Cellular Response and Adaptation Flashcards
Ch 1
Neoplasm
Any new or abnormal growth, specifically a new growth of tissue in which the growth is uncontrolled and progressive
Hyperplasia and it’s mechanism
The increase in the number of cells in a tissue or organ in response to a stimulus
Mechanism: growth factor-driven proliferation of mature cells
Karyorrhexis
A pyknotic nucleus undergoes fragmentation
Disorder
derrangement or abnormality of function
-a morbid physical or mental state/condition
Common causes of atrophy
- Decreased workload
- loss of innervation (denervation)
- diminished blood supply
- inadequate nutrition
- loss of endocrine stimulation
- pressure
What morphological changes are see in dystrophic calcification?
calcium salt deposits have a basophilic, amorphous granular appearance; sometimes can clump together
Pyroptosis involves what cytokine?
IL-1
What cell type is responsible for phagocytosis of apoptotic bodies?
Macrophages
What transcription factor promotes new blood vessel formation, stimulates cell survival pathways, and enhances anaerobic glycolysis in attempt to deal with hypoxic stress?
Hypoxia-inducible factor-1
What pathway is thought to be the most important in physiologic hypertrophy?
AKT pathway
Morphologic changes
structural alterations in cells/tissues that are either characteristic of a disease or diagnostic of an etiologic process
What factors lead to physiologic hyperplasia
the actions of hormones or growth factors
Where do anti-apoptotic proteins reside?
in the outer mitochondrial membrane, cytosol, and ER
What pathway is the major mechanism of apoptosis in mammalian cells?
The intrinsic mitochondrial pathway
What is the function of pro-apoptotic proteins?
Once activated, BAK and BAX oligomerize and promote permeability of the outer mitochondrial membrane, allowing cytochrome C to leak out
Gangrenous necrosis
Used in clinical practice, describing a limb that has lost blood supply and has undergone necrosis
What is the function of the p16 tumor suppressor gene?
protection of cells from uncontrolled signals and promotes senescence
How is the extrinsic pathway of apoptosis initiated?
FasL binds to Fas receptors which recruit FADD adaptor protein
FADD binds to procaspase-8, bringing other procaspase-8 molecules together
Procaspase-8 is cleaved into active caspase-8 which then activated caspases 3 and 6, similar to the mitochondrial pathway
Granulomatous inflammation
A form of chronic inflammation characterized by collections of macrophages, T lymphocyes and sometimes associated with a central caseating necrosis
What tissues are predisposed to metastatic calcification and why?
gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins; they contain an internal alkaline compartment and excrete acid
Morphological changes associated with irreversible injury
Severe swelling of mitochondria
extensive damage to plasma membranes leading to the production of myelin figures
Swelling of lysosomes
Cellular response to injury is dependent on:
nature of the injury, duration, and severity
cells unable to maintain ionic and fluid homeostasis d/t failure of energy-dependent ion pumps in the membrane undergo what change?
Cellular swelling
Pathologic calcification and the types
deposition of calcium salts into tissues
Dystrophic calcification
Metastatic calcification
Metaplasia
Reversible change in which one differentiated cell type is replaced by another cell type
What initiates the necroptotic pathway?
TNF binding to TNFR1
ischemia-reperfusion injury results from:
restoration of blood flow to ischemic tissues, resulting in loss of cells in addition to those cells that underwent irreversible injury
Infarct
Localized area of coagulative necrosis
Connective tissue metaplasia
Formation of cartilage, bone, or adipose tissue within tissues that do not normally contain these elements
What is the conquence of shortening of telomeres in somatic cells?
Somatic cells lack telomerase, therefore with each replication, the telomeres shorten.
Telomere shortening signals cell cycle arrest.
Pathogenesis
sequence of biochemical and molecular events that follow the exposure of cells/tissue to injurious agent
Coagulative necrosis
Ischemia caused by obstruction in a vessel
Injury denatures structural proteins and enzymes, blocking proteolysis of dead cells
What is the end result of progressive cell injury and is the most crucial event in the evolution of disease?
Cell death
What factor separates the mechanism of necroptosis from the mechanism of apoptosis?
Necroptosis does not result in the activation of caspases
What is a consistent feature of most forms of cell injury, except for apoptosis?
early loss of selective membrane permability, leading to overt membrane damage
What is the strongest independent risk factor for chronic illnesses?
Cellular aging
What stimulates production of anti-apoptotic proteins?
growth factors
What is the first manifestation of injury in almost all cell forms?
cellular swelling
Mechanisms of chemically induced cell injury
Direct toxicity
Conversion to toxic metabolites
What tumor suppressor genes does the CDKN2A locus encode?
p16
What is the underlying purpose for which a cell type might undergo metaplasia?
a change in phenotype of a cell can make the cell better able to withstand stress
Physiologic hyperplasia occurs when?
When there is a need to increase the functional capacity of hormone sensitive organs.
When there is a need for compensatory increase after damage or resection (i.e. kidney transplant)
What is the main role of BCL2 anti-apoptotic proteins
Keep the outer mitochondrial membrane impermeable, preventing the release of cytochrome C into the cytosol
Apoptosis
When the cell’s DNA or proteins are damaged beyond repair, the cell kills itself by nuclear dissolution, fragmentation of the cell and rapid removal of cellular debris.
What happens to myelin figures after they are formed during cell injury?
they are phagocytosed by leukocytes or degraded further into fatty acids (can form calcium soaps)
In the process of autophagy, what assists in the elongation of the membrane?
Microtubule-associated protein light chain 3 (LC3)
What receptor associated kinases are attracted to TNFR1 after activation?
receptor associated kinase 1 and 3 (RIP1 and RIP3)
The extrinsic pathway of apoptosis is inhibited by what protein?
Through what mechanism?
FLIP
Binds to pro-caspase 8 and prevents its cleavage, thus preventing apoptosis
What does pathologic hyperplasia provide?
A ground for which malginant proliferations can arise
Through what mechanisms has caloric restrictions been shown to increase longevity?
reducing signaling intensity of the IGF-1 pathway and increasing sirtuins.
What is the function of sensors in the intrinsic mitochondrial pathway?
They sense the loss of growth factors, DNA damage and ER stress, and activate BAK and BAX
Pyknosis
nuclear shrinkage and increased basophilia
Cell injury
limits of adaptation are exceeded or cells are exposed to severe injurious agents/stress
Karyolysis
loss of DNA because of enzymatic degradation by endonucleases
What is the cause behind the common bruise?
Local excess of iron 2/2 the breakdown of hemoglobin
What is often deposited at sites of cell death, and what is it classified as?
Calcium.
Pathologic calcification
What disorders are associated with an increase in apoptotic cell death?
Neurodegenerative diseases including Alzheimer’s dz, Parkinson dz and Huntington dz
Ichemic injury, such as MI
Death of a virally infected cell
Attenuation of IGF-1 signaling leads to
Lower rates of cell growth and metabolism
what are the downstream targets of IGF-1
AKT and mTOR (mammalian target of Rapamycin)
Depletion of ATP to 5-10% of normal levels causes:
- decreased activity of Na-K pump leading to cell swelling and dilation of the ER
- Cellular energy metabolism is altered: switch to anaerobic glycolysis (LA build-up)
- Reduction of protein synthesis 2/2 detachment of ribosomes from the ER and dissociation of polysomes
- Unfolded protein response
What protein responds to DNA damage and what is its role?
What happens if it cannot perform its role?
p53
accumulates within the cell, arresting the cell in the cycle cycle at G1 phase to allow for DNA repair
If damage is too great, then p53 triggers apoptosis by activating pro-apoptotic proteins
Cause of pathological hyperplasia?
excessive or inappropriate actions of hormones or growth factors on target cells.
Ex: increased proliferation of endometrial tissue 2/2 increased levels of estrogen, BPH
What are the morphological characteristics of necroptosis?
Loss of ATP, cell swelling, generation of ROS, release of lysosomal enzymes and rupture of plasma membrane (charateristic of necrosis)
Triggered by a programmed signal transduction, resembling the hallmark of apoptosis
Mechanisms of perfusion injury include?
oxidative stress
intracellular Ca overload
Inflammation
complement system activation
Syndrome
Set of symptoms that occur together; the sum of signs of any morbid state
Pyroptosis involves which caspase?
What does this caspase do?
Caspase-1
Cleaves the precursor form of IL-1 into biologically active, fever inducing, IL-1
Caspase-1 works with Caspase-11 to induce cell death
Dysregulation of autophagy occurs in many disease states including
CA
Neurodegenerative disorders
IBD
Infectious
What is released from necrotic cardiac muscle cells that can be detected within the blood as soon as 2 hrs post-cell death?
Cardiac specific enzymes and proteins (Biomarkers- CRP and troponin)
Muscle atrophy can be accompanied by what other condition?
Osteoporosis
What is the critical initiator caspase and how is it activated?
Caspase-9
Activated by the apoptosome
Adaptations
Reversible functional and structural responses to changes in physiologic states and some pathologic stimuli; a new steady state is achieved
Hemosiderin is the major storage form of
Iron
Liquefactive necrosis
Characterized by digestion of dead cells, resulting in transformation of tissue into a liquid viscous mass
- Commonly seen in the brain
- Seen in focal bacteria because microbes stimulate accumulation of leukocytes
Disease
any deviation from or interruption from the normal structure or function of a part, an organ or system.
-manifested by characteristic signs and symptoms
Necrotic cells show what in an H&E stain?
increased eosinophila d/t loss of cytoplasmic RNA and denaturation of cytoplasmic proteins
Systemic overload of iron leads to what condition?
Hemosiderosis
The accumulation of hemosiderin in organs and tissues
What is the most common stimulus for hypertrophy of muscle?
increased work load
What is the first response to the accumulation of misfolded proteins in the ER?
What happens if this response fails?
Unfolded protein response: protein production halts, increasing production of chaperones which facilitate protein folding
If cell is unable to cope with the increase in misfolded proteins, the ER becomes stressed which triggers the activation of caspases and induces apoptosis
Consequences of cell injury depend on:
the type, state, and adaptability of the injured cell
Metastatic calcification
Occurs in normal tissues whenever there is hypercalcemia
What is a fundamental cause of necrotic cell death?
Reduction in ATP levels
To what family do death receptors belong to?
TNF receptor family
Physiologic apoptosis occurs during?
Embryogenesis
Menstruation (endometrium)
Elimination of self-reactive T-cells
Cells undergo a fixed number of divisions before they halt in a terminally nondividing state, these cells have undergone what process?
Replicative (cellular) senscence
What are the main pro-apoptotic proteins?
What family do they belong to?
BAX and BAK
BCL2 family
Process of autophagy includes?
- Formation of an isolation membrane, usually derived from ER
- Elongation of vesicle
- Maturation of the autophagosome
- Fusion with endosome and eventually lysosome
- Degradation of cell’s own contents within the lysosme
Autophagy
the process in which starved cells eat their own components in an attempt to reduce nutrient demand
Provide examples of lipid accumulation
Steatosis
Atherosclerosis
Xanthomas
Cholesterolosis
Niemann-Pick Disease
What is the most important sites of membrane damage during cell injury?
Mitochondrial membrane
Plasma membrane
Membrane of lysosomes
What is produced in large amounts by activated leukocytes (neutrophils and macrophages) during an inflammatory reaction?
Reactive oxygen species (ROS)
What anti-apoptotic proteins help to control the release of pro-apoptotic proteins from the mitochondria?
What family do they belong to?
BCL2, BCL-XL, MCL1
BCL2 family
Dystrophic calcification can be distinguished from metastatic calcification by what factor?
Serum calcium is normal in dystrophic calcification
Generation of free radicals occurs in what ways?
- redox rxns that occur during normal metabolic processes
- absorption of radiant energy
- Bursts of ROS produced during inflammation by leukocytes
- Transition metals: Fenton reaction
- Nitric oxide
Why does apoptosis not elicit an inflammatory reaction in the host?
Unlike necrosis, the plasma membrane of apoptotic cells remains intact and the dead cell fragments are rapidly devoured.
Cell fragments do not get a chance to leak out and therefore do not have the opportunity to elicit an inflammatory response.
Fenton reaction
H202 + Fe2+ –> Fe3+ + .OH + -OH
Iron must be in the ferrous form (Fe2+) to participate in the Fention rxn
Wet-gangrene
results when a bacterial infection is superimposed onto coagulative necrosis causing more liquefactive necrosis
What is the most common cause of fatty change in the liver?
Alcohol abuse
Nonalcoholic fatty liver disease as a result of DM and obesity
What is the hallmark of cardiac metabolism before birth?
The use of carbohydrates for energy
Fat necrosis
Refers to a focal area of fat destruction resulting from the release of activated pancreatic lipases
In what circumstance would pyroptosis be activated?
In cells that have been infected by microbes
Why does necrosis elicit a host reaction (inflammation)?
Cellular contents leak through damaged plasma membrane into EC space
What is the mechanism of atrophy?
Decreased protein production (2/2 reduced metabolic activity) and increased protein degradation in cells
Necrosis
accidental and unregulated form of cell death resulting from damage to cell membranes and loss of ion homeostasis
Major causes of ATP depletion?
- Reduced oxygen supply
- Reduced nutrient supply
- Mitochondrial damage
- Actions of some toxins (cyanide)
What causes the increase in cell size encountered in hypertrophy?
synthesis and assembly of additional intracellular structural components, including proteins and myofilaments
What causes a more rapid and severe cell and tissue injury than hypoxia?
Ischemia
Through which pathway does degradation of cellular proteins typically occur in atrophy?
Ubiquitin-proteosome pathway
When is autophagy employed by a cell?
Under various stress conditions, including states of nutrient deprivation
Does cell death by apoptosis elicit an inflammatory reaction?
No
What morphological changes are seen in cells undergoing apoptosis?
Cell shrinkage (pyknosis)
Chromatin condensation and fragmentation (karyorrhexis)
Production of cellular blebs and apoptotic bodies
Phagocytosis
Clinical manifestation
signs and symptoms of a disease 2/2 alterations is cells or tissues
What types of cell injury tend to induce apoptosis?
Growth factor withdrawal
DNA damage
Protein misfolding
Mechanism of Ischemic cell injury
is this reversible?
- Oxygen depletion
- decreased ATP production
- failure in Na-K pump, allowing efflux of K and influx of Na and water, ultimately leading to cell swelling
- Loss of glycogen and protein synthesis
If oxygen is restored, these disturbances are reversible
Pathways of cell death
necrosis, apoptosis
Is apoptosis always associated with cell death?
No, it serves many normal functions as well
What type of metaplasia occurs in Barret’s esophagus?
Squamous to columnar type
How does the accumulation of misfolded proteins lead to apoptosis?
Proteins accumulate within the endoplasmic reticulum, resulting in ER stress
This ER stress culminates in apoptotic cell death.
Oxidative stress
increased production or decreased scavenging of ROS leading to an excess of free radicals
Function of sirtuins
promote the expression of gene products that increase longevity
What protein forms hemosiderin granules and under what circumstance does this occur?
Ferritin
When there is a local or systemic excess of iron
What is the stimulus for hypertrophy in cardiac muscle?
chronic hemodynamic overload 2/2 HTN or valve defects
What occurs if hormonal stimulation is reduced?
Hyperplasia regresses
Most common epithelial metaplasia
Columnar to squamous
ex: respiratory tract
What signals the reprogramming seen in metaplasia?
cytokines, growth factors, EC matrix components
What are the mechanisms of membrane damage?
- Reactive oxygen species
- decreased phospholipid synthesis
- increased phospholipid breakdown
- cytoskeletal abnormalities
What constitutes an apoptosome?
When does one form?
Cytochrome C + APAF-1
When cytochrome C leaks into cytosol
Dystrophic calcification is commonly seen in what conditions?
advanced atherosclerosis, damaged heart valves
In what types of cells can hyperplasia occur?
In cells that are capable of dividing
After birth, energy provision is achieved through which mechanism?
Oxidation of fatty acids
What type of cancers are apt to develop psammoma bodies?
Papillary (i.e. thyroid)
What cytokine is thought to be responsible for appetite suppression and lipid depletion, culminating in muscle atrophy?
Tumor necrosis factor (TNF)
An increase in sirtuins, including Sirtuin-6 results in
adaptation of caloric restriction, promotion of genomic integrity by activating DNA repair enzymes through deacylation
Cell injury induced by what is an important mechanism of cell damage in many pathological conditions?
Free radicals, specifically reactive oxygen species (ROS)
Hypertrophy
increase in size of cells, results in increase in size of specific organ
What mechanisms are believed to underie the process of cellular senescence?
Telomere attrition (shortening)
Activation of tumor suppressor genes
How do cells die after injury to lysosomal membranes?
lysosomes leak their contents into the intraceullar space, including: RNases, DNases, proteases, phosphatases, glucosidases
Activation of these enzymes leads to degradation of proteins, the cells die by necrosis
What do the pancreatic lipases do to contribute to fat necrosis?
Split the triglyceride esters contained within fat cells; these FA combine with calcium to create calcium soaps
Necrosis is encountered typically in what kind of injuries?
ischemia, exposure to toxins, infections, trauma
Dystrophic calcification occurs in what tissue types?
Necrotic, damaged, or aging tissues
Fibrinoid necrosis
Seen in immune reactions involving blood vessels, when Ag-Ab complexes are deposited within walls of arteries
-Result in bright pink amorphous appearance on histological imaging
What locus seems to be involved in controlling cell senescence?
CDKN2A
Types of adaptations
- Hypertrophy
- Hyperplasia
- Atrophy
- Metaplasia
The influences that predispose to metaplasia, if persistent, lead to what?
Malignant transformation
What is the most common genetic abnormality found in human cancers?
Mutation in TP53
Caseous necrosis
A structureless collection of fragmented or lysed cells and amorphous granular debris enclosed within a distinct inflammatory border (granuloma)
Causes of cell injury
- oxygen deprivation
- physical agents
- chemical agents and drugs
- infectious agents
- genetic derangement
- nutritional imbalances
What is the most common type of cell injury in clinical medicine?
What does it result from?
Ischemia
hypoxia induced by reduced blood flow, most commonly d/t mechanical arterial obstruction
What are the main causes of hemosiderosis?
Increased absoprtion of dietary iron as seen in Hemochromatosis
Hemolytic anemias
Repeated blood transfusion
Mechanism of metaplasia
reprogramming of stem cells in normal tissues, or of undifferentiated mesenchymal cells present in CT
What factors are present in apoptotic body cell membranes that make them better targets for phagocytes?
Phosphatidylserine
Thrombospondin
C1q
Hyperplasia is a characteristic response to what types of infection?
Viral (i.e. papillomaviruses)
On what cell type is FasL typically found?
T-cells the recognize self Ags
Some CTLs
Distinct patterns of necrosis
- Coagulative necrosis
- Liquefactive necrosis
- Caseous necrosis
- Gangrenous necrosis
- Fat necrosis
- Fibrinoid necrosis
What is the most common exogenous pigment?
Carbon
Caseous necrosis is most often seen in what type of infection?
Mycobacterium Tuberculosis
Nuclear changes appear in three patterns d/t breakdown of DNA
karyolysis, pkynosis, karyorrhexis
When does cell injury change from reversible to irreversible?
If a stimulus persists long enough or if it is severe enough from the beginning, a cell will enter irreversible injury and eventually undergo cell death
In what type of cells is autophagy prominent?
Atrophic cells which are exposed to nutrient deprived states
Microscopic features of reversible cell injury
- Cellular swelling
- Fatty change (i.e. fatty liver 2/2 alcohol use)
What does damaging the mitochondrial membrane result in?
What does this lead to?
Opening of the mitochondrial permeability transition pore.
Leads to a decrease in ATP production and release of proteins that trigger apoptotic death
What enzyme is released from the mitochondria after cell injury which leads to the activation of apoptosis?
Cytochrome C
What do patients with Werner Syndrome typically show and what is the reason for this manifestation?
These pts show premature aging d/t defective helicase.
Defective helicase causes accumulation of chromosomal damage, leading to aging of the cell.
In certain pathophysiologic conditions, what occurs in the heart?
As an adaptive mechanism, the heart returns to it’s “fetal” gene program
In what organ is steatosis typically seen and why?
The liver; it is the primary organ responsible for fat metabolism
What endogenous pigment is insoluble and known as the wear and tear pigment?
In what organs is this pigment commonly found in aging patients or patients who are malnurished?
Lipofuscin
Liver and heart
What cellular components are most significantly affected by injurious stimuli?
mitochondria, cell membranes, protein synthesis and packaging machinery, DNA
Atrophy
Reduction in the size of an organ or tissue d/t a decrease in cell size and number
What occurs when in response to an increase in hemodynamic load?
Heart muscle enlarges (hypertrophies) and can become injured
What factor is a frequent problem in clinical medicine, limiting drug therapy
chemical (toxic) injury
Four aspects of disease process
- Etiology
- Pathogenesis
- Morphologic changes
- Clinical manifestations
What two conditions are associated with mutated genes that are unable to repair double strand breaks?
Bloom syndrome, ataxiatelangiectasia
What is a common example of CT metaplasia and what occurs?
Myositis ossificans
CT within muscle changes to bone during healing s/p trauma
What type of cancer can form as a result of dysplasia from Barrett’s esophagus?
Adenocarcinoma
Hallmark of reversible cell injury
Decrease in ATP production
Cellular swelling
What is the morphologic hallmark of cell death?
Loss of the nucleus
Apoptosis occurs in what pathological states?
DNA damage
Accumulation of misfolded proteins
Infection, specifically viral
Cellular aging is induced by
ROS
Telomere shortening
Defective protein homeostasis
What factors counteract aging?
A decrease in the IGF-1 signaling pathway and an increase in sirtuins leads to altered transcription and an increase in DNA repair and protein homeostasis
What is the most characteristic morphological change seen in apoptosis?
Condensatio of chromatin, aggregating peripherally
An increase in intracellular calcium leads to cell injury in what ways?
Opening of the mitochondrial transition pore, resulting in increased permeability and decreased ATP production
Activation of apoptosis through release of caspases from permeable mitochondria
Activation of enzymes at inappropriate times
What does the Fenton rxn allow for?
Iron to generate ROS
Pathologic effects of ROS include?
Lipid peroxidation leading to membrane damage
Protein modifications, resulting in the breakdown or misfolding and eventual activation of apoptosis
DNA damage leading to mutations
In what diseases is necroptosis a possible mechanism of cell death?
steatohepatitis, acute pancreatitis, reperfusion injury, and neurodegenerative dzs like PD
Vitamin A deficiency leads to what type of cellular change?
Metaplasia
