Human Pathology Cell Adaptation and Injury Flashcards
Class Notes
Pathology
Studies the structural and functional changes in cells, tissues and organs that underlie disease states.
Etiology
The cause of the disease such as genetics or environmental factors
Pathogenesis
The mechanism of the development of the disease
Morphology
Structural alterations in cells and tissues due to the disease process
Clinical Signs and Symptoms
Functional consequences of the morphologic changes
How do cells react to adverse influences?
Adapting
Sustaining Reversible Injury
Suffering Irreversible Injury
What are the causes of cellular injury?
oxygen deprivation physical agents chemical agents infectious agents immunologic agents genetic mutations nutrition deficiency
What is a reversible injury to a cell?
The stage of injury at which the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed.
What is the hallmark of cellular injury?
Cell swelling
What is cell swelling associated with?
Increased permeability of the cell
The appearance of triglyceride containing lipid vacuoles in the cytoplasm
Fatty Change
What is the hint that a cell is undergoing necrosis?
fragmentation of the cell
What happens to the color of the cytoplasm when a cell is injured?
It is eosinophilic or pink
What are the morphologic changes in reversible cell injury?
Pink cytoplasm
Blebbing of the cell membrane
Distortion of microvilli
Loosening of cellular attachments
Mitochondrial changes
Dilation of the ER with detachment of ribosomes
Chromatin clumping within the nucleus
Myelin figures which are phospholipids arise from damage to cell membrane
What are the principal adaptive responses of the cell under stress?
hypertrophy
hyperplasia
metaplasia
atrophy
hypertrophy
an increase in the size of the individual cells and ultimately the tissue.
It usually occurs in the cells that have a limited capacity to divide or replicate
What happens to a cell to cause a myocardial infarction?
Cell death of the myocyte
Can injury affect only morphology of a cell?
No, it can affect both the morphology and the function of a cell. A cell may look normal after a reversible injury but it can lack normal function.
Reversible Changes are known as …
Adaptations
Endogenous Chemical Mediator
A protein located within the cell ( intracellular) that enhance and activate the functions of other proteins.
Physiologic Adaptations
Responses of cells to normal stimulus
Pathological Adaptations
Responses to stress that allow cells to modulate their structure and function
What causes hypertrophy?
An increase in the functional demand of the organ or stimulation by a Growth Factor
Can hypertrophy and hyperplasia occur together?
Yes, like in the uterus during pregnancy
Trophic Triggers
Soluble mediators that stimulate cell growth such as growth factors and andregenic hormones which turn on genes that create proteins and filaments
Hyperplasia
The increase in the number of cells. Usually occur in cells that are capable of replication
Compensatory Hyperplasia
Residual tissue grows after the removal or loss of part of the organ.
Example:
Liver
Excessive hormonal or growth factor stimulation can lead to what pathological condition
pathologic hyperplasia.
A disturbance in the balance between stimulation of the growth factors and inhibition of the growth factors results in pathologic hyperplasia
Normal regulation of the mechanisms that control normal hyperplasia must be balanced.
What cells contribute to the creation of growth factors during repair?
leukocytes that respond to cellular injury in the extracellular matrix.
Can viruses contribute to hyperplasia?
Yes, because viruses contain their own growth factor to produce warts and lesions. The growth factors are encoded in viral genes.
What type of cell adaptation is commonly known to lead to cancer?
hyperplasia
Atrophy
Shrinkage in the size of a cell by the loss of the cell’s substance. The size and function is diminished.
What are the causes of atrophy?
decreased workload immobilization of a limb loss of innervation reduced blood supply loss of endocrine stimulation aging pressure malnutrition protein degredation reduction in protein synthesis
Decreased protein synthesis and increased protein degradation can lead to what kind of cell adaptation?
Atrophy
Why would protein synthesis decrease within a cell?
Due to decrease in metabolic activity.
Due to decrease in nutrition
Defective Ribosomes
What is the main pathway to cause protein degradation?
Ubiquitin- Proteasome Pathway which is activated by nutrient deficiency and disuse.
Ubiquitin tags the proteins to target for degredation by proteasomes.
What molecule degrades proteins?
Proteasomes recognize ubiquitin tag.
Autophagy
Self eating in which the starved cell eats its own components in an attempt to survive.
Metaplasia
A reversible change in which one adult cell type such as epithelial or mesenchymal is replaced by another adult cell type.
Cause stem cells to reprogram or differentiate down another pathway.
What type of metaplasia is common among people who smoke?
Epithelial metaplasia in which the normal ciliated columnar cells of the trachea and respiratory tract become stratified squamous epithelium. The new stratified squamous epithelium may be able to survive the exposure to nicotine better than the ciliated columnar epithelium.
Although this epithelium can survive more, a lot of protective mechanisms are lost such as mucus secretion and ciliary clearance of particulate matter.
What vitamin is critical for normal epithelial differentiation?
Vitamin A
What is the difference in the size of a cell when it undergoes apoptosis versus necrosis?
Apoptosis = shrinkage of the cell Necrosis= cell swelling
Which type of cell death is followed by inflammation?
necrosis
Apoptosis results in pyknosis?
True or False
False.
Necrosis
The cell membrane is disrupted in necrosis.
True or False
True
Enzymatic digestion and leakage of cellular contents follows apoptosis.
True or False
False.
Necrosis
What happens to chromatin during apoptosis?
It condenses
What is released in apoptosis?
Apoptotic bodies that are swallowed by phagosome
Oxygen deficiency is responsible for this condition
hypoxia
The loss of blood supply
ischemia
Carbon Monoxide has a higher affinity for Hb than oxygen.
True or False
True
Can hypoxia arise from a lack of oxygen in the blood?
Yes, if there is less oxygen bound to hemoglobin such as in pneumonia.
Can an excess of water, salt or glucose cause cellular injury?
Yes
How do poisons damage cells?
By altering the cell permeability and osmotic homeostasis
Is too much oxygen harmful to cells?
Yes
Can immunity affect cell injury?
Yes by autoimmune response
How does genetics create cellular injury?
Through a lack of genes needed to make certain proteins and misfolding of proteins.
How does nutrition affect cell injury?
Through the low protein calorie deficiency and diets too rich in fat can cause arthsclerosis.
What are the main two phenomena that characterize a cell’s status as being irreversibly injured?
Inability to correct mitochondrial dysfunction which leads to a lack of oxidative phosphorylation.
Depletion of the production of ATP
What are the two morphological changes that correlate with a reversible injury to a cell?
Cell swelling due to sodium / potassium pumps failure. Water follows sodium
Fatty change which is characterized by the appearance of small or large lipid vacoules in the cytoplasm.
What are intracellular changes associated with reversible cellular injury?
- plasma membrane alterations such as blebbing, blunting or distortion of microvilli and loosening of intercellular attachments.
- Mitochondria swelling
- Dilation of the ER and detachment of ribosomes
- Clumping of chromatin
- Presence of myelin figures. Myelin figures are more prevalent in the cell during reversible injury
Necrosis
The type of cell death associated with the loss of membrane integrity and leakage of cellular contents.
The leakage of cellular contents can cause inflammation response by the host.
Why are necrotic cell’s cytoplasm more eosinophillic?
Due to eosin binding to denatured cytoplasm proteins
Karyorrhexis
The pyknotic nucleus undergoes fragmentation
pyknosis
nuclear shrinkage and increased basophilia
What is the fate of necrotic cells?
They could become replaced by myelin figures which are either digested themselves by the dead cell’s lysosymes or leukocyte lysosomes and turned into fatty acids and then the fatty acids bind to calcium salts therefore allowing the dead cells to become calcified.
Karyolysis
Conducted by ribonuclease and chromatin fades
Coagulative necrosis
A form of necrosis in which the underlying tissue structure is intact for several days following cell death because the injury to the tissue has denatured structural proteolytic enzymes that digest dead cells. Leukocytes are recruited to the site to digest the dead cells within a couple of days.
Characteristic of infarcts
Seen in all areas except the brain
Liquefactive Necrosis
Mostly in bacterial and fungal infections because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest the tissue.
Due to the inflammation, the liquid becomes pus.
Hypoxic death of cells in the brain always produce liquefactive necrosis such as a stroke.
Gangrenous Necrosis
Condition of a limb that has lost blood supply and has undergone coagulative necrosis already.
What causes Wet Gangrene?
When bacteria invades the coagulative necrosis and liquefies it.
Caseous Necrosis
Cheese like necrosis found in tuberculous infections.
A distinctive inflammatory border aligning caseous necrosis
Granuloma
Enzyme that destroys fat cells
Lipases
Fat necrosis
Focal areas of fat destruction that result from the use of activated pancreatic lipases into the substance of the pancreas and peritoneal cavity. The release of the fatty acids combine with calcium to form chalky white areas called saponification.
The combination of fatty acids with calcium
Saponification
How do we detect tissue necrosis?
Through the detection of intracellular proteins circulating within the
What influences the cell’s response to stimuli?
Severity Duration Type of Injury Genetic makeup of the cell Cell adaptability Cell Type
What are the principal targets or alterations of a cell biochemical mechanisms in cell injury?
Mitochondria because it produces ATP
Calcium homeostasis because calcium can activate damaging enzymes due to failure of ATP dependent Calcium pumps which lead to influx of calcium in the cell.
Cellular membrane
DNA Damage and Protein Misfold
What is the main mechanism of ATP production?
oxidative phosphorylation of ADP during the reduction of oxygen within the electron transport chain in the mitochondria.
Which tissues are more able to survive ATP depletion?
Tissues that are capable of glycolysis because glycolysis can produce ATP without oxygen such as the liver rather than the brain which has limited glycolytic capacity.
How is increased glycolytic activity in a cell harmful ?
Reduces glycogen stores and reduces pH due to lactic acid buildup.
Which enzymes do Calcium activate that can have damaging effects on a cell?
phospholipases= membrane damage
proteases= break down membrane and cytoskeletal proteins
Endonucleases= responsible for DNA and chromatin fragmentation
Adenosine triposphatases= remove phosphate and lead to ATP depletion
Increase mitochondrial permeabilty which influences release of capsases and therefore apoptosis
Free Radical
A chemical species with a single unpaired electron in the outer orbital.
Reactive Oxygen Species
A free radical that is derived from oxygen. Normally produced in redox reactions.
ROS is mainly produced by phagocytic leukocytes to destroy microbes during inflammation by a process called respiratory burst.
The process by which leukocytes create ROS species
Respiratory burst
An excess of free radicals results in what condition
oxidative stress
What decays or deactivates ROS superoxide?
superoxide dismutases
What family of enzymes protect cells from oxidative damage?
Glutathione Peroxidase 1
Which enzyme in peroxisomes catalyzes the decomposition of hydrogen peroxide?
Catalase
What blocks the formation of ROS?
Antioxidants
Vitamins E,A,C and beta carotene
What type of process is a normal form of apoptosis?
Depletion of auto reactive T cells in the Thymus
During Embryogenesis
Elimination of cells beyond repair
Which two pathways result in capsase activation?
Mitochondrial Intrinsic pathway
Death Receptor Extrinsic Pathway
Which molecule derived from mitochondria mainly activates capsase?
Cytochrome C
What prevents the release of Cytochrome C from the mitochondria?
Bcl2 and Bcl x which are anti-apoptosis molecules
What molecules besides cytochrome C influences apooptosis?
BAK and BAX by dimerizing and inserting themselves into the mitochondrial channel through which the mitohondrial proteins escape to the cytosol.
Which family does Death Receptors belong to?
Tumor Necrosis Factor TNF and contain a death domain cytoplasmic regions
What are the main two type of Death Receptors?
Type 1 TNF
Fas CD95
Activation of these receptors cause the binding and aggregation of capsase 8
What molecules clear the apoptotic bodies?
Macrophages
Necropoptosis
A hybrid form of cell death.
Resembles necrosis in morphology and biochemically with a loss of ATP, cell swelling , generation of ROS and rupture of cell membrane.
It is like apoptosis because it is triggered and pre programmed genetically
Which receptors are involved with necropoptosis?
RIP1
RIP3
Pyroptosis
A form of cell death associated with activation of cystolic danger sensing protein complex, the inflammasome.
The result of activation of the inflammasome is the activation of capsases.
True or False
True
In what form of apoptosis does inflammation exist?
Pyroptosis
What three mechanisms do cells use to survive a bit longer under hypoxia?
They activate transcription factors of the hypoxia inducible factor 1 which stimulate the synthesis of proteins that help the cell survive in the face of low oxygen.
The stimulation of VEGF ( vascular endothelial growth factor) stimulates the growth of new blood vessels.
Glycolysis activation
What is the ultimate result of hypoxia and ischemia?
Depletion of ATP
The continuation of death after regaining blood flow
Reperfusion Injury
Why would reperfusion cause injury to a cell?
The production of ROS during reperfusion that can damage mitochondrial membranes and production of cytokines and increased expression of adhesion molecules with leukocyte infiltration.
Inflammation induced by ischemic injury increases during reperfusion.
What happens to inflammation during reperfusion?
Increase
Nitric Oxide
ROS
What determines the damage done by ROS?
The damage caused by free radicals is determined by their rates of production and removal
What are the characteristics of ROS?
Unstable
Highly Reactive
Can activate autocatalytic reactions which produce more free radicals
What category of elements on the periodic table are ROS?
Transition metals
What are the effects of Free Radicals?
Lipid Peroxidation of membranes
Oxidative Modification of Proteins by crosslnking and polypeptide fragmentation
DNA fragmentation
What are the free radical scavenging enzymes ?
Catalase
Superoxide dismutases
Glutathione Peroxidase
Toxins
Enviromental chemicals or substances produces by infectious pathogens
What are the two types of toxins in the body?
Direct Acting= toxin itself that act on the cell
Latent Acting= not active but metabolized to target
What are the effects of the accumulation of misfolded proteins within a cell?
Accumulation of a misfolded protein within a cell can stress the compensatory pathways in the ER and lead to cell death by apoptosis.
What influences an increase of misfolded proteins within a cell?
Intracellular accumulation of misfolded proteins may be caused by abnormalies that increase their production or reduce the cell’s ability to eliminate them.
Which medical condition is a result of accumulation of misfolded proteins?
Alzheimer Disease
Why is inflammation harmful to the body?
It can harm normal tissue even though it destroy microbes
What causes DNA damage?
Radiation
Chemotherapeutic Agents
ROS
Cytosolic free calcium is normally maintained 10 to the 4th times lower than that of extracellular calcium.
True or False
True
Which two signals influence cardiac hypertrophy?
Mechanical Trigger
Trophic Trigger
What happens to the contractile proteins in cardiac hypertrophy?
In cardiac hypertrophy , a switch from adult to fetal contractile proteins occur
What degenerative changes occur in hypertrophy of the heart?
Fragmentation and loss of myofibrilar contractile elements
Hyperplasia
An increase in the number of cells leading to an increase in the size of the organ or tissue
Can hyperplasia and hypertrophy occur concurrently?
Yes
What causes hyperplasia?
Hormones imbalance such as estrogen and progesterone
Compensatory
Increased synthesis of the Growth Factor
What type of tissue does hyperplasia occur?
In tissues with replication capacity
Atrophy
The loss of cellular constituents
Autophagic vacoules
Residual bodies such as lipofuscin granules that are yellow in color and form from lipid digestion
Can progress to cell death
What is characteristic protein find within Alzheimer disease?
misfolded proteins
Metaplasia
Replacement of cells sensitive to the stress with those that are better capable to deal with the stress.
The cells are not changed but the replacements are.
What is a consequence of metaplasia?
Loss of function
Reprogramming of the stem cells due to cytokines, growth factors and ECM components.
What type of cells replace the pseudostratified ciliated columnar cells of the respiratory tract of a person who may smoke?
Squamous
Abnormal Accumulation of triglycerides
Steatosis
Caused by toxins, DM, malnutrition, obesity, anoxia
Cholesterolosis
Streaks of yellow fat
Hyaline Change
An alteration within cells or in the extracellular space which gives it a homogeneous pink appearance with H and E
Exogenous Pigment
Carbon Dust
Endogenous Pigment
Lipofuscin
Melanin
Hemosiderin which contain iron and turn blue
Metastatic Calcification
Deposition of calcium into normal tissue which results in hypercalcemia or elevated level of calcium in blood
Dystrophic Calcification
Deposition of calcium in dead, dying or damaged tissue with serum calcium levels being normal
Example: Aortic Stenosis
Cellular Aging
The progressive decline in the lifespan and functional activity of cells due to..
Accumulation of mutations within DNA
ROS
Toxins
Decrease Cellular replication capacity due to shortening of telomeres
Defective protein homeostasis
Persistant inflammation on a low level due to the accumulation of damaged lipids, cells and other endogenous substances over the years.
Why do cancer cells replicate indefinitely?
Active telomerase reestablish the length
What cause protein misfolding ?
Defect in chaperones
What slows down cellular aging?
Calorie restriction due to altering the signaling pathway that affect aging.
Reduced activation insulin like growth factor
What causes pathway causes protein degredation?
Ubiquitin proteasome pathway
Autophagy is seen in which condition
Atrophy
Autophagy is the digestion of organelles
Atrophy in the brain has what characteristics
Narrow Gyrus
Wide Sulcus
What causes hypertrophy
increased demand
increased growth hormone
tissue does not have high replication capacity
What is the morphology of cardiac hypertrophy?
Switch from adult contractile proteins to fetal contractile proteins
Increase in myofibrillar contractile elements
When would there be a decrease in myofibrillar contractile elements in cardiac hypertrophy?
When an increase in mass no longer compensates the increased demand on the heart. This is when degeneration happens and fragmentation occurs as well.
what hormone influences hyperplasia?
Growth Factor
