Innate Immunity:

Inflammation
Chapter 6

Immunity

First line of defense

Second line of defense

Innate resistance physical (skin/epithelial layer, GI &

Resp Tract), , mechanical (Cough, sneeze, vomit, cilia
action in trachea) & biochemical barriers (antimicrobial
peptides, lung secretions, mucus, saliva, tears, earwax)
Inflammation vascular response dilation, histamines
increase vessel leakage, wbc action, cytokines,
leucokines, fever. Usually redness and heat with
swelling.

Third line of defense

Adaptive (acquired) immunity antibody production

First Line of Defense

Physical and mechanical barriers

Skin
Linings of the gastrointestinal, genitourinary, and
respiratory tracts

Sloughing off of cells

Coughing and sneezing
Flushing
Vomiting
Mucus and cilia

First Line of Defense

Biochemical barriers

Synthesized and secreted saliva, tears, earwax,

sweat, and sebum
Antimicrobial peptides

Cathelicidins, defensins, and collectins

Normal bacterial flora

Second Line of Defense

Inflammatory response

Caused by a variety of materials

Infection, mechanical damage, ischemia, nutrient

deprivation, temperature extremes, radiation, etc.

Local manifestations
Vascular response

Blood vessel dilation, increased vascular permeability

and leakage, white blood cell adherence to the inner
walls of the vessels and migration through the vessels

Inflammation

Goals

Limit and control the inflammatory process

Prevent and limit infection and further damage
Interact with components of the adaptive immune
system
Prepare the area of injury for healing

Plasma Protein Systems

Protein systems

Complement system
Coagulation system
Kinin system

All contain inactive enzymes (proenzymes)

Sequentially activated

First proenzyme is converted to an active enzyme

Substrate of the activated enzyme becomes the next
component in the series

Plasma Protein Systems

Complement system

Can destroy pathogens directly

Activates or collaborates with every other
component of the inflammatory response
Pathways

Classical
Lectin
Alternative

Plasma Protein Systems

Coagulation (clotting) system

Forms a fibrinous meshwork at an injured or

inflamed site

Prevents the spread of infection

Keeps microorganisms and foreign bodies at the site
of greatest inflammatory cell activity
Forms a clot that stops bleeding
Provides a framework for repair and healing

Main substance is an insoluble protein called

fibrin

Plasma Protein Systems

Kinin system

Functions to activate and assist inflammatory

cells
Primary kinin is bradykinin
Causes dilation of blood vessels, pain, smooth
muscle contraction, vascular permeability, and
leukocyte chemotaxis

Plasma Protein Systems

Plasma Protein Systems

Cellular Mediators of Inflammation

Cellular components

Granulocytes, platelets, monocytes, and

lymphocytes

Cell surface receptors

Pattern recognition receptors (PRRs)

Pathogen-associated molecular patterns (PAMPs)
Toll-like receptors
Complement receptors
Scavenger receptors

Mast Cells

Cellular bags of granules located in the loose

connective tissues close to blood vessels

Skin, digestive lining, and respiratory tract

Activation

Physical injury, chemical agents, immunologic

processes, and toll-like receptors
Chemical release in two ways

Degranulation and synthesis of lipid-derived chemical

mediators

Mast Cell Degranulation

Histamine

Vasoactive amine that causes temporary, rapid

constriction of the large blood vessels and the
dilation of the postcapillary venules
Retraction of endothelial cells lining the
capillaries
Receptors

H1 receptor (proinflammatory)
H2 receptor (anti-inflammatory)

Histamine

Receptors

H1 receptor

Proinflammatory
Present in smooth muscle cells of the bronchi

H2 receptor

Anti-inflammatory
Present on parietal cells of the stomach mucosa

Induces the secretion of gastric acid

Mast Cell Degranulation

Chemotactic factors

Neutrophil chemotactic factor

Attracts neutrophils

Eosinophil chemotactic factor of anaphylaxis

(ECF-A)

Attracts eosinophils

Mast Cell Synthesis of Mediators

Leukotrienes

Prostaglandins

Product of arachidonic acid from mast cell

membranes
Similar effects to histamine in later stages
Similar effects to leukotrienes; they also induce
pain

Platelet-activating factor

Similar effect to leukotrienes and platelet activation

Mast Cells

Mast Cells

Mast Cells

Phagocytosis

Process by which a cell ingests and disposes

of foreign material
Production of adhesion molecules
Margination (pavementing)

Adherence of leukocytes to endothelial cells

Diapedesis

Emigration of cells through the endothelial

junctions

Phagocytosis

Phagocytosis

Steps

Opsonization, recognition, and adherence

Engulfment
Phagosome formation
Fusion with lysosomal granules
Destruction of the target

Phagocytes

Neutrophils

Also referred to as polymorphonuclear

neutrophils (PMNs)
Predominate in early inflammatory responses
Ingest bacteria, dead cells, and cellular debris
Cells are short lived and become a component of
the purulent exudate

Phagocytes

Monocytes and macrophages

Monocytes are produced in the bone marrow,

enter the circulation, and migrate to the
inflammatory site, where they develop into
macrophages
Macrophages typically arrive at the inflammatory
site 3 to 7 days after neutrophils
Macrophage activation results in increased size,
plasma membrane area, glucose metabolism,
number of lysosomes, and secretory products

Monocytes and Macrophages

Phagocytes

Eosinophils

Mildly phagocytic
Duties

Defense against parasites and regulation of vascular

mediators

Phagocytes

Natural killer (NK) cells

Function is to recognize and eliminate cells

infected with viruses and some function in
eliminating cancer cells

Platelets

Activation results in degranulation and interaction

with components of the coagulation system

Cytokines

Interleukins

Produced primarily by macrophages and

lymphocytes in response to a pathogen or
stimulation by other products of inflammation
Many types
Examples

IL-1 is a proinflammatory cytokine

IL-10 is an anti-inflammatory cytokine

Cytokines

Interferon

Protects against viral infections

Produced and released by virally infected host
cells in response to viral double-stranded RNA
Types

IFN-alpha and IFN-beta

Induce production of antiviral proteins

IFN-gamma

Increases microbiocidal activity of macrophages

Cytokines

Cytokines

Tumor necrosis factoralpha

Secreted by macrophages in response to PAMP

and toll-like receptor recognition

Induces fever by acting as an endogenous pyrogen

Increases synthesis of inflammatory serum proteins
Causes muscle wasting (cachexia) and intravascular
thrombosis

Cytokines

Local Manifestations of Inflammation

Results from vascular changes and

corresponding leakage of circulating
components into the tissue

Heat
Redness
Swelling
Pain

Exudative Fluids

Serous exudate

Fibrinous exudate

Thick, clotted exudate: indicates more advanced

inflammation

Purulent exudate

Watery exudate: indicates early inflammation

Pus: indicates a bacterial infection

Hemorrhagic exudate

Exudate contains blood: indicates bleeding

Systemic Manifestations of
Inflammation

Fever

Leukocytosis

Caused by exogenous and endogenous pyrogens

Act directly on the hypothalamus
Increased numbers of circulating leukocytes

Increased plasma protein synthesis

Acute-phase reactants

C-reactive protein, fibrinogen, haptoglobin, amyloid,

ceruloplasmin, etc.

Chronic Inflammation

Inflammation lasting 2 weeks or longer

Often related to an unsuccessful acute
inflammatory response
Other causes of chronic inflammation:

High lipid and wax content of a microorganism

Ability to survive inside the macrophage
Toxins
Chemicals, particulate matter, or physical irritants

Chronic Inflammation

Chronic Inflammation

Characteristics

Dense infiltration of lymphocytes and

macrophages
Granuloma formation
Epithelioid cell formation
Giant cell formation

Resolution and Repair

Regeneration
Resolution

Returning injured tissue to the original structure

and function

Repair

Replacement of destroyed tissue with scar tissue

Scar tissue

Composed primarily of collagen to restore the tensile

strength of the tissue

Resolution and Repair

Dbridement

Cleaning up the dissolved clots, microorganisms,

erythrocytes, and dead tissue cells

Healing

Filling in the wound

Sealing the wound (epithelialization)
Shrinking the wound (contraction)

Healing

Primary intention

Wounds that heal under conditions of minimal

tissue loss

Secondary intention

Wounds that require a great deal more tissue

replacement

Open wound

Healing

Reconstructive phase

Fibroblast proliferation
Collagen synthesis
Epithelialization
Contraction

Myofibroblasts

Cellular differentiation

Healing

Maturation phase

Continuation of cellular differentiation

Scar tissue formation
Scar remodeling

Healing

Dysfunctional Wound Healing

Dysfunction during inflammatory response

Hemorrhage
Fibrous adhesion
Infection
Excess scar formation
Wound sepsis
Hypovolemia
Hypoproteinemia
Anti-inflammatory steroids

Dysfunctional Wound Healing

Dysfunctional during reconstructive phase

Impaired collagen matrix assembly

Impaired epithelialization

Keloid scar
Hypertrophic scar
Anti-inflammatory steroids, hypoxemia, and
nutritional deficiencies

Impaired contraction

Contracture

Dysfunctional Wound Healing

Dysfunctional Wound Healing

Wound disruption

Dehiscence

Wound pulls apart at the suture line

Excessive strain and obesity are causes

Increases risk of wound sepsis

Pediatrics

Neonates have transiently depressed

inflammatory and immune function
Neutrophils are not capable of efficient
chemotaxis
Neonates express complement deficiency
Deficient in collectins and collectin-like
proteins

Elderly

Impaired inflammation is likely a result of

chronic illness

Diabetes, cardiovascular disease, etc.

Chronic medication intake decreases the

inflammatory response
Healing response is diminished due to loss of
the regenerative ability of the skin
Infections are more common in the elderly