Download Chapter 5 – Innate Defenses: Inflammation

PATHOPHYSIOLOGY
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Chapter 5 – Innate Defenses: Inflammation
I. Human Defense Mechanisms
A. Overview
1. First line of defense: Physical and biochemical barriers
Innate immunity
2. Second line of defense: Inflammation
3. Third line of defense: Adaptive (acquired) immunity
II. First Line of Defense: Physical and Biochemical Barriers
A. Physical and mechanical barriers

Skin

Linings of the gastrointestinal, genitourinary, and respiratory tracts
o
Sloughing off of cells
o
Coughing and sneezing
o
Flushing
o
Vomiting
o
Mucus and cilia
B. Biochemical barriers

Saliva, tears, ear wax, sweat, and mucus – trap bacteria and contain:

Lysozyme and antimicrobial peptides – produced by body cells, kill bacteria and other pathogens

Normal bacterial flora – symbiotic; help prevent growth of pathogens
III. Second Line of Defense: Inflammatory Response
A. Overview of Inflammatory Response

Caused by a variety of stimuli
o

Local manifestations
o

Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc.
Redness, heat, swelling, pain and loss of function
Vascular response
o
Blood vessels dilate and become more permeable, allowing cells and fluid to enter site.
o
White blood cells adhere to the inner walls of the vessels and migrate across the vessel wall.
o
Fluid, inflammatory chemicals and cells can then dilute toxins and battle pathogens.
B. Goals of Inflammation

Limit and control tissue damage

Prevent and limit infection

Initiate adaptive immune response

Initiate healing
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C. Cellular Components of Inflammation

Mast cells – primary mediators of inflammation

Granulocytes (neutrophils & eosinophils), platelets, monocytes, and lymphocytes.
D. Mast Cells

Cellular bags of granules located in the loose connective tissues close to blood vessels
o Skin, digestive lining, and respiratory tract
1. Mast Cell Activation
o
o
Caused by physical injury, burns, toxins, chemical agents, immunologic processes, etc.
Chemicals are released in two ways:
• Degranulation and synthesis of lipid-derived chemical mediators
2. Mast Cell Degranulation - causes rapid release of:
a. Histamine
• Vasoactive amine that causes temporary, rapid constriction of smooth muscle in the large
blood vessels and the dilation of the postcapillary venules
• Retraction of endothelial cells lining the capillaries and increased adherence of leukocytes
 Histamine Receptors
 There are three types (See Chap. 7, Part 2 notes). The most common one is the:
 H1 receptor – proinflammatory; present on nasal mucosa, conjunctiva, skin, bronchi, and
the gastrointestinal tract.
o
Effects smooth muscle in blood vessels and bronchi, resulting in vasodilation and
bronchoconstriction.
o Increase capillary permeability by stimulating endothelial cells to retract, opening the
spaces between cells, which allows cells and proteins to move out of the vessel and
into the tissues (edema).
o H1 receptors located on white blood cells help to activate neutrophils and
macrophages that provide the cellular inflammatory response.
• Other types of histamine receptors perform different functions and are located in the
stomach lining and heart (H2) and in the central nervous system (H3).
b. Chemotactic factors
•
•
Neutrophil chemotactic factor – attracts neutrophils
Eosinophil chemotactic factor of anaphylaxis (ECF-A) – attracts eosinophils
3. Mast Cell Synthesis of Mediators - results in slower, longer lasting effect than histamine:
a. Leukotrienes
• Product of arachidonic acid from mast cell membranes
• Similar effects to histamine in later stages
b. Prostaglandins
• Product of arachidonic acid from mast cell membranes
• Cause increased vascular permeability, smooth muscle contraction, and induce pain and fever
• Synthesis inhibited by NSAIDs (nonsteroidal anti-inflammatory drugs like aspirin, ibuprofen)
c. Platelet-activating factor
•
Similar effect to leukotrienes; cause platelet activation
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1. Why are antihistamines given to people suffering from an allergic inflammatory response?
2. Why is aspirin effective in lowering fever and reducing pain?
E. Plasma Protein Systems
1. Types
o
Complement system
o
Coagulation system
o
Kinin system
2. Characteristics
o
Made by liver
o
All contain inactive enzymes (proenzymes)
o
Sequentially activated (cascade)
•
First proenzyme is converted to an active enzyme
•
Substrate of the activated enzyme becomes the next component in the series
3. Complement system (10% of serum protein)
o
Can destroy pathogens directly
o
Activates or collaborates with every other component of the inflammatory response
o
Three pathways, but all result in formation of membrane attack complex (MAC)
•
o
MAC creates pores in outer membranes of cells and bacteria which kills them.
Roles of various components:
•
Opsonins – C3b coats bacteria and makes it easier for phagocytes to engulf them
•
Chemotactic factors – C5a attracts inflammatory cells
•
Anaphylatoxins – C3a and C5a induce rapid degranulation of mast cells
4. Coagulation (clotting) system
o
Forms a fibrinous meshwork at an injured or inflamed site
•
Prevents the spread of infection and keeps microorganisms at site of inflammatory cell activity
•
Forms a clot that stops bleeding
•
Provides a framework for repair and healing
o
Main substance is an insoluble protein called fibrin.
o
Excess clotting is opposed by plasmin, which breaks down fibrin.
5. Kinin system
o
Functions to activate and assist inflammatory cells
o
The primary kinin is bradykinin
o
Bradykinin causes dilation of blood vessels, pain, smooth muscle contraction, vascular
permeability, and leukocyte chemotaxis
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ACTIVITY 2: Answer the following questions.
1. Why would a person with alcoholic cirrhosis of the liver have problems with blood clotting and
fighting infections?
2. What two chemical substances have we mentioned that cause pain?
F. Cellular Components of Inflammation
1. Neutrophils
o
Also referred to as polymorphonuclear neutrophils (PMNs)
o
Predominate in early inflammatory responses (6-12 hours after injury)
o
Phagocytes - ingest bacteria, dead cells, and cellular debris
o
Cells are short lived and become a component of the purulent exudate (pus)
2. Monocytes and macrophages
o
Monocytes are produced in the bone marrow, enter the circulation, and migrate to the
inflammatory site, where they develop into macrophages
o
Macrophages typically arrive at the inflammatory site 24 hours or later (after neutrophils)
o
Can phagocytize larger particles; more effective than neutrophils.
3. Eosinophils
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Defend against parasites and are mildly phagocytic.
o
Anti-inflammatory effects - regulate vascular mediators released by mast cells.
4. Natural killer (NK) cells
o
Function is to recognize and eliminate cells infected with viruses.
o
Some function in eliminating cancer cells.
5. Platelets
o
Activation results in degranulation and interaction with components of the coagulation system.
G. Phagocytosis

Process by which a cell ingests and disposes of foreign material.

Attracted to site by production of adhesion molecules by vascular endothelium.

Margination (pavementing) – adherence of leukocytes to blood vessel endothelial cells.

Diapedesis – emigration of cells through the endothelial junctions into tissues.

Opsonization - molecules like C3b and antibodies bind and mark substances for phagocytosis.

Steps in Phagocytosis
o
Adherence to target particle (enhanced by opsonization)
o
Engulfment
o
Phagosome formation and fusion with lysosomal granules → phagolysosome
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o
Destruction of the target
•
Oxygen-dependent mechanisms – due to production of toxic free radicals by phagosome enzymes
•
Oxygen-independent mechanisms – various, including acidic pH of phagosome, hydrolytic
enzymes, lactic acid, and inhibiting bacterial growth by binding of free iron.
1. How does the complement system aid the process of phagocytosis?
2. When macrophages die they break open and release their contents. How would this affect the
surrounding tissue?
H. Cytokines
1. Interleukins
o
Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by
other products of inflammation
o
Many types – examples:
•
IL-1 is a pro-inflammatory cytokine; causes fever
•
IL-10 is an anti-inflammatory cytokine; suppresses lymphocytes and cytokine production
2. Interferon
o
Protects against viral infections
o
Produced and released by virally infected host cells in response to viral double-stranded RNA
o
Types
•
IFN-alpha and IFN-beta – induce production of antiviral proteins
•
IFN-gamma – increases microbiocidal activity of macrophages
3. Tumor necrosis factor-alpha (TNF-α)
o
Secreted by macrophages and mast cells
•
Induces fever by acting as an endogenous pyrogen
•
Increases synthesis of inflammatory serum proteins
•
Causes muscle wasting (cachexia) and intravascular thrombosis
I. Local Manifestations of Inflammation
1. Results from vascular changes and corresponding leakage of circulating components into the tissue
o
Heat - due to vasodilation
o
Redness- due to vasodilation
o
Edema (swelling) - due to increased vascular permeability
o
Pain - due to edema (puts pressure on nerve endings) & chemicals like prostaglandins & bradykinin
2. Exudative Fluids
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Serous exudate - watery exudate: indicates early inflammation (blister)
o
Fibrinous exudate - thick, clotted exudate: indicates more advanced inflammation (pneumonia)
o
Purulent exudate - pus: indicates a bacterial infection
o
Hemorrhagic exudate - exudate contains blood: indicates bleeding
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ACTIVITY 4:
1. Identify at least one cell and one chemical that decrease or moderate inflammation.
2. Identify at least one cell and one chemical that combat viral infections.
3. Identify at least two substances that cause fever.
J. Systemic Manifestations of Inflammation
1. Fever
o
Caused by exogenous and endogenous pyrogens
o
These act directly on the hypothalamus to raise the set point for body temperature
2. Leukocytosis - increased numbers of circulating leukocytes
o
Neutrophilia (increased number of neutrophils) - seen in bacterial infections
o
Lymphocytosis (increased number of lymphocytes) - seen in viral infections
3. Increased plasma protein synthesis by the liver
o
Acute-phase reactants - C-reactive protein, fibrinogen, complement components, etc.
•
Elevated levels cause increased erythrocyte sedimentation (indicator of inflammation)
•
Elevated C-reactive protein is associated with increased risk of coronary heart disease
K. Chronic Inflammation

Inflammation lasting 2 weeks or longer

Often related to an unsuccessful acute inflammatory response

Other causes of chronic inflammation:

o
High lipid and wax content of a microorganism
o
Ability of organism to survive inside the macrophage
o
Toxins
o
Chemicals, particulate matter, or physical irritants
Characteristics of Chronic Inflammation
o
Dense infiltration of lymphocytes and macrophages
o
Granuloma formation
o
Granulomas:
•
Form around areas of infection (ex. tuberculosis)
•
Central area of caseous necrosis
•
Surrounded by a zone of activated macrophages
•
Outer layers of lymphocytes and fibroblasts
•
A wall of fibrin is laid down around exterior
•
Contents eventually breakdown and liquefy
Review information on Wound Healing (Resolution and Repair in 4th ed.) at the end of the chapter.
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Chapter 5 – Answer Key to Activities
ACTIVITY 1:
1. Why are antihistamines given to people suffering from an allergic inflammatory response?
Antihistamines block binding of histamine to its receptor, thus preventing the vascular changes
of inflammation that cause more fluid to enter tissues and also prevent constriction of smooth
muscle in the airways.
2. Why is aspirin effective in lowering fever and reducing pain?
Aspirin inhibits production of prostaglandins, which are responsible for triggering fever and
causing some of the pain of inflammation.
ACTIVITY 2: Answer the following questions.
1. Why would a person with alcoholic cirrhosis of the liver have problems with blood clotting and
fighting infections?
Damage to the liver would interfere with the production of plasma proteins, including those of
the complement, clotting and kinin systems.
2. What two chemical substances have we mentioned that cause pain?
Prostaglandins and bradykinin
ACTIVITY 3:
1. How does the complement system aid the process of phagocytosis?
Complement proteins coat the surface of bacteria and other pathogens, marking them for
attack. This is called opsonization.
2. When macrophages die they break open and release their contents. How would this affect the
surrounding tissue?
Release of free radicals and hydrolytic enzymes would damage the surrounding tissue.
ACTIVITY 4:
1. Identify at least one cell and one chemical that decrease or moderate inflammation.
Eosinophil and IL-10
2. Identify at least one cell and one chemical that combat viral infections.
Natural killer cell and IFN-alpha and -beta
3. Identify at least two substances that cause fever.
IL-1, TNF-α and prostaglandins