Lecture 2 Flashcards
Causes of cell injury and disease
aging
ischemia
infectious agents
immune reactions
genetic factors
nutritional factors
physical factors
chemical factors
Response of cells when injured
Cell injury
inflammation
healing
atrophy/hypertrophy/hyperplasia/dysplasia
Free Radical theory
increase in free radical production or exposure causes a decline in cell function
Cellular senescence
viable nondividing state
What promotes free radical formation?
high levels of oxygen
UV exposure
cigarette smoke
pesticides
being given O2 too quickly after injury
intense or prolonged exercise
What antioxidants neutralize extra free radicals?
Endogenous (inside our body) = superoxide dismutase, produced by exercise
Exogenous
Free Radicals
has less than 8 electrons
naturally unstable so tries taking electrons from other atoms
formed in ATP formation
Telomere aging clock theory
every time a cell replicates, the telomere breaks down
Epigenetic clock theory
methylation changes as we age
Age-related cellular markers
telomere shortening
lipofuscin: intracellular pigment
Cellular aging
age-related cellular changes impair healing
certain lifestyle choices influence aging related markers
Ischemia
lack of blood supply below the minimum necessary to maintain cellular function
Hypoxia
decrease in oxygen delivery to cells or tissue
Anoxia
absence of oxygen delivery to cells or tissue
Influences on cell injury
infectious agents
immune reactions
genetic, nutritional, physical, chemical, psychosocial factors
Cell injury potential outcomes
Reversible = sublethal
Irreversible = cell death
Reversible cell injury
Can be acute or chronic
determined if the cell nucleus and membrane are INTACT
Chronic cell injury
Continued stress
results in cellular adaptations (atrophy, hypertrophy, hyperplasia, dysplasia) and intracellular accumulations of fats, proteins, carbs, pigments
Dysplasia
increase in number abnormal cells
HYperplasia
increase in number of cells within an area
Irreversible cell injury
changes in cell nuclei, mitochondria, lysosomes, breakdown of membrane
active cellular breakdown occurs
Enzymes and injured cells
dissolve dead cells
Phagocytes and injured cells
must remove dead tissue before healing can occur
Types of necrosis
Coagulative
Caseous
Liquefactive
Coagulative necrosis
Internal organs. Cells are dead, but architecture of tissue is intact and recognizable under microscope.
Frostbite, ischemia, dry gangrene
Caseous Necrosis
Usually associated with mycobacterium infection
tuberculosis
Liquefactive necrosis
overwhelming cell destruction with enzymatic breakdown of tissue structure. Can occur in brain, skin, wound, joints
wet gangrene, stroke
What happens when a single cell becomes hypoxic?
Mitochrondria: decreased ATP production, swelling of inner mitochondrial membrane
Plasma Membrane: loss of selective permeability, enzymes leak out of the cell
Gap junctions: loss of coupling
organelles that breakdown without oxygen
mitochondria
cell membrane
gap junctions
Key clinical pathology findings with hypoxia
leakage of soluble enzymes from damaged dying cells, leads to elevation of enzymes and other proteins into plasma
Heart attack leakage
CK leaks within 1 day
Troponin leaks within 1-2 days
Lactate dehydrogenase leaks within 3 days
Plasma
water
albumin
globulins/antibodies
fibrinogen/clotting factors
solutes
Albumin
major contributor to osmotic oressure of plasma. Its presence pulls water toward it.
Oncotic pressure
osmotic pressure of proteins
Blood makeup
Plasma
Formed Elements
Formed elements
RBC
WBC
platelets
Erythrocytes
lack nuclei, transport O2 + CO2, short lived, 120 days
Platelets
also known as thrombocytes
involved in clotting, plug the area
Leukocytes
WBC
include granular and nongranular
Granular leukocytes
neutrophils = 1st on scene w/bacteria
eosinophils = allergies
basophils = heparine, histamine
Nongranular leukocytes
monocytes = circulate short time, become macrophages in tissue
lymphocytes = B-cells and T-cells
Inflammation
coordinated reaction of tissues to cellular injury and death caused by microbes or physical insult
Acute inflammation
immediate and early response to injury
characterized by exudative response and PMNs (neutrophils)
defensive reaction and vital
Chronic inflammation
ongoing response to an injurious agent
characterized by mononuclear cells (monocytes, lymphocytes) and fibroblasts
What does acute inflammation help with?
tissues are protected against microorganisms
any tissue damage that does occur is swiftly repaired
the process of healing can begin
Inflammation can be problematic…
can lead to chronic inflammation and disease
can spiral out of control
Major events in acute inflammation
Vascular changes
cellular events
hemostasis
Intracellular compartment
inside cell plasma membranes, 2/3 of total body water
Extracellular compartment
1/3 total body water
interstitium tissue = 80%
intravascular/plasma makes rest
Net filtration pressure
pushes fluid out of the capillary and into interstitial tissue
Oncotic pressure
plasma proteins exert a pressure that pulls fluid back into capillary from the interstitial tissue
Lymph vessels and nodes
widely distributed throughout body
drain excess interstitial tissue fluid, returns to venous system
infectious agents can spread via lymph nodes
Vascular changes
1st step of inflammation
Transient vasoconstriction
vasodilation of arterioles
increased vascular permeability
Transient vasoconstriction
helps prevent blood loss
Vasodilation
of arterioles, capillaries, venules
due to relaxation of smooth muscle lining vessels
slows blood velocity which allows WBC to move to edge of capillaries
Increased vascular permeability
endothelial cells contract, leading to increased space between cells
leakage of fluid and plasma proteins out of capillaries and into the interstitial
Edema
accumulation of plasma in interstitial tissue
“inflammatory leakage”
Transudate edema
protein-poor fluid
Exudate edema
protein-rich fluid that may also contain phagocytic cells
Effusion
“inflammatory leakage”
leakage material that fills an anatomic space
Hemorrhagic Exudate
sanguinous
bright red or bloody
expected after surgery/trauma
concerning when its sudden, large amounts may indicate hematoma
Serosanguinous exudate
blood-tinged yellow or pink
expected 48-72 hours after injury/trauma
concerning when there is a sudden increase may indicate wound dehiscence
Wound dehiscence
wound opening up
Exudate
a mass of cells and fluid that has seeped out of blood vessels or an organ, especially in inflammation
Types of exudates
serous
purulent
hemorrhagic
serosanguinous
Serous exudate
watery, clear yellow, or straw-colored, contains albumin and antibodies
expected in early stages of most inflammations. Common with blisters, joint effusions, viral infections
concerning when there is sudden increase may indicate draining seroma
Purulent exudate
viscous cloudy pus, contains cellular debris from necrotic cells and during PMNs
usually caused by pus forming bacteria and indicates infection
Cellular events in acute inflammation
Step 2 includes:
movement and accumulation of WBC
recognition and adherence
Phagocytosis and intracellular degradation
Movement and accumulation of WBCs
comes from the blood to the tissues
Neutrophils, first line of defense
Monocytes; next cells to emigrate
Recognition and adherence
Opsonization: coating of foreign particles with proteins that accelerates phagocytosis
Phagocytosis and intracellular degradation
neutrophils and macrophages ingest particles and degranulate. granules within phagocytes contain bactericidal enzymes that digest invading bacteria
Margination
blood stasis allows WBCs to accumulate and stick to lining of blood vessels at injury site
Diapedesis
WBCs actively move out of blood vessels into interstitial space
neutrophils and monocytes squeeze through tiny gaps between endothelial cells
Chemotaxis
WBCs actively move toward injured/infected area by attraction to cytokines released from tissue or cells
Oposonization/phagocytosis/degranulation
neutrophils and monocytes/macrophages engulf and destroy foreign substances and debris
Neutrophilia
neutrophils are the primary cell type in tissue/fluid during acute inflammation
How do WBCs move toward an area of tissue damage or infection?
chemotaxis
Circulating platelets produce…
serotonin, help with vasoconstriction
Tissue mast cells
between internal and external boundaries
secrete histamine, increases vasodilation and permeability
Basophils
secrete histamine
Endothelial cells
line every capillary, contraction, increase space when needed
Injured tissues release
arachidonic acid derivatives. helps to keep inflammation going
Cytokines
chemical signals that help to guide cells
produced by WBCs
interleukin produces multiple effects on metabolic and endocrine systems
produces fever by making PGE in hypothalamus
Enzymes derived from plasma
blood coagulation cascade
fibrinolytic system
complement system
Vasoactive amines
Serotonin
Histamine
Serotonin
Vasoactive amine
causes vasocontriction
primary source from platelets
Histamine
vasoactive amine
vasodilation of arterioles
leads to endothelial cell contraction, increased permeability
short duration of action
primary source are mast cells, basophils, platelets
Arachidonic acid metabolites
Released from injured tissue, specifically from phospholipid bilayer
prostaglandins/thromboxane
leukotrienes
prostaglandins E2
type of AA metabolites
induce fever and mediates pain responses
prostacyclin
AA metabolite
inhibits platelet aggregration and causes vasodilation
Thromboxane
type of AA metabolite
facilitates platelet aggregation
Leukotrienes
potent bronchoconstrictor
increased vascular permeability
AA metabolites promote…
the 5 classic local signs/symptoms of acute inflammation
rubor, calor, tumor, dolor, functio laesa
Chemical mediators of acute inflammation
Plasma proteases
complement system
cytokines
AA metabolites
Vasoactive amines
Plasma proteases
kinins
same vascular action as histamine
induce pain by activating nocioceptors
Complement system
group of plasma proteins that lie dormant until activated
cause opsonization, formation of membrane attack complex
Hemostasis
all the processes that minimize blood loss when a blood vessel is opened
causes 4 events; vasoconstriction, formation of plug, formation of fibrin web/clot, clot retraction/dissolution
Systemic response to inflammation
fever
leukocytosis
elevated erythrocyte sedimentation rate
Fever
due to pyrogens released from WBCs
Leukocytosis
increased # of WBCs in the blood
Erythrocyte Sedimentation Rate
ESR or sed rate
rate at which RBCs in unclotted blood plasma sink to bottom of test tube
sed rate increases during inflammatory processes
Why? high proportion of fibrinogen causes RBCs to stick and sink faster
nonspecific measure of inflammation
Potential outcomes of inflammation
Complete resolution
healing by scarring
abscess formation
progression to chronic inflammation
Chronic Inflammation
healing of tissues, but not full return to function
can be caused by extensive injury, tissue necrosis, inability of parenchymal cells to regenerate, persistence of agent, repeated episodes of inflammation, low immune system
Characteristics of chronic inflammation
chronic inflammatory cells
tissue destruction
fibroblast proliferation
Chronic inflammatory cells
macrophages, lymphocytes, and plasma cells infiltrate involved areas
possible granuloma formation
Tissue destruction
hallmark of chronic inflammation
Fibroblast proliferation
common cause for compromise/failure of organ system (fibrosis)
Type 1 collagen
predominant collagen in the body, prominent in mature scars, tendon, bonem joints, labrums. most abundant
Type 2 collagen
predominant type in growth plate and hyaline cartilage
Type 3 collagen
primarily in vascular and visceral tissue. first type of collage deposited in wound healing
Type 4 collagen
found in basement membranes
Regeneration
process by which destroyed or lost cells are replaced by vital cells. restores tissue to intactness. EXACT cells are replaced
only occurs if parenchymal cells undergo mitosis
Repair
process by which damaged tissue is replaced by connective scar tissue
may result from tissue necorsis with removal of the connective tissue matrix
Labile cells
can regenerate
cells with high turnover rate. Skin, GI, etc
Stable cells
can regenerate
cells with low turnover rate
do not normally divide, can undergo mitosis with certain stimulus
skeletal cells, kidney cells
Regeneration can only occur if….
normal connective tissue matrix and basement membrane are intact
Basement membrane
provide mechanical support for resident cells as well as a scaffold for accurate regeneration of pre-existing structures
Regeneration does not occur in
permanent cells
Permanent cells
cells that do not have the ability to divide and there are no apparent stem cells. most neurons, myocardial cells
How does the body repair damaged tissue?
synthesis of extracellular matrix
proliferation and migration of parenchymal cells and endothelial cells
tissue contraction
tissue regernation or repair
Synthesis of extracellular matrix
Fibroblasts migrate into the damaged area and proliferate, synthesize, and secrete several proteins that make up extracellular matrix: fibronectin, collagen, proteogylcans/elastin
Fibronectin
the glue
made from certain plasma proteins that leaked out of blood vessels
stabilizes fibrin
provides tensile strength and attracts more fibroblasts
Collagen
structural integrity
most important protein to provide structural support and tensile strength for almost all tissues and organs
Proteoglycans and elastin
hydration and strechability
proteogylcans bind to fibronectin and collagen, retain water, provide stability of collagen
Tissue contraction
ECM shrinks due to the work of myofibroblasts. these help to approximate the wound margins
Pathological repair
Deficient scar formation
Excessive scar formation
Contracture
Deficient scar formation
can result in wound dehiscence, which is rupture or splitting open
Excessive scar formation
hypertrophic scar
keloid
Keloid
exaggerated growth of scar tissue
Hypertrophic scar
widened scar, characterized by being red, raised, and rigid
Contracture
remember that wound contraction is shrinkage, and is normal
a contracture is EXCESSIVE shrinkage, decreases ROM. it is pathological
Local influences on tissue healing
adequacy of local blood supply
presence of infection or foreign body at injured site
type of cell
chance for immobilization/protection during healing
General factors affecting healing
general health
age
vascular sufficiency and oxygen perfusion
substance use/abuse
nutritional status
systemic diseases
Lung cell healing
can occur after injury if basement membranes are intact (pneumonia)
repair happens when theres damage to basement membrane (pulm fibrosis)
some agents can cause formation of scar tissue when not needed
Peripheral nerve healing
axons can regenerate if nerve cell body is intact
myelin degeneration –> new axon, proliferation of schwann cells –> maintenance of neurotubules is necessary
skeletal muscle cell healing after infection
cells can regenrate within sheaths and get return of function
if severe, fibers will be destroyed
skeletal muscle cell healing after contusion/strain
incomplete healing with loss of strength and high rate of reinjury
skeletal muscle cell healing after transection
regeneration can occur from undamaged stumps or satellite cells
skeletal muscle cell healing after severe trauma
results in scar
Phases of fracture healing
inflammatory
reparative phase
remodeling
Inflammatory phase of fracture healing
pain, swelling, heat
local internal bleeding
initial fibrosis occurs at end of 1st week
Reparative phase
6-12 wks
osteoclasts remove debris
soft callous formation
hard callous starts
many bone growth factors help
Remodeling phase of fracture healing
months to years
clincal union to radiological union
healing depends on lots of different factors
Tendon/ligaments cell healing
REPAIR not regeneration, replaced with weaker types of collagen
may take >40-50 weeks to regain normal strength
max contraction should be avoided for 2 months
ligaments follow the same pattern. Intra-ligaments heal poorly
Articular cartilage healing
does not regenerate after adolescence
wihtout intervention, healing of cartilage occurs by scar tissue or doesn’t heal
Fibrocartilage healing
tears heal by migration of cells from the synovial membrane
lacerations need surgery
