis
2. Inappropriately directed towards host proteins / cells e.g., autoimmune disease
3. Hyper reaction of leukocytes to normal stimuli or harmless environmental substances

Mostly “frustrated macrophages” that fail to engulf the threat release a large quantity of granule
enzymes damaging the surrounding tissue or
Engulfed materials such as urate, silica crystals may damage the phagolysosome membrane and
release the damaging content in the surrounding tissues.

Termination of Acute Inflammation Response


Apoptosis of Inflammatory cells
Triggering of stop signals to inflammation
Release of anti-inflammatory signals (TGF-β, IL-10 etc.)

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