Innate Immunity:

Inflammation
Chapter 6
Immunity
First 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)
Second line of defense
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
H
1
receptor (proinflammatory)
H
2
receptor (anti-inflammatory)
Histamine
Receptors
H
1
receptor
Proinflammatory
Present in smooth muscle cells of the bronchi
H
2
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
Product of arachidonic acid from mast cell
membranes
Similar effects to histamine in later stages
Prostaglandins
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
Watery exudate: indicates early inflammation
Fibrinous exudate
Thick, clotted exudate: indicates more advanced
inflammation
Purulent exudate
Pus: indicates a bacterial infection
Hemorrhagic exudate
Exudate contains blood: indicates bleeding
Systemic Manifestations of
Inflammation
Fever
Caused by exogenous and endogenous pyrogens
Act directly on the hypothalamus
Leukocytosis
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
Keloid scar
Hypertrophic scar
Impaired epithelialization
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