CELL INJURY, CELL DEATH AND ADAPTATION Flashcards
It is the study of the structural, biochemical, and functional changes in cells, tissues, and organs that
underlie disease
PATHOLOGY
concerned with the common reactions
of cells and tissues to injurious stimuli
General Pathology
these reactions are not tissue specific
(e.g., acute inflammation in response to
bacterial infections)
General Pathology
examines the alterations and underlying mechanisms in organ specific diseases (e.g., ischemic heart disease)
Systemic Pathology
THE FOUR ASPECTS OF DISEASE PROCESS THAT FORM THE CORE OF
PATHOLOGY
- Etiology
- Pathogenesis
- Morphologic Changes
- Clinical manifestations
refers to the cause of the disease process
Etiology
2 classes of etiology
genetic
acquired
what type of etiology:
inherited mutations and disease-associated gene variants or polymorphisms
genetic
what type of etiology:
– infectious, nutritional, chemical, or
physical
acquired
refers to the sequence of cellular, biochemical , and molecular events that follow the exposure of cells or tissues to an injurious agent
Pathogenesis
refers to the the mechanisms of disease development
Pathogenesis
refer to the structural alterations in cells or tissues
that are either characteristic of a disease or
diagnostic of an etiological process
Morphologic Changes
used to determine the nature of disease and to
follow its progression
Morphologic Changes
refer to the signs and symptoms
Clinical manifestations
caused by functional abnormalities that are end
results of genetic, biochemical, and structural
changes in cells and tissues
Clinical manifestations
Refers to the steady state of a cell that must be maintained
HOMEOSTASIS
In the steady state, a normal cell is confined to a fairly narrow range of function and structure by:
a) its state of metabolism, differentiation, and specialization
b) constraints of the neighboring cells
c) availability of metabolic substrates
Are reversible functional and structural responses to changes in physiologic states (e.g., pregnancy) and
some pathologic stimuli
ADAPTATIONS
New but altered steady states are achieved, allowing the cell to survive and continue to function
ADAPTATIONS
increase in the size of cells
hypertrophy
increase in number of cells
hyperplasia
decrease in the size and metabolic activity of cells
atrophy
change in phenotype of cells
metaplasia
Adaptations may consist of the following: (5)
a) increase in the size of cells → hypertrophy
b) increase in functional activity
c) increase in number of cells → hyperplasia
d) decrease in the size and metabolic activity of cells → atrophy
e) change in phenotype of cells → metaplasia
What happens when stress is eliminated?
the cell can recover to its original state without having suffered
any harmful consequences
What happens if the limits of adaptive responses are exceeded?
cell injury
Cell injury to a sequence of events that occurs when:
a) the limits of adaptive responses are exceeded
b) cells are exposed to injurious agents or stress
c) cells are deprived of essential nutrients
d) cells become compromised by mutations
occurs when the stimulus persists or it is severe enough from the beginning
Irreversible injury
irreversible injury may lead to ___
cell death
the end result of progressive cell injury
CELL DEATH
One of the most crucial events in the evolution of disease in any tissue or organ
CELL DEATH
a normal and essential process in embryogenesis, the development of organs, and the maintenance of
homeostasis
CELL DEATH
principal pathways of cell death
a) apoptosis
b) necrosis
c) autophagy (triggered by nutrient deprivation)
associated with metabolic derangements in cells and sublethal, chronic injury
*include proteins, lipids, and carbohydrates
Intracellular accumulations
deposition of calcium at sites of cell death
Pathologic calcification
- normal process
- accompanied by characteristic morphologic and functional changes in cells
Aging
are reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in
response to changes in their environment
adaptation
it is the increase in the size of cells, that results in an increase in the size of the affected organ
hypertrophy
due to the synthesis and assembly of additional intracellular structural components
hypertrophy
In non-dividing cells (e.g., myocardial fibers): only ___ causes increase in tissue mass
hypertrophy
In cells capable of division: both ____ and ___ contribute to the increase in size
hypertrophy
hyperplasia
hypertrophy can be:
physiologic only
pathologic only
both
physiologic & pathologic
____ hypertrophy
caused by increased functional demand or by stimulation by hormones and growth factors
physiologic
the striated muscle cells in the heart and skeletal muscles respond to increased metabolic demands by undergoing ___
hypertrophy
most common stimulus of muscle hypertrophy
increased workload
Mechanisms of hypertrophy
(1) Increased production of cellular proteins
(2) Switch of contractile proteins (from adult → fetal/neonatal forms)
(3) Re-expression of some genes present only during early development
Three basic steps in the molecular pathogenesis of cardiac hypertrophy:
1) Integrated actions of mechanical sensors and other agents
2) Activation of signal transduction pathways
3) Activation of transcription factors
increased workload trigger mechanical sensors which work together with ___ and ___
growth factors (e.g., TGF-β, IGF1) and
vasoactive agents (e.g., a-adrenergic agonists, endothelin-1, and Ang II)
Activation of signal transduction pathways:
▪ Most important:
(for physiologic)
(for pathologic)
Phosphoinositide 3-kinase/AKT pathway
G-protein signaling
transcription factors
GATA4
nuclear factor of activated T cells (NFAT)
myocyte enhancer factor 2 (MEF2)
work coordinately for synthesis of muscle proteins
transcription factors
in muscle hypertrophy, α isoform of myosin heavy chain is replaced with the ___ for slower, more energetically economical contraction
β isoform
___ participate in the cellular response to stress
gene products
the increase in the number of cells in an organ or tissue in response to a stimulus
HYPERPLASIA
hyperplasia occurs in a tissue only if it contains cells capable of ____
dividing
hyperplasia can be
physiologic only
pathologic only
both
physiologic and pathologic
__ hyperplasia
due to the action of hormones or growth factors
Physiologic hyperplasia
occurs when there is a need to increase functional capacity of hormone sensitive organs
HYPERPLASIA
hyperplasia occurs when there is need for compensatory increase after ___
damage or resection
_____ hyperplasia
mostly caused by excessive or inappropriate actions of hormones or growth factors acting on target cells
Pathologic hyperplasia
___ due to disturbed balance between estrogen and progesterone
endometrial hyperplasia
*cause abnormal menstrual bleeding
in ____, the growth control mechanisms become deregulated or ineffective because of genetic aberrations that
drive unrestrained proliferation
Cancer
Mechanisms of hyperplasia (2)
(1) Growth factor-driven proliferation of mature cells
(2) Increased output of new cells from tissue stem cells
In hepatitis: hepatocytes regenerate from ___
intrahepatic stem cells
In liver hepatectomy: ____are produced in the liver that engage receptors on the surviving
cells and activate signaling pathways that stimulate cell proliferation
growth factors
the reduction in size of an organ or tissue due to a decrease in cell size and number
ATROPHY
atrophy can be
physiologic
pathologic
both
both
some embryonic structures undergo ___ during fetal development
atrophy
common causes of atrophy
Decreased workload (atrophy of disuse)
Loss of innervation (denervation atrophy)
Diminished blood supply
Inadequate nutrition
Loss of endocrine stimulation
Pressure
In chronic inflammatory diseases: cachexia results from overproduction of ___ that causes appetite suppression and lipid depletion
cytokine TNF
Mechanisms of atrophy:
(1) Decreased protein synthesis
(2) Increases protein degradation
accumulation of lipofuscin granules
brown atrophy
Increases protein degradation
* Occurs mainly by the ____
ubiquitin-proteasome pathway
nutrient deficiency and disuse → activate ____ → attach ubiquitin to cellular proteins to target them for degradation in proteasomes
ubiquitin ligases
starved cell eats its own components to reduce nutrient demand to match the supply
autophagy
the reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by
another cell type
metaplasia
once cell type that is sensitive to a particular stress is replaced by another cell type that is better able to withstand the adverse environment
metaplasia
Most common epithelial metaplasia
Columnar to squamous
In response to chronic irritation → normal ciliated columnar epithelium of trachea and bronchi are replaced by _____ cells
stratified squamous epithelial
In excretory ducts of the salivary glands, pancreas, or bile ducts → from secretory columnar epithelium to ____
stratified squamous epithelium
Barrett esophagus: esophageal squamous epithelium is replaced by intestinal-like ___ under the influence of refluxed gastric acid
columnar cells
Formation of cartilage, bone, or adipose tissue (mesenchymal tissues) in tissues that do not normally contain these elements
Connective tissue metaplasia
bone formation in muscle that may occur after intramuscular hemorrhage
Myositis ossificans
examples of metaplasia
(1) Columnar to squamous
(2) Squamous to columnar
(3) Connective tissue metaplasia
Metaplasia does not result from a change in the phenotype of an already differentiated cell type, but a result of
reprogramming of:
- stem cells that are known to exist in normal tissues
- undifferentiated mesenchymal cells in connective tissue
CELL INJURY & CELL DEATH results when:
a) cells are stressed so severely that they are no longer able to adapt
b) cells are exposed to inherently damaging agents
c) cells suffer from intrinsic abnormalities
in early stages or mild forms of injury, the functional and morphologic changes are reversible if the damaging stimulus is removed
Reversible cell injury
injury becomes irreversible → cell cannot recover and dies
Cell death
Reversible cell injury Hallmarks
a) reduced oxidative phosphorylation with resultant ATP depletion
b) cellular swelling due to changes in ion conc. and water influx
c) alterations in intracellular organelles such as mitochondria and cytoskeleton
accidental and unregulated form of cell death due to damage to cell membranes and loss of ion homeostasis
Necrosis
necrosis is always a ___ process
pathologic
[necrosis]
___ enter cytoplasm → digest the cell → leakage of cellular contents into ____ → ___
lysosomal enzymes
ES space
inflammation
serves as the pathway of cell death in injuries such as ischemia, toxin exposure, infections, and trauma
Necrosis
the cell kills itself when its DNA or proteins are damaged beyond repair
Apoptosis
characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of cell debris
Apoptosis
cellular contents do not leak out → no inflammation
necrosis/apoptosis
apoptosis
Apoptosis is a highly regulated process driven by genetic pathways which is why its called
programmed cell death
serves many normal functions; not necessarily associated
with cell injury
necrosis/apoptosis
apoptosis
a term that implies that necrosis can also be a form of
programmed cell death
Necroptosis
WHAT ARE THE CAUSES OF CELL
INJURY?
Oxygen Deprivation
Physical Agents
Chemical Agents & Drugs
Infectious Agents
Immunologic Reactions
Genetic Derangements
Nutritional Imbalances
in ___ and ___ techniques changes can be seen within minutes to hours after injury
histochemical and ultrastructural techniques
in ___ and ___ examination, it may take hours to days before changes can be seen
light microscopy and gross examination
Reversible injury is characterized by
a) general swelling of the cell and its organelles
b) blebbing of the plasma membrane
c) detachment of ribosomes from the ER
d) clumping of nuclear chromatin
appears whenever cells are incapable of maintaining ionic and fluid homeostasis
Cellular swelling
result of failure of energy-dependent ion pumps in the plasma membrane
Cellular swelling
The cell can repair these derangements and may return to normalcy.
Reversible injury
the changes in reversible injury are associated to:
- decreased ATP generation
- loss of cell membrane integrity
- defects in protein synthesis
- cytoskeletal damage
- DNA damage
occurs in hypoxic injury and various
forms of toxic or metabolic injury
Fatty change
manifested by the appearance of lipid
vacuoles in the cytoplasm
Fatty change
seen in cells involved in and dependent
on fat metabolism (e.g., hepatocytes and myocardial cells
Fatty change
unable to maintain membrane integrity → contents often leak out → elicit ____
inflammation
The enzymes that digest the necrotic cell are derived from:
a) lysosomes of the dying cells themselves
b) lysosomes of the leukocytes that are part of the inflammatory reaction
PATTERNS OF TISSUE NECROSIS
Coagulative necrosis
Liquefactive necrosis
Gangrenous necrosis
Caseous necrosis
Fat necrosis
Fibrinoid necrosis
type of pattern of necrosis:
architecture of dead tissues is preserved for a span of at least some days
Coagulative necrosis
example of coagulative necrosis
infarct in all organs except the brain
type of pattern of necrosis:
- digestion of dead cells, resulting in transformation of the tissue into a liquid viscous mass
Liquefactive necrosis
seen in focal bacterial or fungal infections
Liquefactive necrosis
necrotic material is creamy yellow (pus) due to dead ___
leukocytes
type of pattern of necrosis:
not a specific pattern of cell death
Gangrenous necrosis
type of pattern of necrosis:
term applied to the limb, generally the lower leg, that has lost its blood supply and has undergone necrosis
involving multiple tissue planes
Gangrenous necrosis
type of pattern of necrosis:
typically coagulative necrosis but if bacterial infection of superimposed there is more liquefactive necrosis
Gangrenous necrosis
type of pattern of necrosis:
encountered often in foci of tuberculous infection
Caseous necrosis
type of pattern of necrosis:
friable white appearance of the area of necrosis
Caseous necrosis
type of pattern of necrosis:
on microscopic examination: appears as a structureless collection of fragmented/lysed cells and amorphous granular debris enclosed within a distinct inflammatory border (granuloma)
Caseous necrosis
type of pattern of necrosis:
refer to focal areas of fat destruction due to release of activated pancreatic lipases into the substance of the
pancreas and peritoneal cavity
Fat necrosis
pancreatic enzymes leak out of acinar cells and liquefy the membranes of fat cells in the peritoneum
- Acute pancreatitis
[Acute pancreatitis]
the released lipases split the triglyceride esters contained within fat cells → fatty acids combine with calcium → _____ (visible chalkywhite areas)
fat saponification
type of pattern of necrosis:
Histologic examination: takes the form of foci of shadowy outlines of necrotic fat cells
Fat necrosis
type of pattern of necrosis:
seen in immune reactions involving blood vessels
Fibrinoid necrosis
type of pattern of necrosis:
occurs when complexes of antigens and antibodies are deposited in the walls of arteries
Fibrinoid necrosis
deposits of immune complexes + fibrin = bright pink and amorphous appearance called ___
fibrinoid
type of pattern of necrosis:
seen in immunologically mediated vasculitis syndrome
Fibrinoid necrosis
The cellular response to injurious stimuli depends on the nature of the ____
injury, its duration, and severity
The consequences of cell injury depend on the ____ of the injured cell
type, state, adaptability
Biochemical mechanisms of cell injury:
(1) Depletion of ATP
(2) Mitochondrial damage
(3) Influx of calcium and loss of calcium homeostasis
(4) Accumulation of Oxygen-Derived Free Radicals
(5) Defects in membrane permeability
(6) Damage to DNA and proteins
Depletion of ATP
▪ Major causes:
a) reduced supply of oxygen and nutrients
b) mitochondrial damage
c) actions of some toxins (e.g., cyanide
Mitochondrial damage
▪ Causes:
a) increases in cytosolic Ca2+
b) reactive oxygen species
c) oxygen deprivation
Influx of calcium and loss of calcium homeostasis
▪ Causes:
a) release from intracellular stores
b) influx across plasma membrane
Accumulation of Oxygen-Derived Free Radicals
▪ Causes:
a) redox reactions that occur during normal metabolic processes
b) absorption of radiant energy
c) inflammation
d) enzymatic metabolism of exogenous chemicals or drugs
e) transition metals
f) nitric oxide
Defects in membrane permeability
Causes or mechanisms:
a) reactive oxygen species
b) decreased phospholipid synthesis
c) increased phospholipid breakdown
d) cytoskeletal abnormalities
Damage to DNA and proteins
▪ Results in death by ___
apoptosis
What characterizes irreversibility?
a) inability to reverse mitochondrial dysfunction
b) profound disturbances in membrane function
induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that
degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins
APOPTOSIS
Characteristic of apoptotic cells
break up into fragments (apoptotic bodies) which contain portion of the cytoplasm and nucleus
- plasma membrane: remains intact but altered (become tasty for phagocytes)
- the dead cell and its fragments
become rapidly devoured before the contents leak out → no inflammatory reaction elicited
[physiologic/pathologic apoptosis]
Remove unwanted, aged, or potentially harmful cells → maintain a steady number of various cell populations in
tissues
physiologic
[physiologic/pathologic apoptosis]
Eliminates cells that are injured beyond repair without eliciting a host reaction
pathologic
MORPHOLOGIC CHANGES IN APOPTOSIS
(1) Cell shrinkage
(2) Chromatin condensation
(3) Formation of cytoplasmic blebs and apoptotic bodies
(4) Phagocytosis of apoptotic cells or cell bodies usually by macrophages
cysteine proteases that cleave proteins after aspartic residues
caspases
exist as inactive proenzymes or zymogens → undergo enzymatic cleavage to become active
caspases
The process of apoptosis is divided into:
Initiation phase
Execution phase
Caspases become catalytically active
Initiation phase
Other caspases trigger degradation of critical cellular components
Execution phase
The activation of caspases depends on a finely tuned balance between production of ___ proteins
pro-apoptotic and antiapoptotic
Two pathways converge on caspase activation:
Mitochondrial (Intrinsic) Pathway
Death Receptor (Extrinsic) Pathway
Results from increased permeability of the mitochondrial outer membrane with release of pro-apoptotic molecules from the intermembrane space (e.g., cytochrome c → initiate apoptosis)
Mitochondrial (Intrinsic) Pathway
Initiated by engagement of plasma membrane death receptors on a variety of cells
Death Receptor (Extrinsic) Pathway
members of the TNF receptor family that has a cytoplasmic portion called death domain as it is essential for delivering apoptotic signals
Death receptors
best known death receptor:
type 1 TNF receptor (TNFR1) and related protein Fas (CD95)
hybrid form of cell death that shares aspects of both necrosis and apoptosis
NECROPTOSIS
Resembles necrosis in that it also characterized by loss of ATP, swelling of the cells and organelles,
generation of ROS, release of lysosomal enzymes, and rupture of plasma membrane
NECROPTOSIS
Similar to apoptosis, it is triggered by genetically programmed signal transduction events
NECROPTOSIS
caspase-independent
programmed cell death”
NECROPTOSIS
Activation of caspase-8 →
Failure to activate caspase-8 →
APOPTOSIS
NECROPTOSIS
another form of programmed cell death
PYROPTOSIS
pyroptosis is accompanied by release of fever inducing __
cytokine IL-1
PYROPTOSIS Characteristics:
- cell swelling
- loss of membrane integrity
- release of inflammatory mediators
a process in which a cell eats its own contents
AUTOPHAGY
it is a survival mechanism → in states of nutrient deprivation, the starved cells lives by cannibalizing itself and recycling digested contents
AUTOPHAGY
WHAT ARE THE 3 CATEGORIES OF AUTOPHAGY?
Chaperone-mediated autophagy
Microautophagy
Macroautophagy
direct translocation across
lysosomal membrane by
chaperone proteins
Chaperone-mediated autophagy
inward invagination of
lysosomal membrane for
delivery
Microautophagy
major form;
- involves sequestration and
transportation of portions of
cytosol in an autophagosome
Macroautophagy
serve as a manifestation of metabolic derangements
INTRACELLULAR ACCUMULATIONS
accumulations of triglycerides within parenchymal cells;
caused by toxins, protein malnutrition, diabetes, obesity, anoxia
Steatosis (fatty change)
smooth muscle cells and macrophages within the intimal layer of the
aorta and large arteries are filled with lipid vacuoles made up of cholesterol and cholesterol esters
Atherosclerosis
intracellular accumulation of cholesterol within macrophages cause
tumorous masses in subepithelial connective tissue of the skin and in tendons
Xanthomas
focal accumulations of cholesterol-laden macrophages in lamina
propria of gallbladder
Cholesterolosis
lysosomal storage disease caused by an enzyme for
cholesterol trafficking
Niemann-Pick Disease (Type 3)
Alteration within cells or in the extracellular space that gives a homogenous, glassy, pink
appearance in routine histological sections with H&E
Hyaline change
wear-and-tear pigment
Lipofuscin
hemoglobin-derived, golden yellow-to-brown pigment which is the
storage form of iron
Hemosiderin
Seen in patients with an abnormality in either glucose or glycogen metabolism such as
Diabetes mellitus
Glycogen
ubiquitous air pollutant which, when inhaled, is picked up by macrophages within the alveoli and is then transported through lymph
- cause coal worker’s pneumoconiosis
Carbon (coal dust)
Appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
Proteins
abnormal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and
other mineral salts
PATHOLOGIC CALCIFICATION
TWO FORMS OF PATHOLOGIC
CALCIFICATION
Dystrophic calcification
Metastatic calcification
type of pathologic calcification:
occurs locally in dying tissues (i.e. areas of necrosis)
Dystrophic
type of pathologic calcification:
occurs in normal tissues
Metastatic
type of pathologic calcification:
occurs despite normal serum calcium levels and in the absence of derangements in calcium metabolism
Dystrophic
type of pathologic calcification:
calcium salts appear as fine, white granules or
clumps, often as gritty deposits
Dystrophic
type of pathologic calcification:
Observed in:
a) atheromas of advanced atherosclerosis
b) aging or damaged heart valves
c) tuberculous lymph node
Dystrophic
type of pathologic calcification:
almost always results from hypercalcemia
secondary to some disturbance in calcium
metabolism
Metastatic
type of pathologic calcification:
▪ principally affects the interstitial tissues of the
gastric mucosa, kidneys, lungs, systemic arteries,
and pulmonary veins
Metastatic
causes of hypercalcemia:
(1) increased secretion of PTH
(2) resorption of bone tissue
(3) vitamin-D related disorders
(4) renal failure
result of progressive decline in cellular function and viability
CELLULAR AGING
caused by genetic abnormalities and accumulation of cellular and molecular damage due to the effects
of exposure to exogenous influences
CELLULAR AGING
MECHANISMS OF CELLULAR AGING
(1) DNA damage
(2) Cellular senescence
(3) Defective protein homeostasis
(4) Deregulated nutrient sensing
