Chapter 9 Stress and Adaptation

General Adaptation Syndrome (GAS) Hans Selye

o Stress as a term to mean an orchestrated set of bodily responses to
any form of noxious stimuli
o Selye injected rats with ovarian extract and saw:
Enlarged adrenal cortex
Thymic atrophy
Bleeding ulcers in stomach and duodenum
o Stages of the General Adaptation Syndrome (GAS)
Alarm stage: arousal of body defenses
CNS aroused fight-or-flight concept
Generalized stimulation of the sympathetic nervous
system and the HPA (Hypothalamus-pituitaryadrenocortical axis) resulting in release of catecholamines
and cortisol
Resistance or adaptation stage:
Body selects the most effective and economical channels
of defense
Remove it or adapt to it
If body does not adapt, it goes into the exhaustion stage
Adaptation implies that an individual has successfully
created a new balance between the stressor and the
ability to deal with stress
Exhaustion stage: compensatory mechanisms breakdown
Resources are depleted and signs of wear and tear
appear, stress overwhelms the bodys defenses/disease or
death
Increased cortisol levels = GI ulcers, etc.
Homeostasis: the purposeful maintenance of a stable internal environment
o Does not occur by chance is the result of organized self-government
o Physiologic processes opposing change each stress response
involves:
Operates by negative feedback mechanisms constancy of the
internal environment
When monitored function or value decreases below the
set point of the system, the feedback mechanism causes
the function or value to increase (ideally back to within
set point)
When the function or value is increased above the set
point, the feedback mechanism causes it to decrease
A sensor detects a change
An integrator/comparator sums and compares incoming data
with set point (normal)
Effector system returns the sensed function to within the range
of the set point (normal)
o Functions of the bodys control systems

Regulate cellular function

Control life processes
Integrate functions of the different organ systems

Stress
o A state manifested by symptoms that arise from the coordinated
activation of the neuroendocrine and immune systems (GAS)
Neuroendocrine responses
Hormones associated
with the stress
response
Catecholamines (NE,
epinephrine)

Source of the
hormone

Physiologic effects

Locus Caeruleus (LC,

adrenal medulla

Corticotropin-releasing
factor (CRF)

Hypothalamus

Adrenocorticotropic
hormone (ACTH)
Glucocorticoid hormones
(e.g., cortisol)

Anterior pituitary

Mineralocorticoid
hormones (e.g.,
aldosterone)
Antidiuretic hormone (ADH
vasopressin)

Adrenal cortex

Increase in insulin rele

and increase in glucag
release resulting in
increased glycogenoly
gluconeogenesis,
lipolysis, proteolysis, a
decreased glucose
uptake by peripheral
tissues.
Increase in HR, cardia
contractility, and vasc
smooth muscle
contractions.
Relaxation of bronchia
smooth muscle.
Stimulates ACTH relea
from anterior pituitary
and increased activity
the LC neurons.
Stimulates the synthe
and release of cortisol
Potentiates the action
epinephrine and
glucagon.
Inhibits the release
and/or actions of the
reproductive hormone
and thyroid-stimulatin
hormone.
Produces a decrease i
immune cells and
inflammatory mediato
Increases sodium
absorption by the
kidneys.
Increases water
absorption by the

Adrenal cortex

Hypothalamus, posterior
pituitary

kidneys.
Produces vasoconstric
of the blood vessels.
Stimulates the release
ACTH.

Locus Caeruleus
o Central to the neural component of the
neuroendocrine response to stress
o Densely populated with neurons that produce NE
and is thought to be the central integrating site for
the ANS response to stressful stimuli
o LC-NE system has afferent pathways to the
hypothalamus, the limbic system, the
hippocampus, and the cerebral cortex
Corticotropin-releasing factor (CRF)
o A small peptide hormone found in both the
hypothalamus and in extrahypothalamic structures
(limbic system and brain stem)
Growth hormones: decrease during stress
Thyroid hormones: decrease during stress
Reproductive hormones: may decrease during stress
ADH (from posterior pituitary): increased = water
retention and vasoconstriction
Cortisol (from adrenal cortex): suppresses immune
function, increases glucose levels = decreased healing,
suppressed inflammatory process, reduces WBCs to fight
infections, stimulates gastric acid secretion
NE and epinephrine

o Everyday wear and tear on the body

Adaptation
o The ability to respond to challenges of physical or psychological
homeostasis and to return to a balanced state
Stressors
o Events or environmental agents responsible for initiating the stress
response
o Can be endogenous (age, gender, genes) or exogenous (diet,
environment) or a mix of both
o NOT ALL STRESS IS DETRIMENTAL
o Types of stress
Eustress: mild, brief, controllable stress
Distress: severe, long uncontrolled stress

Allostasis
o Physiologic changes in the neuroendocrine, autonomic and immune
system in response to altered homeostasis
Factors affecting ability to adapt
o Physiological reserve and previous learning
o Time: acute or chronic
o Genetics
o Age: very old and very young less adaptable
o Health status: other illnesses present may interfere with adaptation
o Nutrition: deficiency or excess
o Sleep-wake cycles: immunity affected
o Hardiness
o Psychosocial factors
Physiologic reserve
o The ability of the body systems to increase their function given the
need to adapt
o RBCs and oxygen your body can carry more than you actually use
Anatomic reserve
o Paired organs that are nor needed to ensure the continued existence
and maintenance of the internal environment
o Lungs, kindeys, and adrenals you have 2 of each so you can survive!!
PTSD
o Intrusion (flashbacks)
The occurrence of flashbacks during waking hours or
nightmares in which the event is relived, often in vivid and
frightening detail
o Avoidance (emotional numbing)
The emotional numbing that accompanies this disorder and
disrupts important personal relationships-depression- may have
survivor guilt
o Hyperarousal (irritability, vigilance, exaggerated startles reflex, over
concern with safety)
The presence of increased irritability, difficulty concentrating, an
exaggerated startle reflex, and increased vigilance and concern
over safety
o Must have these symptoms for at least a month for a diagnosis of PTSD
Nonpharmacologic tx for stress
o Relaxation techniques
o Guided imagery
o Music therapy
o Massage
o Biofeedback

Cellular Adaptation, Injury, and Death

All disease processes and most injuries are a result of cellular injury or
death
Cellular adaptation

o
o

o
o

A cell responds to it environment by adjusting structure and function to

meet demands
In response to physiologic stresses or pathologic stimuli, cells adapt to
achieve a steady state (homeostasis)

The adaptive responses are:

Atrophy (decrease in size)
Cell shrinks in an attempt to reduce its workload
Hypertrophy (increase in size)
2 types
o Physiologic
A uterus enlarges in response to estrogen
signals
o Pathologic
The enlargement of the heart in response to
hypertension
Hyperplasia (increase in number)
Cells that are capable of mitotic division will accelerate
mitosis in order to increase their number and functional
ability
Metaplasia (change in form)
When exposed to persistent injury, cells will replace
themselves with a different type that is better able to deal
with that injury
Example: Barretts Esophagus after long exposure to
reflux
Dysplasia
A dysfunctional effort to adapt
Usually considered pre-neoplastic
Cellular injury
o In early stages, mild forms of cell injury us reversible in the injurious
agent is removed

o
o

Continual cell damage and injury causes an irreversible state that the
cell cannot recover from and the cell dies
Causes of cell injury
Oxygen deprivation
Hypoxia most common cause of cell injury
o Cell swells
o Anaerobic glycolysis tries to compensate
o Lactate is produced
o Cellular pH, impairing other cell functions
o This process can be reversed until plasma
membrane and mitochondrial membranes are
critically damaged
Interferes with cellular metabolism and generation of ATP
o NO O2 = NO ATP!
o Decrease in ATP slows cell processes
The energy dependent Na+K+ pump
Na+ accumulates in the cell drawing water in
Highly reactive oxygen species (ROS)
o Highly volatile free radicals will react with any
chemical with which they come in contact with
Can damage proteins, fats, DNA
Chemical agents
Some toxic chemicals are inherently reactive
o Heavy metals (lead, mercury)
o Toxic gases (carbon monoxide)
o Corrosives (acids, alkalis)
o Antimetabolites (cyclophosphamide, vincristine)
Physical agents
Mechanical forces
o Direct trauma to cell membranes
o Blunt force trauma
o Direct penetrating trauma
Hypothermic injury
o Severe vasoconstriction and increased blood
viscosity causes ischemia
o With continued exposure, vasodilation may occur
o Cytosol freezes and intracellular ice crystals form
Hyperthermic injury
o Microvascular coagulation
o Increased metabolic processes
o Direct tissue destruction
Electrical injury
o Cells of the body act as conductors of electricity
o Neural and cardiac impulses are interrupted
o Hyperthermic destruction occurs
o Current flows through the path of least resistance
Electromagnetic radiation

Direct-hit: breakage of chemical bonds holding DNA

together
o Ionizing radiation: orbital electrons are knocked off
Activated oxygen molecules act like free
radicals and steal other electrons
o Genetic damage
o Radiation induced cell death
Infectious agents
Immunological reactions
Genetic defects
Nutritional imbalances
Most vitamins, minerals, and some amino acids must
come from diet
Cell injury can come from a deficiency or excess of
nutrients
Aging
Reversible cell injury and cell death
o Cell destruction and removal can involve 2 mechanisms
Apoptosis
Programmed cell death
Highly selective process that eliminates injured and aged
cells thereby controlling tissue regeneration
Cell death/necrosis
Refers to cell death in an organ or in tissues that are still
part of a living person
Cellular autodigestion
Also initiates an inflammatory process
In contrast to apoptosis which functions in removing cells
so new ones can replace them, necrosis often interferes
with cell replacement and tissue regeneration
o Gangrene occurs with a considerable mass of tissue
undergoes necrosis
Types of necrosis
o Liquefaction neuron and glial cells of the brain
Turn to softened center of abscess with
discharge of contents
Cells dies but catalytic enzymes are not
destroyed
o Coagulation
Dead cells convert to gray, firm mass
Opaque state
Seen in heart, kidney, and adrenal glands
o Caseous exclusive to TB
Body walls this off and middle becomes
white, soft, and fragile
Dead cells persist as a cheese-like debris in
lungs
o

Immune mechanism
Gangrene (wet/dry/gas)
When a considerable amount of tissue
undergoes necrosis
Dry
SLOW
Affected tissues becomes dry and
shrinks, skin wrinkles
Color changes to dark brown or black
Causes an inflammatory reaction
Line of demarcation between dead
and healthy tissue
Typically and arterial problem
Mainly confined to the extremities
(clot)
Wet
RAPID
It is a form of liquefaction necrosis
Due to interference of venous blood
return
Affect area is cold, swollen, and
pulseless
Skin is moist, black, and under tension
Blebs form on the surface
Liquefaction occurs
Foul odor caused by bacterial action
Can become systemic = death if not
stopped
Can affect internal organs/extremities
Dry can convert to wet if bacteria
invade
Gas
RAPIDLY FATAL
Gangrene that results from clostridium
bacteria, usually clostridium perfringes
Anaerobic spore-forming organisms
o Produce toxins that cause cell
membrane to dissolve =
edema, death to muscle cells,
renal failure
Prone to occur in trauma and
compound fractures in which dirt and
debris are embedded in wounds
Produces hydrogen sulfide gas
o This is why it is so serious and
rapidly fatal

Antibiotics are used and may need

surgical intervention and amputation
to stop the spread

Phases of wound healing

o Inflammatory
Begins at time of injury
Prepares wound environment for healing
Hemostasis first (to promote blood clotting)
Next come the vascular and cellular phases of inflammation
Cleans debris (phagocytosis) WBCs
Promotes growth of blood vessels
Attracts fibroblasts
o Proliferative
Begins 2-3 days after injury, may last 3 weeks
Fibroblasts synthesize collagen (peaks in 5-7 days)
Proliferation of fibroblasts and vascular endothelial cell form
granulation tissue serve as foundation of scar tissue
Tissue is fragile, bleeds easily due to newly developing capillary
beds
o Remodeling (Maturation)
Begins 3 weeks after injury; lasts for months to 2 years
Continuous remodeling: collagen synthesis and lysis of scar
tissue cell
Increases tensile strength of the wound over time
Really only ever gets to 70-80% of normal strength

Neoplasia

Characteristics of cancer
o Disorder of altered cell differentiation and growth results in neoplasia
(new growth)
o Growth is uncoordinated and relatively autonomous
Lacks normal regulatory controls over cell growth and division
Tends to increase in size and grow after stimulus eases or needs
of the organism are met
Components of tissue renewal and repair
o Cell proliferation
Process of cell division
Inherent adaptive mechanism for replacing body cells
o Cell differentiation
Process of specialization
New cells acquire the structure and function of cells they replace
o Apoptosis
A form of programmed cell death to eliminate unwanted cells
Cell division
o G1 (gap 1): the postmitotic phase

DNA synthesis ceases, while ribonucleic acid (RNA) and protein

synthesis and cell growth take place
o S phase: DNA synthesis occurs
Gives rise to 2 separate set of chromosomes, one for each
daughter cell
o G2 (gap 2): the premitotic phase
DNA synthesis ceases
RNA and protein synthesis continues
o M phase: the phase of cellular division or mitosis
Stem cells
o Reserve cells that remain inactive until there is a need for cel
replacement
o Self-renewal
o Potency
Totipotent: produced by fertilization of an egg
Can differentiate into embryonic and extraembryonic cells
Pluripotent: can differentiate into the three germ layers of the
embryo (echoderm, mesoderm, endoderm: all organs)
Multipotent: give rise to only a few cell types
Unipotent: give rise to one type of differentiated cell, but retain
the property of self-renewal
Muscle satellite cell
Epidermal stem cell
Spermatogonium
Basal cell of the olfactory epithelium
Tumors
o Adding the suffix oma to the parenchymal tissue type from which the
growth originated
o Neoplasms
Benign
Slow, progressive rate of growth that may come to a
standstill or regress
An expansive manner of growth
Inability to metastasize to distant sites
Composed of well-differentiated cells that resemble the
cells of the tissue of origin
Malignant
Grow rapidly and spread widely
Have the potential to kill regardless of their original
location
Compress blood vessels and outgrow their blood supply,
causing ischemia and tissue necrosis
Rob normal tissues of essential nutrients
Liberate enzymes and toxins that destroy tumor tissue
AND normal tissue
Factors that differentiate benign and malignant tumors

Cell characteristics
o Benign = well-differentiated cells
o Malignant = loss of differentiation in cells
Manner of growth
o Benign = expansive manner of growth, but typically
remain in one place
o Malignant = use seeding, direct invasion, and
blood/lymph to grow
Rate of growth
o Benign = slow and progressive
o Malignant = rapid and spread widely
Potential for metastasizing or spreading
o Benign = little chance of metastasizing
o Malignant = great chance of metastasizing
Tendency to cause tissue damage
o Benign = tissue damage minimal
o Malignant = compresses blood vessels causing
ischemia and tissue necrosis
Liberates enzymes that may kill both tumor
tissue but healthy tissue as well
Capacity to cause death
o Benign = may press on vital organs, but overall
lower potential of death
o Malignant = may rapidly invade or seed into organs
and other sites which give high chance of death
Anaplasia = term used to describe the loss of differentiation in
cancerous tissue cells
Genes that control cell growth and replication
o Proto-oncogenes normal genes that become cancer causing
oncogenes if mutated
They are heavily involved in growth factors and promoted
cancer when turned on
They get erroneously activated
o Tumor suppressor genes
They actually inhibit cellular proliferation, but when switched
off they can create an environment in which cancer is promotes
TP53 gene mutation in this gene is implicated in the
development of breast, lung, and colon cancer
o Genes that control programmed cell death or apoptosis
o Genes that regulate repair of damaged DNA
Steps involving the transformation of normal cells into cancer cells
o Initiation irreversible event
Cell exposed to doses of carcinogenic agents making them
susceptible to malignant transformation
Proliferation is required (cell must be able to divide)
o Promotion

Unregulated accelerated growth in already initiated cells caused

by various chemical and growth factors
o Progression
Tumor cells acquire malignant phenotypic changes that promote
invasiveness, metastatic competence, autonomous growth
tendencies, and increased karyotypic instability
DNA damage (mutation) Initiation
Proliferation (growth promoters) promotion
Development of cancerous phenotype progression
o Detectable tumor size is 1 cm by then it already has 1 billion
cells in it
o Tumors cannot grow more than about 2mm unless they grow
blood vessels into the tumor (angiogenesis)
Treatments
o Chemotherapy
o Radiation
Contraindicated in childhood cancer treatment as it has been
shown to have long-lasting and even delayed effects

Innate and Adaptive Immunity

Immune response
o Immune response = the collective, coordinated response of the cells
and molecules of the immune system to protect against infectious
disease
o Purpose of the immune system
To neutralize, eliminate, or destroy microorganisms that invade
the body
To recognize and eliminate aberrant cell like cancer
o Immune Defenses
Innate/NON-specific immunity
The natural resistance a person is born with
Adaptive/Specific immunity
2nd line of defense
Response is less rapid than innate, but more effective
o Can also produce undesirable effects:
Allergies: an excessive immune response
Autoimmune disease: immune system recognizes self-tissue as
foreign
o Components of the immune system
Skin, mucous membranes, phagocyte system, lymphoid system
(spleen, thymus gland, and lymph nodes), bone marrow
o Principle cells in the immune system
Lymphocytes: recognize and respond to foreign antigens
Accessory cells:
Macrophages and dendritic cells (monocytes)

Function as antigen-presenting cells by the processing of

a complex antigen into epitopes required for the
activation of lymphocytes
Mediators of immune system
Cytokines
o Soluble proteins secreted by cells of both the innate
and adaptive immunity
Chemokines
o Cytokines that stimulate the migration and
activation of immune and inflammatory cells
Colony-stimulating factors
o Stimulate the growth and differentiation of bone
marrow progenitors of immune cells
Cells in innate immunity
Macrophages
Dendritic cells bridge between innate and adaptive
immunity
Mast cells
NK cells
o Can be divided into 2 main subsets based on their
ability to excrete proinflammatory cytokines
o Ability to spontaneously kill target organisms which
relies on the recognition of specific PAMPs with the
microorganism type
Complement proteins
Basophils
Eosinophils
Neutrophils
Granulocytes
Cells in adaptive immunity
B cells
o antibodies
T cells
o CD4+ T cells
o CD8+ T cells
Components for Innate immunity
o Epithelial barriers
o Phagocytic cells (neutrophils and macrophages)
o NK cells
o Plasma proteins
o Opsonins facilitates phagocytosis
o Cytokines chemical signaling
TNF (tumor necrosis factor)
Interleukins (IL)
Interferons (IFN)
Chemokines

Acute-phase proteins/reactants
Two types
Mannose-binding ligand binds specifically to mannose
residues
C-reactive protein binds to both phospholipids and
sugars that are found on the surface of the microbes
Both act as costimulatory opsonins and enhance the binding of
phagocytic cells to invading microorganisms
Complement system a process that involves plasma proteins found
in the blood which are essential for the activity of antibodies
When foreign bodies invade, this system activates
Primary function: promotion of inflammation and
destruction of the microbes
Three phases of complement system reactions
Initiation or activation
o Activation by one of the three pathways listed
below
Amplification of inflammation
o All pathways lead to the activation of complement
protein C3 and its enzymatic cleavage into C3b
(larger) and C3a (smaller) segments
o C3a = chemoattractant for neutrophils
o C3b = becomes attached to the microbe and acts
as an opsonin for phagocytosis and acts as an
enzyme to cleave C5 into 2 components
C5a = produces vasodilation and
increases vascular permeability
C5b leads to late-step membrane attack
responses
Membrane attack response
o C3b bind to other complement proteins to form an
enzyme that cleaves C5
C5a = stimulates the influx on
neutrophils in the vascular phase of acute
inflammation
C5b = remains attached to the microbe
initiates the formation of a complex of
complement proteins C6, C7, C8, and C9 into
a membrane attack complex protein, or pore
that allows fluids and ions to enter and
cause cell lysis
Multiple pathways that result in recognizing microbes and
complement system activation
Classic pathway
o Activated by certain types of antibodies bound to
antigen and is part of humoral immunity
Lectin pathway

Activated by plasma lectin that binds to mannose

on microbes and activates the classical pathway in
the absence of antibody
Alternative pathway
o Activated on microbial cell surfaces in the absence
of antibody
o Is a component of innate immunity
Cytolysis
Opsonization
Chemotaxis
Anaphylaxis
Adaptive immunity
o Types of adaptive immune response
Humoral immunity/antibody mediated
Mediated by molecules in the blood
The principal defense against extracellular microbes and
toxins
Cellular immunity/cell mediated
Mediated by specific T lymphocytes
Defends against intracellular microbes such as viruses
o Lymphocytes
B cells
Humoral immunity that have memory
Produce antibodies
Matures in the bone marrow and differentiate into
memory cells or immunoglobulins
o IgA found in mucous, saliva, tears, and breast
milk. Protects against pathogens
o IgD part of the B cell receptor. Activates basophils
and masts cells
o IgE protects against parasitic worms. Responsible
for allergic reactions
o IgG Secreted by plasma cells in the blood. Able to
cross the placenta into the fetus
o IgM may be attached to the surface of a B cell or
secreted into the blood. Responsible for early
stages of immunity
Antigens are substances foreign to the host that can
stimulate an immune response
o Production begins about 72 hours after exposure
Antibodies recognize antigens
o Receptors on immune cells
o Secreted proteins
o

T cells
Cell mediated immunity that have memory
Destroys antigens

Matures in the thymus

Regulatory cells (helper and suppressor cells)
o Assist in orchestrating and controlling the immune
response
o Helper T cells activate other lymphocytes and
phagocytes
o Regulatory T cells keep these cells in check so
that an exaggerated immune response does not
occur
o Cytotoxic T cells effector cells
Effector cells (killer cells)
o Accomplish the final stages of the immune
response with the elimination of the antigen
o Activated T lymphocytes, mononuclear phagocytes,
and other leukocytes function as effector cells in
different immune responses
An antigen presenting cell (APC) eats a virus the APC breaks
down that virus molecule but take a piece of it and presents it
on the cell surface via a major histocompatibility complex type 2
(MHC II) A helper-T cell with a T cell receptor attaches to the
epitope of the virus piece (antigen) which activates the helper-T
cell helper-T cell sends out cytokines to cytotoxic T cells so
that they can bind to the viral epitope of the target cell via the T
cell receptor (TCR) and releases toxic materials into the target
cell resulting in target cell death the helper-T cell sends out
cytokines which activates the B cell with membrane bound Ig
molecules that make up receptor sites that can bind with
specific epitopes of antigens that the B cells then divide
several times to form populations (clones) of cells that continue
to differentiate into several types of effector and memory cells
(helper-T cell differentiates into the cytotoxic [as stated before]
and memory T cells; B cells differentiate into plasma cells [to
make more antibodies for that specific antigen] and memory B
cell)
B cells may even recognize and antibody before the T cell and
interact with a helper-T cell by presenting part of the antigen on
its surface via an MHC II and connecting with the TCR on the
helper-T cell
MHC helps immune system recognize foreign substances
Class I: all nucleated cells
o Present processed antigen to cytotoxic CD8+ T
cells
o Restrict cytolysis to virus-infected cells, tumor cells,
and transplanted cells
Class II: are immune cells, APC, B cells, and macrophages
o Present processed antigenic fragments to CD4+ T
cells

Necessary for effective interaction among immune

cells

Inflammation, Tissue Repair, and Wound Healing

Immunity
o First line of defense: innate immunity
o Second line of defense: Inflammation
o Third line of defense: Adaptive immunity
Inflammation
o Goals:
Limit and control the inflammatory process
Prevent and limit infection and further damage
Initiate adaptive immune response
Initiate healing
o Inflammatory response is a protective mechanism that is stimulated
when tissue is injured
3 purposes:
Neutralize invading agents
Limit spread to other tissues
Prepare damages tissue for repair
o Inflammatory response involves:
Vascular response
Vasoconstriction from seconds to 10 minutes
o Produces tissue hypoxia and acidosis
Vasodilation follows vasoconstriction
o Produces redness, pain, heat, edema, and impaired
function
o Platelets move to site and adhere to vascular
collagen
o Platelets release fibronectin (fibrin) to form
meshwork and stimulate clotting
o Venous capillaries become permeable
o Fluid (protein-rich) leaks into the surrounding tissue
to wall off the site
Also is the exudate
As fluid moves out of the vessels, stagnation
of blood occurs allowing for next phase
Cellular response
Margination and adhesion
o Leukocytes (mainly) neutrophils (that were
recruited to the site on injury via cytokines) line the
endothelium of blood vessels
Transmigration
o Leukocytes (mainly) neutrophils slide through pores
of the vessels into the inflamed tissue
Chemotaxis

Migration of leukocytes (mainly) neutrophils to site

of tissue injury via a chemical gradient (like
chemokines)
Activation of leukocytes (mainly) neutrophils
o Enclose the foreign substances
o Intracellular killing
Chemical response
Activated granulocytes, lymphocytes, and macrophages
release chemical mediators
o Histamine (released by mast cells and basophils
Among first to be released during acute
inflammation
Increases vasodilation and vascular
permeability
Primary activator of endothelial cell
retraction
H1 receptor: smooth muscle cells in bronchi
H2: parietal cell of the stomach mucosa
o Bradykinins (activated kinin system results in its
release)
Increases vascular permeability
Vasodilates
Contracts smooth muscle cells
o Platelet activating factor
Generated from a complex lipid stored in cell
membrane
Induces platelet aggregation
Activates neutrophils
Potent eosinophil chemoattractant
o Cytokines
IFN
Primarily protect host against viral
infections
Primarily play role in modulation of
inflammatory response
IFN and IFN produces primarily by
macrophages
IFN produced primarily by T
lymphocytes
TNF
Endogenous pyrogen
Induces synthesis of proinflammatory
substances in liver
Prolonged exposure can cause
intravascular coagulation with
subsequent thrombosis production
IL
o

Produced by macrophages and

lymphocytes
Produced in response to presence of
invading microorganism or activation
of inflammatory process
Primary function is to enhance
acquired immune response though:
o Molecular expression
o Induction of leukocyte
maturation
o Enhance leukocyte chemotaxis
o General enhancement or
suppression of inflammatory
process
o Arachidonic acid
Released by phospholipases
Initiates series of complex reactions which
Leads to production of eicosanoid family
inflammatory mediators
Lipooxygenase (LOX)
o Leukotrienes
o Induces smooth muscle
contraction
o Constricts pulmonary airways
o Increases microvasculature
permeability
Cyclooxygenase (COX)
o Prostaglandins
Induces vasodilation and
bronchoconstriction
Stimulate platelet
aggregation
Act as chemotactic factor
Responsible for increased
sensation of pain
o Thromboxane
Vasoconstricts
Increases
bronchoconstriction
Promotes platelet
function
Aspirin and other NSAIDs work as COX
inhibitors
Acute and chronic inflammation
o Acute
Of relatively short duration
Nonspecific early response to injury

Infiltration of neutrophils
Aimed primarily at removing the injurious agent and limiting
tissue damage
Heat, swelling, redness, pain, exudative fluids
Exudate
Serous watery exudate: indicates early inflammation
Fibrinous Thick, clotted exudate: indicated more
advanced inflammation
Purulent pus: indicated a bacterial infection
Sanguineous/hemorrhagic contains blood: indicated
bleeding
Systemic manifestations
Fever
Sepsis
Leukocytosis
o Increased number of circulating leukocytes
Increased plasma protein synthesis
o Acute phase reactants
C-reactive protein
Fibrinogen
Haptoglobin
o Chronic
Self-perpetuating and may last from weeks to years
Infiltration by mononuclear cell (macrophages) and lymphocytes
Proliferation of fibroblasts
Unsuccessful acute inflammatory response
Characteristics
Dense infiltration of lymphocytes and macrophages
Granuloma formation
Epithelioid cell formation
Giant cell formation
Wound healing
o Primary intention
Wounds that heal under conditions of minimal tissue loss and
wound edges are approximated
o Secondary intention
Great loss of tissue with contamination
Phases of wound healing
o Inflammatory
Begins at time of injury
Prepares wound environment for healing
Hemostasis first (to promote blood clotting)
Next come the vascular and cellular phases of inflammation
Cleans debris (phagocytosis) WBCs
Promotes growth of blood vessels
Attracts fibroblasts

Proliferative
Begins 2-3 days after injury, may last 3 weeks
Fibroblasts synthesize collagen (peaks in 5-7 days)
Proliferation of fibroblasts and vascular endothelial cell form
granulation tissue serve as foundation of scar tissue
Tissue is fragile, bleeds easily due to newly developing capillary
beds
Granulation, epithelialization, collagen formation
Remodeling (Maturation)
Begins 3 weeks after injury; lasts for months to 2 years
Continuous remodeling: collagen synthesis and lysis of scar
tissue cell
Continuation of cellular differentiation
Scar tissue formation
Scar remodeling
Increases tensile strength of the wound over time
Really only ever gets to 70-80% of normal strength

Disorders of the Immune Response

Alterations of the immune system

o Hypersensitivity or allergic reactions
Inappropriate or excessive activation of the immune system
4 types
Type I IgE mediated (immediate hypersensitivity)
o Begins rapidly following antigen challenge
o Allergic reaction Anaphylaxis
o Begins with mast cell of basophil sensitization
Mast cells are normally in connective tissue
beneath skin and mucous membranes of
respiratory, GI, and Gu tracts
o Primary or initial phase response
5-30 minutes after exposure
Vasodilation
Vascular leakage
Smooth muscle constriction
Histamine mediated
o Secondary or late phase response
2-8 hours after exposure and may last
several days
Intense infiltration of tissues with
inflammatory cells
Tissue destruction and epithelial damage
Arachidonic acid and cytokine mediated
Type II antibody mediated
o Reaction is mediated by IgG or IgM
o 3 mechanisms reactions can affect cell

Cell destruction by activation of complement

cascade
Antibody dependent cell mediated
cytotoxicity NK cells release toxins
Antibodies cause cell destruction
through phagocytosis
o Hemolytic disease of newborns
Rh factor
o Mismatched blood transfusions
Cell inflammation caused by neutrophil byproducts (reactive oxygen intermediates and
enzymes)
Cell dysfunction which prevents normal
interactions by inappropriately stimulating or
destroying the receptor
Graves disease
Myesthenia Gravis
Type III complex mediated
o Insoluble Antigen-Antibody (immune) complexes
formed in circulation and deposited in vessel walls
or tissues.
o Binds to soluble antigen released into blood or body
fluids and subsequently deposited in tissues (large
area)
o Once deposited, immune response elicits an
inflammatory response and lysosomal enzymes are
released into the inflammatory site instead of into
the phagolysosomes causing tissue damage
o Systemic Immune Complex
Serum sickness (antibiotics, food, venom),
autoimmune vasculitis, glomerulonephritis
o Local Immune Complex
Arthus Reaction
Type IV cell mediated
o Cell-mediated: sensitized T cells attack antigen
o Direct cell-mediated cytotoxicity
Cytotoxic T cells
Viral reactions Hepatisis
o Delayed-type hypersensitivity
Macrophages, T helper cells
Tuberculin test, allergic contact dermatitis,
hypersensitivity pneumonitis
Transplant rejection
Categories of transplant tissue:
ALLOGENIC: may or may not be related but have similar
HLA types
SYNGENEIC: identical twins

AUTOLOGOUS: same person

Organ graft rejection
Hyper-acute
o Circulating antibodies react with the graft
o Type III Arthus-type reaction
o Immediate post transplant
Acute
o Generation of T cells, antibodies against graft
o Within first few months post transfer
Chronic
o Blood vessels in the graft gradually damaged
o Manifests in the dense intimal fibrous tissue of
blood vessels in the transplanted organ
o Mechanism is NOT well understood
o Prolonged period of time
o GRAFT vs Host Disease (GVHD)
Transplant needs a functional immune
component.
Host tissues has antigens foreign to donor
tissue.
Host immunity compromised.
Autoimmune disorders
Normally, self-reactive immune cells are destroyed or
suppressed.
In autoimmunity, self-tolerance breaks down and the immune
system attacks self-antigens destroys body tissues
Autoimmune disorders
Systemic Lupus Erythematosus (SLE)
Autoimmune Hemolytic Anemia (AIHA)
Hashimoto Thyroiditis
Immunodeficiency states
Primarygenetic
Humoral (B-cell) deficiencies
Cellular (T-cell) deficiencies
Severe combined immunodeficiencies (SCID)
Wiskott-Aldrich syndrome
Acquiredconsequence of another event
Malnutrition
Immunosuppressant drugs
AIDS