CELLULAR INJURY, CELL DEATH, AND ADAPTATIONS Flashcards
cell can go back to its normal state after the cellular injury is identified
Reversible
There is persistence of the injury and the cells can no longer cope up with the stress
Irreversible
In hypertension, there is ______ in workload
increase
In AMI, there is ______ blood flow to the heart
decreased
The major and important cause of cell injury
Oxygen deprivation
causes of oxygen deprivation
reduced blood flow
cardiorespiratory failure
decreased oxygen-carrying capacity of blood
Causes of cell injury: PHYSICAL AGENTS
Mechanical trauma, extremes of temperature, sudden changes in atmospheric pressure, Radiation, Electric shock
serves an essential function in defense against infectious pathogens, but immune reactions may also cause cell injury.
Immune system
A functional and structural alteration in early stages or mild forms of injury
Reversible cell injury
FEATURES OF REVERSIBLE CELL INJURY
Generalized swelling of the cell and its organelles
Blebbing of the plasma membrane
Detachment of ribosomes
Clumping of nuclear chromatin
Ultrastructural changes visible by electron microscopy:
PLASMA MEMBRANE
Blebbing
Blunting
Loss of microvilli
Ultrastructural changes visible by electron microscopy:
Mitochondria
Swelling
small densities
reversible functional and structural responses to changes in physiologic states and some pathologic stimuli
Adaptations
increase in size
hypertrophy
increase in cell number
hyperplasia
decrease in size and metabolic activity of cells
atrophy
change in the phenotype of cells
metaplasia
Calcium may be deposited at sites of cell death, resulting in __________
Pathological classification
On microscopic examination, small clear vacuoles may be seen within cytoplasm; this pattern of nonlethal injury is sometimes called________
Hydropic change or vacuolar degeneration
the cytoplasm of injured cells appear __ when stained w hematoxylin and eosin
red
Ultrastructural changes visible by electron microscopy:
Myelin figures in the cytoplasm
Derived from phospholipids of damaged membranes
Ultrastructural changes visible by electron microscopy:
Nuclear alterations
Disaggregation of granular and fibrillar elements.
Causes of necrosis
- Ischemia
- Exposure to microbial toxins
- Burns and other forms of chemical and physical injury
- unusual situations in which active proteases leak out of the cells and damage surrounding tissues.
basophilia of the chromatin
may fade; presumably reflects loss of
DNA because of enzymatic degradation
by endonucleases
Karyolysis
characterized by nuclear shrinkage and increased basophilia, chromatin condenses into a dense, shrunken basophilic mass (also seen in apoptotic cell death)
Pyknosis
pyknotic nucleus
undergoes fragmentation
Karyorrhexis
● Architecture of dead tissue is preserved for a
span of at least some days only with loss of
Nuclei
● Affected tissue has a firm texture
COAGULATIVE NECROSIS
Coagulative necrosis is commonly seen in _____in any tissue
EXCEPT the brain which undergo liquefactive
necrosis
Ischemia
Localized area of coagulative necrosis is called
an _______
infarct
● Digestion of the dead cells, resulting in
transformation of the tissue into a viscous liquid
● Seen in focal bacterial or, occasionally, fungal
infections
LIQUEFACTIVE NECROSIS
● Accumulation of leukocytes (predominantly
neutrophils) and the liberation of enzymes from
these cells known as
pus
● not a specific pattern of cell death, but the term
is commonly used in clinical practice, usually
applied to a limb
GANGRENOUS NECROSIS
this term is derived from the
friable white appearance of the area of necrosis
caseous
Necrotic area appears as a structureless
collection of fragmented or lysed cells and
amorphous granular debris enclosed within a
distinctive inflammatory border
CASEOUS NECROSIS
Focal areas of fat destruction, typically resulting
from release of activated pancreatic lipases into
the substance of the pancreas and the
peritoneal cavity
FAT NECROSIS
Fatty acids are generated that combine with
______to produce grossly visible chalky-white
areas
calcium
Special form of vascular damage usually seen in
immune reactions involving blood vessels
-Occurs when complexes of antigens and
antibodies are deposited in the walls of arteries
called “fibrinoid” (fibrin-like)
FIBRINOID NECROSIS
● Basically cell shrinkage or reduce size
● Induced by tightly regulated suicide program
APOPTOSIS
this pathway is responsible for apoptosis in
most physiologic and pathologic situations
Mitochondrial
presence of active
_____ is therefore a marker for cells
undergoing apoptosis
caspases
A phase wherein caspases become active
Initiation phase
The mitochondrial pathway is initiated by____
Capsase 9
Intrinsic pathway
When \_\_\_\_\_\_\_ is released into the cytoplasm, it initiates a suicide program of apoptosis
cytochrome c
Release of cytochrome c is determined by integrity of the outer mitochondrial membrane, which is tightly controlled by \_\_\_\_\_\_
BCL2 family of proteins
Death receptor pathway is initiated by
CASPASE 8,10
Extrinsic activity
Extrinsic pathway is Initiated by engagement
of plasma membrane
death receptors that are
members of the ___________
TNF
receptor family [TNFR1,
fas (CD95)]
In this phase, Capsapses trigger cellular
fragmentation
Execution phase
Apoptotic bodies may also become coated with natural antibodies and proteins of the complement system, notably \_\_\_\_, which are recognized by phagocytes
C1q
Acts as a backup mechanism in host defense
against certain viruses that encode caspase
inhibitors (e.g., cytomegalovirus)
NECROPTOSIS
Physiologic necroptotsis occurs during
the formation of the
mammalian bone growth plate
Form of apoptosis that is accompanied by the
release of the fever-inducing cytokine IL-1
PYROPTOSIS
Triggered when excessive intracellular levels of
iron or reactive oxygen species overwhelm the
glutathione-dependent antioxidant defenses to
cause unchecked membrane lipid peroxidation
FERROPTOSIS
● process in which a cell eats its own contents
AUTOPHAGY
Nucleation and formation of an isolation membrane, also called a \_\_\_\_\_ derived from the ER and other membrane sources such as the plasma membrane and mitochondria.
phagophore
The elongation and closure of
the initiation membrane require the coordinated
action of two ubiquitin-like conjugation systems
that result in the covalent linkage of the lipid
_______ to
microtubule-associated protein light chain 3
(LC3)
phosphatidylethanolamine (PE)
characterized by impaired autophagosome maturation, and in mouse models of the disease genetic defects in autophagy accelerate neurodegeneration.
Alzheimer disease
Macrophage-specific deletion of
_____ increases susceptibility to
tuberculosis
Atg5
Genome-wide association studies have linked both \_\_\_\_\_\_to single-nucleotide polymorphisms (SNPs) in the autophagy-related gene ATG16L1.
Crohn
disease and ulcerative colitis
Decreased ATP synthesis and
ATP depletion are frequently associated with
both hypoxic and chemical (toxic) injury. It
produces ______
ATP utilizing oxidative phosphorylation
and glycolytic pathway
Mitochondrial damage often results in the
formation of a high-conductance channel in the
mitochondrial membrane, called the__________
mitochondrial permeability transition pore
Cellular energy metabolism is altered: If the
supply of oxygen to cells is reduced, as in
ischemia, oxidative phosphorylation ceases,
resulting in a _____in cellular ATP and
associated increase in AMP.
decrease ; increase
These changes
stimulate phosphorylase and
phosphofructokinase activities, leading to
increased rates of____
glycogenolysis and glycolysis.
Leakage of mitochondrial proteins due to
__________is the initial step in apoptosis by the
intrinsic pathway
channel formation by pro-apoptotic BAX and BAK
Oxygen free radicals cause injury to cell
membranes by lipid peroxidation
ROS
With _______ there is Decreased
phospholipid synthesis which may affect all
cellular membranes, including those of
mitochondria
lipid peroxidation
Damage to nuclear DNA activates sensors that
trigger p53-dependent pathways which arrests
cells in the _____of the cell cycle and
activates DNA repair mechanisms (important in
development of tumors)
G1 phase
are chemical species that have a
single unpaired electron in an outer orbit which
are highly reactive and “attack” and modify
adjacent molecules, such as inorganic or
organic chemicals—proteins, lipids,
carbohydrates, nucleic acids—many of which
are key components of cell membranes and
nuclei.
Free radicals
ROS are produced normally in cells during
__________,
but they are degraded and removed by
intracellular ROS scavengers
mitochondrial respiration and energy generation
Increased production or decreased scavenging
of ROS may lead to an excess of free radicals, a
condition called ___
oxidative stress
Rapid bursts of ROS are produced in
activated ______during inflammation
leukocytes
Pathologic Effect of Free radicals:
○ Lipid peroxidation in membranes
○ Oxidative modification of proteins
○ Lesions in DNA
T or F
free radicals can also trigger apoptosis.
T
normally serve as second
messengers in several signalling pathways but if released into cytoplasm in excessive amounts,
are also an important source of cell injury.
Calcium ions
T or F
Cytosolic free Ca2+ is normally maintained at
very low concentrations (~0.1µmol)
T
Accumulation of ____ in mitochondria
result in opening of mitochondrial
permeability transition pore and failure
of ATP generation
Ca2+
_____ control the proper folding
of newly synthesized proteins
Chaperones in the ER
Triggered by the accumulation of
unfolded or misfolded proteins in the ER
Unfolded Protein response
Occurs when the cytoprotective response is unable to cope with the accumulation of misfolded proteins in the cell leading to the activation of caspases and induces apoptosis
ER Stress
is the most common cause of cell
injury in clinical medicine
Ischemia
Results from hypoxia induced by
reduced blood flow, most often due to a
mechanical arterial obstruction
Ischemia
T or F In ischemic tissues, not only does aerobic metabolism cease but anaerobic energy generation also fails after glycolytic substrates are exhausted or glycolysis is inhibited by the accumulation of metabolites
T
Blood flow is maintained and during which energy production by anaerobic glycolysis can continue, ischemia compromises the delivery of substrates for glycolysis
Hypoxia
Restoration of blood flow to ischemic tissues can
promote recovery of cells in reversible injury
ISCHEMIA REPERFUSION INJURY
These free radicals may be produced in
reperfused tissue as a result of
__________
incomplete reduction of oxygen
leukocytes, and in damaged endothelial
cells and parenchymal cells
Intracellular and mitochondrial calcium
overload begins during reperfusion due
to __________
influx of calcium resulting from cell
membrane damage and ROS-mediated
injury to sarcoplasmic reticulum
some ____
antibodies have propensity to deposit in
ischemic tissues
IgM
is often the reason for
terminating the therapeutic use or development
of a drug
Toxic liver injury
Mercury binds to the _________ of cell membrane
proteins, causing increased
membrane permeability and
inhibition of ion transport
sulfhydryl
groups
○ Most toxic chemicals are not biologically
active in their native form but must be
converted to reactive toxic metabolites,
which then act on target molecules
○ This modification is usually
accomplished by the cytochrome P-450
mixed-function oxidases in the ____ of the liver and other organs
smooth
ER
● Increased functional demand (body builders)
● Stimulation by hormones and growth factors
PHYSIOLOGIC HYPERTROPHY
● Common to permanent cells - nondividing cells
(skeletal muscles, myocytes, brain cells)
● Increased workload
● Synthesis of more protein by increasing the
number of myofilaments per cell, increase the
amount of force, more strength and work
capacity
PATHOLOGIC HYPERTROPHY
MECHANISM OF HYPERTROPHY
Mechanical sensors detect the increased load ->
activate a complex downstream web of signaling
pathways, including PI3K/AKT pathway
(physiologic) and G-protein-coupled
receptor-initiated pathways (pathologic) ->
stimulate increased production of growth factors
and vasoactive agents -> activate transcription
factors [GATA4, NFAT, MEF2] which increase
the expression of genes that encode muscle
proteins
Increase in number of cells and (consequently)
organ
HYPERPLASIA
● Action of hormones or growth factors
● Increase functional capacity of the organ
● Compensatory increase after damage or
resection
PHYSIOLOGIC HYPERPLASIA
● Excessive or inappropriate action of hormones
and growth factors on target cells
● Usually benign but it can initiate cancer
● Constitutes a fertile soil in which cancerous
proliferations may eventually arise
PATHOLOGIC HYPERPLASIA
Prostatic hyperplasia
there is significant amount of stroma in
between the glands (normal)
there is significant amount of stroma in
between the glands (normal)
there are more glands and are seen in a
haphazard/random fashion
Result of growth factor-driven proliferation of
mature cells and, in some cases, by increased
output of new cells from tissue stem cells
MECHANISM OF HYPERPLASIA
● Reduction in size of organ or tissue
● Decrease in cell size and number
ATROPHY
● Regression of the uterus after pregnancy
● Regression of the breast after pregnancy and
lactation
● Regression of the thyroglossal duct - (during
development) originates at the base of the
tongue and transports the thyroid to the anterior
neck; this duct normally regress
● Common during normal development
PHYSIOLOGIC ATROPHY
In _____, there is a decrease in blood supply because
of atherosclerotic cerebrovascular disease -> widened
sulci because of the thinning of some of the gyri
atrophy
Degradation of proteins occurs mainly by the
_________. Nutrient
deficiency and disuse may activate ubiquitin
ligases.
ubiquitin-proteasome pathway.
Reversible change in which one differentiated
cell type is replaced by another cell type
(change should be from a stronger or more
stable type of cell)
METAPLASIA
● Reprogramming of local tissue stem cells (there
is transition of the cells to a more durable cells
depending on the condition that stimulated the
metaplastic reaction)
● Colonization by differentiated cell population
from adjacent sites (extension of squamous
epithelium going into the endocervical region
and replacing glandular epithelium)
METAPLASIA
*Squamous metaplasia of cervix
the glandular
epithelium is replaced by squamous epithelium
BARRETT’S METAPLASIA
Esophagus - squamous epithelium; gastric - glandular
epithelium -> glandular epithelium is starting to replace
your squamous epithelium because glandular epithelium
is more resistant to acid
● Manifestations of metabolic derangements
● Harless or can cause injury
● Location- cytoplasm, organelles, or nucleus
● Endogenous or exogenous
INTRACELLULAR ACCUMULATIONS
(abnormal
accumulations of triglycerides within
parenchymal cells)
steatosis
Cholesterol and cholesterol esters
atherosclerosis, xanthomas, cholesterolosis, and
niemann pick disease type c
) there is deposition of
cholesterol esters in the wall; sometimes there is
corresponding fibrosis
Atheroma
yellow bright color in the mucosa because
of the deposition of your cholesterol esters
*gallbladder
intracellular accumulations of __________ usually
appear as rounded, eosinophilic droplets,
vacuoles, or aggregates in the cytoplasm.
proteins
T or F
Proteins can be amorphous, fibrillar, or crystalline in
appearance under electron microscopy.
T