1.

Definition of Inflammation

Inflammation is characterized by a series of events driven by various mediators,

including cytokines and chemokines. These mediators orchestrate changes in:

• Blood vessels: Increased blood flow and permeability.

• Leukocytes: Migration of white blood cells from the bloodstream to the site of
injury.
• Connective tissue: Increased production of extracellular matrix components
for repair.

The cardinal signs of inflammation, discussed later, offer a clinical presentation of

these changes.

2. Stimuli for Inflammation

Multiple factors can trigger an inflammatory response:

• Infectious agents: Bacteria, viruses, parasites, and fungi.

• Tissue injury: Physical trauma, burns, chemical exposure.
• Immune reactions: Hypersensitivity reactions to allergens or self-antigens.
• Necrosis: Cell death due to various causes.
• Foreign bodies: Inert materials like splinters or dust particles.

3. Cardinal Signs of Inflammation

These classic signs, first described by Roman physician Celsus, are:

• Rubor (redness): Increased blood flow to the inflamed area causes redness.
• Tumor (swelling): Fluid accumulation and leukocyte infiltration lead to
swelling.
• Calor (heat): Increased metabolic activity in the inflamed tissue generates
heat.
• Dolor (pain): Activation of pain receptors by inflammatory mediators causes
pain.
• Functio laesa (loss of function): Tissue damage and swelling can impair
organ or tissue function.

These signs may not always be present in all types of inflammation.

4. Classification of Inflammation

Inflammation can be classified based on various criteria:

• Duration:
o Acute inflammation: Rapid onset, short duration (hours to days),
typically resolves completely.
o Chronic inflammation: Long-lasting (weeks to years), often
associated with persistent tissue damage.
 • Exudate: Fluid leaking from blood vessels into the inflamed tissue:
o Serous inflammation: Thin, watery exudate (e.g., blisters).
o Fibrinous inflammation: Rich in fibrin protein, leading to formation of
a fibrinous membrane (e.g., croup).
o Suppurative inflammation: Pus formation due to high numbers of
neutrophils (e.g., abscesses).
o Hemorrhagic inflammation: Presence of red blood cells in the
exudate (e.g., some types of pneumonia).
• Cellular infiltrate: The types of leukocytes predominantly present:
o Neutrophilic inflammation: Characterized by neutrophils, typically
associated with acute bacterial infections.
o Eosinophilic inflammation: Dominated by eosinophils, often seen in
allergic reactions and parasitic infections.
o Lymphocytic inflammation: Primarily lymphocytes present, involved
in chronic inflammation and immune reactions.
o Granulomatous inflammation: Formation of granulomas with
epithelioid macrophages and lymphocytes, seen in tuberculosis and
other chronic infections.

Please note: These are just the main categories; there's significant overlap and
other classification systems based on specific causes or locations.

5. Acute Inflammation: Major Events and Components

Acute inflammation is a rapid and well-orchestrated response typically lasting from

hours to a few days. It involves a series of vascular and cellular events:

Diagram:

Major Events:

• Release of Mediators: Tissue damage triggers the release of various

mediators, including histamine, cytokines, and chemokines. These act on
local blood vessels and leukocytes.
• Vascular Changes:
o Vasodilation: Increased blood flow to the inflamed area, causing
redness and warmth.
o Increased Vascular Permeability: Plasma leaks from blood vessels,
leading to edema (swelling).

Cellular Events:

1. Leukocyte Adhesion & Rolling:

o Selectins on the surface of endothelial cells (lining of blood vessels)
and leukocytes mediate initial contact.
o Leukocytes "roll" along the endothelium, searching for activation
signals.
2. Leukocyte Diapedesis (Migration Through Vessel Wall):
 o Mediators like chemokines activate leukocytes, causing them to adhere
more firmly to the endothelium.
o Integrins on leukocytes and endothelial cells play a crucial role in this
tight adhesion.
o Leukocytes squeeze between endothelial cells (diapedesis) and
migrate into the inflamed tissue.

Order of Leukocyte Arrival:

* **Neutrophils:** The first responders, arriving within minutes to hours,

are adept at phagocytosis of bacteria and other pathogens.
* **Monocytes/Macrophages:** Arrive later, phagocytize debris from dead
neutrophils and pathogens, and can also differentiate into other cell types
involved in tissue repair.

3. Phagocytosis:
o Neutrophils engulf and destroy pathogens using various mechanisms,
including reactive oxygen species (ROS) and enzymes.
4. Tissue Repair & Resolution:
o After the initial response, neutrophils undergo apoptosis (programmed
cell death).
o Macrophages orchestrate the removal of dead cells and debris.
o Granulation tissue, a vascularized connective tissue, forms to facilitate
repair and healing.
o If the injurious agent is eliminated, the inflammatory process resolves,
and normal tissue architecture is restored.

5. Comparison of Acute vs. Chronic Inflammation:

Feature Acute Inflammation Chronic Inflammation

Duration Rapid onset, short duration (hours to Long-lasting (weeks to years)
days)
Cause Typically caused by infections, tissue Persistent tissue damage,
injury, or foreign bodies autoimmune reactions, or
unresolved infections
Cellular Primarily neutrophils in early stages, Variable; may involve
infiltrate followed by monocytes/macrophages lymphocytes, macrophages,
plasma cells, and eosinophils
Tissue Minimal; aims to remove pathogens Can lead to significant tissue
destruction and initiate repair destruction and fibrosis
(scarring)
Outcome Ideally resolves completely with May not resolve completely
restoration of normal tissue and can lead to long-term
architecture organ dysfunction

7. Leukocyte Adhesion Molecules:

Leukocyte adhesion molecules are specialized proteins expressed on the surface of
leukocytes and endothelial cells that play a critical role in leukocyte adhesion and
migration during inflammation. Here are some key types:

• Selectins: mediate initial rolling interactions between leukocytes and

endothelium.
• Integrins: facilitate firm adhesion and diapedesis.
• Ig-CAMs (Immunoglobulin superfamily cell adhesion
molecules): involved in later stages of adhesion and activation.

The interaction between these molecules is tightly regulated, ensuring leukocyte

recruitment to specific sites of inflammation.

8. Chemotaxis:

Chemotaxis refers to the directed movement of leukocytes towards higher

concentrations of chemical attractants, such as chemokines and bacterial products.
These attractants bind to specific receptors on leukocytes, triggering a signaling
cascade that leads to cell migration towards the source of the signal. Chemotaxis is
essential for leukocyte recruitment to sites of inflammation.

9. Phagocytosis:

Phagocytosis is the process by which specialized cells, called phagocytes, engulf

and eliminate foreign particles, including bacteria, dead cells, and debris.

Phagocyte Cells:

• Neutrophils: Primary phagocytes in acute inflammation.

• Macrophages: More versatile phagocytes present in various tissues and
involved in both acute and chronic inflammation.

Steps of Phagocytosis (Diagram):

1. Recognition and Attachment: Phagocytes recognize opsonized particles

(coated with antibodies or complement proteins) through specific receptors.
2. Engulfment: Pseudopodia (extensions of the cell membrane) extend around
the particle, forming a phagosome (an engulfing vacuole).
3. Phagosome-Lysosome Fusion: The phagosome merges with lysosomes,
forming a phagolysosome.
4. Killing and Degradation: Enzymes and reactive oxygen species (ROS)
within lysosomes digest and destroy the engulfed material.
5. Exocytosis or Retention: In some cases, digested material may be released
outside the cell, while in others, it may be retained for antigen presentation.

Diagram:

10. Chemical Mediators of Inflammation:

Chemical mediators are signaling molecules that orchestrate various aspects of the
inflammatory response. They can be broadly categorized into:

A. Plasma-Derived Mediators:

• Complement System: A cascade of proteins in the blood that promotes

opsonization (facilitates phagocytosis), chemotaxis, and direct lysis of
pathogens.
• Kinins: Short-lived peptides involved in vasodilation, increased vascular
permeability, and pain.
• Coagulation Cascade: Plays a role in clot formation and limits blood loss at
the site of injury.

B. Cell-Derived Mediators:

• Histamine: Released from mast cells and basophils, causes vasodilation,

increased vascular permeability, and contributes to pain and itching.
• Cytokines: A broad group of signaling molecules produced by various cells,
including leukocytes, endothelial cells, and fibroblasts. They have diverse
effects, including promoting leukocyte recruitment, activation, and tissue
repair. Some key examples:
o Interleukins (ILs): IL-1 is a potent pro-inflammatory cytokine, while IL-
10 has anti-inflammatory effects.
o Tumor necrosis factor-alpha (TNF-α): Involved in promoting
inflammation, cell activation, and apoptosis

11. Arachidonic Acid Metabolites (Eicosanoids):

Eicosanoids are a diverse group of signaling molecules derived from arachidonic

acid, a polyunsaturated fatty acid found in cell membranes. They play a crucial role
in various physiological processes, including inflammation. The two main pathways
for eicosanoid biosynthesis are:

• Cyclooxygenase (COX) pathway: Generates prostaglandins, prostacyclin,

and thromboxane. These mediators influence:
o Vasodilation and vascular permeability (prostaglandins)
o Platelet aggregation and vasoconstriction (thromboxane)
o Pain, fever, and inflammation (prostaglandins)
• Lipoxygenase (LOX) pathway: Produces leukotrienes, which contribute to:
o Bronchoconstriction (important in asthma)
o Increased vascular permeability
o Smooth muscle contraction

Non-steroidal anti-inflammatory drugs (NSAIDs) work by inhibiting COX

enzymes, thereby reducing prostaglandin synthesis and mitigating
inflammatory symptoms.

12. Role of TNF and IL-1 in Inflammation:

 • Tumor Necrosis Factor-alpha (TNF-α): A potent pro-inflammatory cytokine
produced by macrophages and other cells. Its effects include:
o Increased vascular permeability
o Leukocyte recruitment
o Activation of other inflammatory mediators
o Tissue damage in chronic inflammatory conditions.
• Interleukin-1 (IL-1): Another primary pro-inflammatory cytokine released by
macrophages and other immune cells. It shares many functions with TNF-α,
including:
o Inducing fever
o Stimulating the production of other inflammatory mediators
o Promoting tissue destruction.

TNF-α and IL-1 are key targets for therapeutic intervention in inflammatory
diseases.

13. Chemokines:

Chemokines are a family of small signaling molecules responsible for directing the
migration and activation of leukocytes during inflammation. They bind to specific
receptors on leukocytes and induce chemotaxis, the directed movement towards
higher chemokine concentrations. This ensures targeted recruitment of leukocyte
populations best suited to combat the specific inflammatory challenge.

14. Role of the Complement System in Inflammation:

The complement system is a group of plasma proteins that work in a cascade to

amplify the inflammatory response. Key functions include:

• Opsonization: Complement proteins coat pathogens and debris, making

them more recognizable for phagocytosis by neutrophils and macrophages.
• Direct lysis: Certain complement components can directly cause the lysis
(destruction) of some pathogens.
• Inflammation promotion: Complement activation fragments can trigger the
release of inflammatory mediators, such as histamine, and contribute to
increased vascular permeability.

Dysregulation of the complement system can lead to various inflammatory

diseases.

15. Factors Determining the Inflammatory Response in Individuals:

The intensity and nature of the inflammatory response can vary significantly between
individuals due to several factors:

• Age: As we age, the immune system becomes less efficient, leading to

potentially weaker inflammatory responses.
• Genetic Predisposition: Certain genetic variations can influence the
expression and function of inflammatory mediators, making some individuals
more susceptible to chronic inflammatory conditions.
 • Nutritional Status: Nutritional deficiencies, particularly deficiencies in
vitamins and antioxidants, can impair immune function and dampen the
inflammatory response.
• Comorbidities: Existing health conditions, such as diabetes or obesity, can
alter immune function and influence the inflammatory response.
• Medications: Certain medications, like corticosteroids, can suppress the
inflammatory response, while others may inadvertently trigger or exacerbate
inflammation.

16. Morphological Patterns of Acute Inflammation:

The appearance of inflamed tissue can vary depending on the nature of the exudate
(fluid leaking from blood vessels) and the predominant cell type involved. Here are
some common morphological patterns of acute inflammation:

• Serous Inflammation: Thin, watery exudate, often seen in blisters caused by

burns or viral infections.
• Fibrinous Inflammation: Rich in fibrin protein, leading to the formation of a
fibrinous membrane or exudate. Examples include croup (respiratory
condition) and pericarditis (inflammation of the sac surrounding the heart).
• Suppurative Inflammation (Purulent Inflammation): Characterized by pus
formation, a thick, yellow fluid containing dead neutrophils, cellular debris, and
plasma. Common in bacterial abscesses.
• Hemorrhagic Inflammation: Presence of red blood cells in the exudate,
often due to increased vascular permeability or damage to blood vessels. Can
be seen in some types of pneumonia or meningitis.

17. Definition of Ulcer:

An ulcer is a localized area of erosion or excavation of the epithelial surface (skin or

mucous membrane) extending into the deeper tissues. It can be caused by various
factors, including:

• Inflammation: Chronic inflammatory bowel disease (IBD) can lead to ulcers

in the gastrointestinal tract.
• Infection: Bacterial or viral infections can cause ulcers in the skin or mucous
membranes.
• Ischemia (Reduced Blood Flow): Insufficient blood supply can cause tissue
death and ulcer formation, such as diabetic foot ulcers.
• Pressure Ulcers (Bedsores): Prolonged pressure on skin over bony
prominences can impair blood flow and lead to ulceration.

18. Outcomes of Acute Inflammation:

The ideal outcome of acute inflammation is complete resolution with restoration of

normal tissue architecture. This process involves:

• Removal of the injurious agent by phagocytes and other immune

mechanisms.
 • Neutrophil apoptosis (programmed cell death) and clearance of dead
cells.
• Macrophage-mediated tissue repair through granulation tissue formation
and collagen deposition.

However, depending on the severity and persistence of the inflammatory stimulus,

other outcomes are possible:

• Healing with fibrosis (scarring): If significant tissue damage occurs, the

repair process may lead to scar formation.
• Chronic inflammation: In some cases, the inflammatory response fails to
resolve completely, leading to a transition to chronic inflammation, which can
cause ongoing tissue damage.

19. Systemic Effects of Inflammation:

Acute inflammation can trigger various systemic responses, collectively known as

the systemic inflammatory response syndrome (SIRS). These effects can include:

• Fever: Increased body temperature due to the release of pyrogens (fever-

inducing substances) by immune cells.
• Leukocytosis: Elevation of white blood cell count, reflecting increased
production and release of leukocytes from the bone marrow.
• Acute phase response: A coordinated set of changes in the liver's protein
synthesis, leading to the production of acute-phase proteins.
• Fatigue and malaise: General feeling of tiredness and discomfort associated
with the inflammatory response.

20. Acute Phase Response and Acute Phase Proteins:

The acute phase response is a complex set of systemic changes that occur during
inflammation. The liver plays a central role in this response, increasing the synthesis
of specific proteins called acute-phase proteins (APPs). These proteins have diverse
functions, including:

• Opsonization: Certain APPs enhance the ability of phagocytes to engulf and

destroy pathogens.
• Inflammation modulation: Some APPs can dampen the inflammatory
response to prevent excessive tissue damage.
• Nutrient transport: APPs like C-reactive protein (CRP) may play a role in
transporting nutrients to sites of inflammation and tissue repair.
• Tissue repair: Specific APPs contribute to wound healing and tissue
regeneration.

The levels of some APPs, like CRP, can be measured in blood tests and are often
used as markers of inflammation.
Chronic inflammation, unlike its acute counterpart, is a long-lasting (weeks to years)
inflammatory response characterized by persistent tissue damage and attempts at
repair. Let's delve into its complexities:

1. Define Chronic Inflammation:

Chronic inflammation is a persistent inflammatory response where the initial

causative agent may or may not be eliminated. It leads to a cycle of tissue injury,
repair attempts, and ongoing inflammation, often resulting in significant tissue
destruction and fibrosis (scarring).

2. Pathophysiology or Causes of Chronic Inflammation:

Multiple factors can trigger chronic inflammation:

• Persistent Infections: Bacteria, viruses, or parasites that evade complete

eradication by the immune system can lead to chronic inflammation.
Examples include tuberculosis and chronic hepatitis.
• Autoimmune Reactions: When the immune system mistakenly attacks self-
tissues, chronic inflammation ensues. Rheumatoid arthritis and systemic
lupus erythematosus (SLE) are examples.
• Exposure to Noxious Agents: Chronic exposure to irritants, such as
cigarette smoke or environmental pollutants, can induce chronic inflammation
in the lungs.
• Foreign Bodies: Inert materials like asbestos fibers can trigger chronic
inflammation as the body attempts to wall them off.

3. Morphological Types of Chronic Inflammation:

Chronic inflammation can manifest in different forms depending on the predominant

cell types involved and the nature of the tissue damage:

• Chronic Granulomatous Inflammation: Characterized by the formation of

granulomas, aggregates of epithelioid macrophages surrounded by
lymphocytes. Seen in tuberculosis and sarcoidosis.
• Chronic Lymphocytic Inflammation: Dominated by lymphocytes, often B
cells and T cells. This type is found in autoimmune diseases like Hashimoto's
thyroiditis.
• Chronic Suppurative Inflammation: Persists with ongoing pus formation,
often due to recurrent infections or fistulae (abnormal connections between
organs or tissues).
• Chronic Fibrotic Inflammation: Characterized by extensive scar tissue
formation due to repeated cycles of injury and repair. Examples include liver
cirrhosis and pulmonary fibrosis.

4. Role of Macrophages in Chronic Inflammation:

Macrophages play a pivotal role in chronic inflammation:

 • Phagocytosis: They attempt to engulf and eliminate foreign material or
damaged cells.
• Antigen Presentation: They present antigens to T lymphocytes, perpetuating
the immune response.
• Cytokine Secretion: They release various cytokines and growth factors that
can contribute to tissue damage, fibrosis, and angiogenesis (new blood vessel
formation).

5. Granulomatous Inflammation:

Granulomatous inflammation is a specific type of chronic inflammation characterized

by the formation of granulomas. These are microscopic structures consisting of
epithelioid macrophages (activated macrophages with a distinctive appearance),
surrounded by lymphocytes and sometimes giant cells (formed by the fusion of
macrophages). Granulomas serve to wall off and contain persistent infections or
foreign bodies.

Causes of Granulomatous Inflammation:

• Infectious Agents:
o Bacteria: Mycobacterium tuberculosis (tuberculosis), Mycobacterium
leprae (leprosy)
o Fungi: Histoplasma capsulatum (histoplasmosis)
o Parasites: Schistosoma mansoni (schistosomiasis)
• Non-infectious Agents:
o Foreign bodies (e.g., talc)
o Certain medications
o Sarcoidosis (cause unknown)

By understanding chronic inflammation and its various forms, we gain valuable

insights into the pathogenesis of numerous diseases. This knowledge is crucial for
developing effective diagnostic and therapeutic strategies.

6. Granuloma:

A granuloma is a microscopic structure found in chronic inflammation, particularly

granulomatous inflammation. It serves to wall off and contain persistent infections,
foreign bodies, or areas of persistent tissue damage. Here's the breakdown:

• Composition: Primarily consists of epithelioid macrophages (activated

macrophages with a distinctive appearance) surrounded by lymphocytes and
sometimes giant cells (formed by the fusion of macrophages).
• Function: Isolates and neutralizes the offending agent, preventing its spread
and promoting tissue repair.

Types of Granulomas:
 • Foreign Body Granuloma: Reaction to inert materials like talc or sutures.
• Langhans Giant Cell Granuloma: Classic granuloma seen in tuberculosis,
with centrally located Langhans giant cells (multinucleated giant cells with
horseshoe-shaped nuclei).
• Epithelioid Granuloma: Composed primarily of epithelioid macrophages,
seen in sarcoidosis (cause unknown).
• Cholesterol Granuloma: Accumulation of cholesterol crystals surrounded by
macrophages, often found in atherosclerotic plaques.

7. Granulation Tissue:

Granulation tissue is a vascularized connective tissue that forms during the repair
process following tissue injury or inflammation. It's a temporary structure that paves
the way for definitive repair with scar tissue formation. Here's what sets it apart from
granulomas:

• Composition: Consists of newly formed blood vessels, fibroblasts, and

inflammatory cells (mainly neutrophils and macrophages) migrating into the
wound site.
• Function: Provides a vascular supply for repair processes, facilitates
migration of leukocytes, and lays down collagen, the building block of scar
tissue.

8. Giant Cells:

Giant cells are large, multinucleated cells typically formed by the fusion of
macrophages or other cells. They can be physiological or pathological:

Physiological Giant Cells:

• Osteoclasts: Responsible for bone resorption during bone remodeling.

• Langhans Giant Cells of the Placenta: Support nutrient exchange between
mother and fetus.

Pathological Giant Cells:

• Foreign Body Giant Cells: Formed by the fusion of macrophages around

foreign bodies.
• Langhans Giant Cells: Seen in granulomatous inflammation, often
associated with infectious agents.
• Touton Giant Cells: Characteristic of some tumors, particularly malignant
ones.

9. Differentiation Between Granuloma and Granulation Tissue:

Feature Granuloma Granulation Tissue

Composition Epithelioid macrophages, Blood vessels, fibroblasts,
lymphocytes, giant cells neutrophils, macrophages
Function Wall off persistent infections/foreign Facilitate tissue repair and
bodies scar formation

Inflammatory Chronic inflammation, specifically Both acute and chronic

Context granulomatous inflammation inflammation

Location Can occur anywhere in the body Typically forms at sites of

tissue injury

Specificity Often indicates a specific Non-specific response to

underlying cause (e.g., tissue injury
tuberculosis)