Path Cell Injury (1/2)
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Lecture 1 - Cell Injury I
- the medical discipline that deals w/ the essential nature, causes, & development of abnormal conditions
- the pathologist strives to understand the mechanisms underlying the changes observed & provide a rational basis for clinical care & therapy
- the bridge between the basic sciences & clinical medicine
deals with structural changes caused by disease processes
deals with biochemical & functional changes caused by disease processes
the reactions of cells & tissues to abnormal stimuli & to inherited defects, these being the main causes of disease
deals with changes in specialized organs & tissues responsible for disorders involving said organs
What are the four aspects of a disease that form the core of pathology?
- 1. its cause
- 2. the mechanisms of its development
- 3. the biochemical & structural changes of cells & organs it causes
- 4. the functional consequences of such changes
- cause of a disease
- most diseases are multifactorial & arise from the effects of various external triggers on a genetically susceptible person
What are the 2 major classes of etiologic factors?
- 1. genetic (intrinsic, eg. inherited mutations & disease-associated gene variants, or polymorphisms)
- 2. acquired (extrinsic, eg. infectious, nutritional, chemical, physical
- the mechanism of how a disease develops
- involves the sequence of events that takes place from the response of the cells or tissues, to the initial stimulus, to the ultimate expression of the disease
With what have the traditional diagnostic methods based on morphological changes been augmented?
- with molecular biologic & immunologic approaches
- eg. a pathologist may use both an old- fashioned glass slide & a ‘gene chip’ to make a diagnosis
Rudolf Virchow Idea:
the fundamental changes in disease can ultimately be traced to alterations in cells
What produces the typical manifestation of disease?
the cellular response to injury - either adjustment or failure to adjust to newly imposed conditions
Homeostasis in the Normal Cell
- the maintenance of constant conditions in the internal environment of cells → is an energy-dependent process
- cell must maintain an organization capable of producing energy; must establish a structural & functional barrier separating its internal milieu from the external environment (plasma membrane)
Singer-Nicolson ‘Iceberg’ Model
- the plasma membrane is made up of a phospholipid bilayer w/ embedded globular proteins that can move laterally but usually do not ‘flip over”
- the MORE metabolically active the membrane, the more PROTEIN is present
- CHO molecules are attached to the external surface
Cell Volume Regulation
- important factor in maintaining homeostasis
- the plasma membrane serves as a selective barrier & plays a critical role in volume regulation
an uneven distribution of diffusible ions created by the charge distribution that results from negatively charged proteins being found inside the cell
Side A [anions] x [cations] = Side B [anions] x [cations]
the product of the ionic activities on one side of a membrane is equal to the product of the ionic activity on the other side
How do cells regulate their volume?
- with the action of ionic pumps in the plasma membrane: an Na+/K+ ATPase exchanger
- extracellular Na+ is 10-12x higher than intracellular
- intracellular K+ is higher than extracellular
- as Na+ enters the cell, there is an isotonic gain of water; the cell will swell & eventually burst if the force is unopposed
How much of the cell’s energy expenditure is directed to the maintenance of the ionic balance between the inside and the outside of the cell?
as much as 25%
- the process by which cells achieve a new but altered steady state & preserve viability and function when subjected to physiological stress or pathologic stimuli
- when the stress is removed, the cells can recover to their original state
- is reversible within a certain limit, however severe or persistent stress can cause irreversible injury → cell death
- develops if:
1. a cell’s adaptive capability is exceeded
2. the stress is inherently harmful
3. the cell is deprived of nutrients
4. is compromised by mutations that affect essential cellular constituents
What are the 2 principal pathways of cell death?
- an increase in cell size & functional capacity, leading to an increase in the size of the organ
- the increase in cell size is caused by synthesis of more structural components of the cell; NO cell division is involved in this process
- describes tissues & organs that have enlarged
- (NOT an altered proliferative state)
Triggers of Cellular Hypertrophy
Activation of mechanical sensors (eg. stretching)
Growth Factors (TGF-β, IGF, fibroblast growth factor)
Vasoactive Agents (angiotensin II, α-androgenic agonists, endothelin)
Hormones (eg. sex hormones affect uterus)
Oxygen Supply (eg. low oxygen tension, angiogenesis)
What happens during Hypertrophy
- Increase in protein production
- *Increase in protein degradation
- Increase in gene expression
- Increase in cell survival
- Gene activation or re-activation
Physiologic Hypertrophy Examples
- bulking up skeletal muscles by lifting weights
- stimulus: increased workload
- result: increase in size of the muscle fibers
- increase in size of the uterus during pregnancy
- caused by estrogenic hormones stimulating smooth muscle cells
ventricular hypertrophy in the heart of a cyclist in response to increased demand on the heart w/ increased production of cellular proteins (is reversible when training stops)
Pathologic Hypertrophy Examples
Ventricular hypertrophy in the heart when the ventricular wall thickens b/c of hypertension or faulty valves (s be irreversible)
What is cardiac failure the result of?
unrelieved chronic stress, which taxes the heart beyond its ability adapt via hypertrophy, leading to functionally significant cell injury
Under what circumstances might a subcellular organelle undergo hypertrophy?
- when a patient is treated w/ drugs such as barbiturates & hypertrophy of the smooth endoplasmic reticulum (sER) in hepatocytes occurs
- the cell upregulates its amount of enzymes (cytochrome P-450 mixed function oxidases) which detoxify the drugs
- this can result in decreased sensitivity to the drug or others metabolized similarly b/c of this adaptation (development of tolerance)
What is an example of an organ that can undergo both hypertrophy & hyperplasia?
the uterus during pregnancy increases in size as a result of enlargement of the smooth muscle cells (hypertrophy) + increases in its number of cells (hyperplasia)
- an increase in the number of cells in a tissue or organ, usually resulting in an increase in organ or tissue mass
- an increase in the number of cells is the result of growth-factor driven proliferation of mature cells or increased production of new cells from tissue stem cells
- can be physiologic or pathologic
- eg. restenosis [following vascular surgery], Grave's disease
What is one way to induce physiologic hyperplasia?
eg. during pregnancy, glandular epithelium of the mammary glands proliferates
eg. during the proliferative phase of the menstrual cycle the number of endometrial & uterine stromal cells increases
a type of hyperplasia that occurs as a result of increased functional demands or due to damage, removal, or a loss of function
eg. living at high altitude leads to an increase in the number of erythrocyte precursors as well as the number of circulating erythrocytes
eg. if a portion of the liver is removed, proliferation of the remaining hepatocytes can return the organ back to its original size
What can cause pathologic hyperplasia?
- an excess of hormonal signals or growth factors
- eg. endometrial hyperplasia is due to an imbalance between estrogen & progesterone
- benign prostatic hyperplasia is due to tissue response to androgens
- growth factors produced by viral genes, as in the case of papillomavirus infection, cause proliferation of affected cells
How is pathologic hyperplasia distinct from cancer?
- while it is an abnormal process, the proliferation is under control & doesn't result from a mutation in a gene that regulates cell division
- if the causative stimulation is removed, hyperplasia will regress
- it is, however, considered a fertile ground in which dysregulation of growth control mechanisms or genetic aberrations arise → leading to cancer
In NON-dividing cells what is increased tissue mass caused by?
- eg. myocardial fibers
- an adaptive process in which there is a decrease in the size of an organ or tissue caused by a decrease in cell size & number (can be physiologic or pathologic)
- is the result of decreased protein synthesis & increased protein degradation (facilitated by the ubiquitin-proteasome pathway or autophagy)
- reduction in cell size and organelles
- diminished metabolic activity
- decreased protein synthesis
- increased protein degradation
- cells reach a new equilibrium
Physiologic Atrophy Example
- the thyroglossal duct (thymus) in adults deteriorates with age
- the uterus decreases in size after parturition (giving birth)
Causes of Atrophy:
- Reduced functional demand (atrophy of disuse)
- Denervation atrophy
- Inadequate blood supply
- Inadequate nutrition
- Interruption of trophic signals (a lack of endocrine stimulation)
- Pressure (eg. from a benign tumor)
Atrophy of Disuse
- eg. muscles in the leg undergo atrophy after immobilization of the limb in a cast
- can usually be reversed by resuming normal activity
- prolonged immobilization may reduce muscle cell numbers due to apoptosis → irreversible condition
- normal skeletal muscle cell function depends on intact nerve supply to the tissue
- damage to nerves deprives muscle cells of stimulation which leads to atrophy
How could inadequate blood supply lead to atrophy?
- ischemia (interference with blood supply) results in chronic reduced oxygen supply to the tissue → atrophy
- eg. an organ (like the brain) of an older individual may undergo atrophy due to vessel atherosclerosis supplying that organ (manifests as senile atrophy w/ a loss of brain mass)
How can inadequate nutrition lead to atrophy?
when muscles are used as a source of energy, causing atrophy of skeletal muscles & wasting (cachexia)
- a reversible change w/ the conversion of one differentiated cell type to another
- is usually an adaptive response to chronic persistent stress in which a tissue assumes the phenotype that provides it with better protection from insult
What does metaplasia result from?
- the reprogramming of stem cells present in the tissue in question, or of undifferentiated mesenchymal cells in the connective tissue
- external signals generated by cytokines, growth factors, & extracellular components in the stem cells’ environment lead to differentiation into the new cell type
- is usually a reversible condition but may predispose cancer/malignant transformation
What is the most common form of metaplasia?
the conversion of glandular/columnar to squamous epithelium
eg. in cigarette smokers where the normal ciliated columnar epithelial cells of the conducting airways are replaced by stratified squamous epithelial cells
- eg. in the endocervix when affected by chronic infection
- while squamous epithelium may protect tissue better, some of the normal functions of the tissue (eg. mucociliary clearance in the respiratory epithelium) will be lost with a change
Where might metaplasia come about in response to Vitamin A deficiency?
squamous metaplasia may be found in the respiratory tract.
- when acidic contents of the stomach chronically bypass the lower esophageal sphincter (one-way valve), the esophageal SSNKE cells undergo a transition to simple columnar epithelium
- associated with the subsequent development of esophageal adenocarcinoma (lethal)
formation of bone in muscle (metaplasia)
What are the two places metaplasia is commonly seen in?
- 1) Lung – in smokers, heat & smoke cause normal cells to be replaced by other, more protective cells
- 2) Cervix: Chronic Inflammatory Pelvic Disease
- • normal columnar is replaced by a stratified squamous epithelium
- • more protective squamous epithelium lacks cilia and can't move mucus along well creating a rich environment for bacterial/viral replication
- the disordered growth and maturation of a tissue's cells
- manifests as variation in cell size & shape, nuclear enlargement, irregularity & hyperchromatism, and disarray in the arrangement of the cells within the epithelium (instead of an orderly appearance of cells in a tissue)
- eg. in the stratified squamous epithelium of the uterine cervix, such as colonic mucosa, Barrett esophagus, or urothelium of the bladder
- IS reversible if the causative influence is removed
- is a preneoplastic lesion: a necessary stage in the multi-step cellular evolution of cancer
- changes in mitotic rate of cells, loss of positional control, & loss in the uniformity of cell shape (pleiotropy)
- • often a precursor to cancer
- • seen in the exocervix where it is often a precursor to CERVICAL CANCER (reason for pap smears)
Lecture 2 - Cell Injury II
- when stress & pathologic stimuli exceed the capacity of the cell to maintain normal homeostasis or adapt
- injury may progress from reversible to irreversible stages, cumulating in cell death
Causes of Cell Injury
- Oxygen Deprivation (hypoxia/ischemia)
- Physical Agents
- Chemical Agents & Drugs
- Infectious Agents
- Immunologic Reactions
- Genetic Derangements
- Nutritional Imbalance
- when oxygen levels decrease below normal in inspired gases (eg. air is low in O2), arterial blood, or tissue (not quite anoxia)
- is system wide
- local anemia due to mechanical obstruction (usually in an artery) of the blood supply
- there is compromised supply of oxygen & metabolic substrates, which can lead to severe & rapid cell injury
- MORE clinically important than hypoxia, eg. arteriosclerosis
Examples of Physical Agents that can cause Cell Injury
- mechanical trauma (MBTA crash)
- extremes of temperature (hot coffee, frostbite)
- sudden changes in atmospheric pressure (‘bends’)
- electric shock
Infectious Agents & Cell Injury
- range from submicroscopic virus & prions to parasites such as tapeworms
- rickettsiae, bacteria, fungi, & higher forms of parasites
- chromosomal anomaly, to a point mutation
- defects can involve deficiency of functional proteins, such as enzyme defect in inborn errors of metabolism, or accumulation of damaged DNA or misfolded proteins
- starvation in war-torn areas, near-starvation in numerous regions of the world, sub-par nutritional intake in many populations, self-induced starvation in anorexia
- obesity due to nutritional excess
What intracellular systems are vulnerable to injurious stimuli?
- cell membrane (essential to maintain homeostasis)
- aerobic respiration (mitochondrial ATP production)
- protein synthesis
- gene maintenance
When do morphologic changes of cell injury become apparent?
- only after critical biochemical systems within the cell have been deranged
- there's a temporal relationship between the development of biochemical & morphologic changes in cell injury
Process of Cell Injury
- is a continuum without sharply defined steps
- 1. a cell starts at normal homeostasis; when subjected to stress it may adapt & enter a new but altered state
- 2. the cell becomes INJURED when its limits of adaptation are exceeded
- 3. if the cell is injured reversibly if when the harmful stimulus is removed it reverts back to normal homeostasis
- 4. if the cell is injured sublethaly it can't return to normal homeostatic balance → it remains alive but at reduced capacity
- 5. if adaptation is IMPOSSIBLE the cell undergoes irreversible injury & dies via necrosis or apoptosis
What is the most common pathway for ATP production?
- oxidative phosphorylation of ADP
- ATP depletion & decreased ATP synthesis are common consequences of reduced supply of oxygen and nutrients, mitochondrial damage, & the actions of some toxins (eg. cyanide)
Why does long-term energy production require intact mitochondria?
for oxidative phosphorylation - the integrity of the mitochondrial membrane is critical to this process
What intracellular events that come about as a result of injury to the cell can lead to mitochondrial damage?
- increased cytosolic calcium
- oxidative stress
- enzyme activation
- oxygen deprivation
- the consequence of such damage is the appearance of mitochondrial permeability transition pore (MPTP), a high-conductance channel in the mitochondrial membrane
What would make the MPTP become permanent?
- persistent injurious stimuli to the cell
- along with it a loss of membrane potential & interference with the proton pump (critical for oxidative phosphorylation)
- irreversible MPTP formation leads to cell death
What does damage to the mitochondrial membrane lead to?
- leakage of cytochrome C into the cell cytoplasm
- normally an integral part of the electron transport chain, leakage of this compound into the cytoplasm means that ATP production is compromised AND it's an apoptotic pathway trigger
What is the relationship between mitochondrial Ca2+ uptake & oxidative phosphorylation?
- mitochondria can accumulate calcium against a gradient in a process energetically coupled to electron transport, however it CANNOT take up calcium AND perform oxidative phosphorylation at the same time
- when presented with Ca2+, mitochondria will take in the ion at the EXPENSE of ATP production
What damaging events may take place if calcium homeostasis is lost?
- calcium-dependent enzymes become activated & lead to membrane (by phospholipases, proteases) and structural proteins & cytoskeleton damage (by proteases)
- ATP depletion (ATPase)
- chromatin fragmentation (by endonucleases)
What is a potentially harmful byproduct of mitochondrial respiration?
- a small amount of partially reduced reactive oxygen is produced when a cell makes energy
- ROSs can damage lipids, proteins, & nucleic acids, however cellular defense mechanisms (eg. enzymes) can scavenge & deactivate free radicals
What causes oxidative stress?
- an imbalance between free radical generating & scavenging systems in a cell
- this condition is associated with chemical/radiation injury, ischemia-reperfusion injury, cellular aging, or microbial killing by phagocytes
What is a classic example of free radical injury to cells?
carbon tetrachloride poisoning (CCl4)
Cellular Defense Mechanisms Against Free Radicals
- Antioxidants A C E
- Metal Binding Proteins (transferrins, ferritin, lactoferrin)
- Enzymes (catalase, superoxide dismutases, glutathione peroxidase)
a paradoxic phenomenon in which a re-perfused tissue sustains further loss of cells
What types of changes occur during reversible cell injury?
temporary loss of volume & energy regulation
General Ion movement during Changes in Volume Regulation
- sodium, calcium, & water enter the cell
- potassium & magnesium leave the cell
- along with the swelling there can be leakage of small molecule from inside the cell due to changes in membrane permeability
What happens when cells switch from oxidative phosphorylation to the glycolytic pathway for energy when they experience a drop in oxygen levels?
- anaerobic glycolysis rapidly depletes glycogen stores & causes an accumulation of lactic acid + inorganic phosphates in the cell
- this reduces intracellular pH → decreased enzyme activity
What happens when protein synthesis is disrupted as a result of reversible cell injury?
- ribosomes detach from the granular endoplasmic reticulum (RER) & polysomes dissociate into monosomes → a reduction in protein synthesis
- cellular swelling due to an influx of water
- such a cell stains lighter due to the dilution of intracellular proteins by water
- small vacuoles containing water can be seen in the cytoplasm using light microscopy
- in cells involved in lipid metabolism, additional accumulation of lipid droplets (fatty change) may occur
- (also called hydropic swelling, vacuolar degeneration, & cloudy swelling)
What is a visual manifestation that may be seen via light microscope when intracellular pH is low as a result of increase anaerobic glycolysis?
a slight clumping of chromatin (may not be obvious)
What can be seen by electron microscopy when the endoplasmic reticulum is dilated by water entering the cell?
ribosomes can bee seen detached from the ER
Mitochondrial changes visible using Electron Microscopy
- in normal cells mitochondria are in the ‘orthodox state’, during which they undergo slow respiration
- in injured cells mitochondria assume the ‘condensed configuration’, or low amplitude swelling
What are some changes on the surface of the cell due to cell injury detectable with electron microscopy?
- blebbing of the plasma membrane
- blunting of microvilli
- loosening of intercellular attachments
What visible nuclear change occurs with cell injury?
is subtle, usually consists of disaggregation of granular & fibrillar elements
Changes occurring during the irreversible phase of cell injury are largely characterized by what?
permanent loss of volume & energy regulation
What is a clinically significant manifestation of permanent membrane damage?
- when large molecules leak out of the cell & appear in the blood
- eg. the presence of cardiac specific creatine kinase isoenzyme, CK-MB, & troponin in the blood is an indication of damaged/dead myocytes caused by infarction
How are endogenous phospholipases activated?
- by increased cytoplasmic calcium levels
- these enzymes cause phospholipid degradation, the products of which accumulate in the cell & have a detergent effect on membranes
What may result from the activation of proteases due to increased in cytoplasmic calcium?
damage to the cytoskeleton, which may separate the cell membrane from the cytoskeleton, making the cell susceptible to stretching & rupture
loss of differential staining
- a phenomenon seen in irreversibly injured cells
- shows up in a section stained with routinely used eosin & hematoxylin, such cells have increased eosinophilia (more pinkish) & reduced basophilia (less blueish)
- the reduced basophilia can come from the disintegration of polyribosomes, detachment of ribosomes from the ER, or degradation of RNA
- denatured proteins + other cytoplasmic components contribute to the increased eosinophilia
Nuclear changes in Irreversibly injured Cells
- karyolysis: chromatin basophilia may fade (due to the effects of DNase)
- pyknotic nucleus: condensed into a small basophilic structure
- karyorrhexis: pyknotic nucleus becomes fragmented into small dark bits
- normal nuclei are basophilic w/ H&E due to the binding properties of the nucleic acids & associated proteins
- dark nuceli = pyknotic
- spotted = karyorrhexis
When does cell death take place?
- when the cell can no longer maintain itself as a metabolic unit
What are two features that consistently characterize irreversible cell injury?
- 1. the inability to reverse mitochondrial dysfunction
- 2. profound disturbances in membrane functions
What constitutes the only unequivocal evidence that a cell is dead?
nuclear changes in the tissue
Mechanisms of Reperfusion Injury
- free radicals may form from parenchymal & endothelial cells or infiltrating leukocytes during reoxygenation
- new Ca2+ available after reperfusion, mitochondria may accumulate Ca2+ (instead of replenishing the ATP supply)
- the influx of inflammatory cells during reperfusion can cause further tissue damage
- IgM antibodies have a propensity to deposit in ischemic tissue; when blood flow is restored, the activation of complement proteins in response to deposited antibodies can cause more cell injury/inflammation
- chemical species that have a single unpaired electron in an outer orbit
- eg. H•, OH•
Reactive Oxygen Species (ROS)
- a type of oxygen-derived free radical that can cause cell injury
- ROS are produced in cells normally during mitochondrial respiration, energy generation, & inflammatory reactions during which leukocytes are recruited and activated
- are degraded & removed by cellular defense systems
- caused by an excess of free radicals, either due to their increased production or ineffective removal
- has been implicated in many pathologic processes such as cell injury, cancer, aging & degenerative diseases such as Alzheimer disease
How are free radicals generated?
- 1. reduction-oxidation reactions
- 2. absorption of radiant energy
- 3. products of inflammatory process
- 4. enzymatic metabolism
- 5. transitional metal reactions (eg. Fenton rxn)
- occur during normal metabolic processes like respiration, where molecular O2 is reduced by transfer of 4 electrons to H2 → 2 H2O molecules
- a small amount of partially reduced intermediates is produced: superoxide anion radical (O2- • , 1 electron), hydrogen peroxide (H2O2, 2 electrons), & hydroxyl ions (•OH, 3 electrons)
Absorption of Radiant Energy Generates:
- free radicals
- such as with UV and X-rays
- ionizing radiation can hydrolyze water into •OH & •H) free radicals
Where in the inflammatory process do free radicals come from?
activated polymorphonuclear leukocytes generate free radicals during a ‘respiratory burst’
Enzymatic metabolism of what can generate free radicals?
- exogenous chemicals or drugs
- the free radicals generated aren't ROS however they have similar effects
- eg. CCl4 can generate •CCl3
- H2O2 + Fe2+ → Fe3+ + •OH + OH–
- the production of oxy- & hydroxy- radicals + ferric iron from the non-enzymatic reaction of ferrous iron w/ hydrogen peroxide
- can induce oxidative stress in blood cells & various tissues
- the oxidative degradation of lipids
- the process in which free radicals "steal" electrons from lipids in cell membranes → cell damage
- it most often affects PUFAs b/c they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess reactive Hs
Radical Reaction Steps in Lipid Peroxidation
- initiation: oxygen-derived free radicals attack double bonds in unsaturated FAs of membrane lipids
- propagation: lipid peroxides are formed (themselves unstable & reactive) & cause an autolytic chain reaction → massive membrane damage
- termination: the reaction is stopped when scavengers (eg. Vitamin E) capture free radicals
How do free radicals affect proteins?
- they can promote their modification, rendering them unusable & subsequently targeted for degradation
- specifically they can promote oxidation of AA side chains, forming protein cross-linkage (eg. disulfide bonds) or oxidation of the protein backbone
- this signals for the degradation of critical enzymes by the multi-catalytic proteasome complex
How do free radicals affect genetic material?
- they can cause SS & DS breaks in the DNA, cross-linking of DNA strands, & formation of adducts
- such issues are implicated in cell aging & the malignant transformation of cells
- also •OH (hydroxyl radicals) interact w/ DNA & inhibit replication → the inability to proliferate
Cellular Defense Mechanisms Against Free Radicals
- 1. Antioxidants
- 2. Metal binding Proteins
- 3. Enzymes (that can act as scavengers)
Vitamin E, A, ascorbic acid (C), & glutathione etc. block the initiation of free radical formation or inactivate free radicals already formed
How can metal binding proteins defend a cell against damage by free radicals?
- the binding of metals to storage & transport proteins keep them from catalyzing free radical formation
- eg. transferrins, ferritin, lactoferrin
What are some enzymes that can act as scavengers & in doing so prevent damage from free radicals?
- 1. Catalase (in peroxisomes): 2H2O2 → O2 + 2H2O
- 2. Superoxide Dismutases (SODs)
- 2•O2- + 2H → H2O2 + O2
- 3. Glutathione Peroxidase
- H2O2 + 2GSH → GSSG (glutathione homodimer) + 2H2O
What is the intracellular ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) a reflection of?
- the oxidative state of a cell
- it's an important indicator of the cell’s ability to detoxify ROS
How does carbon tetrachloride poisoning cause cell damage?
- through the production of free radicals
- CCl4 + e- → •CCl3 + Cl-
- the enzyme cytochrome P450 in hepatocytes converts CCl4 to the highly reactive & toxic free radical CCl3•
- CCl3• causes lipid peroxidation & breakdown of the endoplasmic reticulum membrane autolytically, meaning significant lipid damage can be done which can result in cell death
- a highly toxic, naturally occurring lectin (carbohydrate-binding protein)
- it prevents cells from assembling various amino acids into proteins, inhibiting protein synthesis
Examples of Direct Injury to Plasma Membranes
- phospholipases & the lipid domains (eg. from Clostridium infection)
- mercurial compounds & membrane-bound proteins
- Immune-mediated injury & MAC
- Killer T-cells & perforin
- these result in colloid osmotic lysis
membrane attack complex (MAC)
- one of the effector proteins of the immune system that forms on the surface of pathogenic bacterial cells as a result of the activation of the host's complement system
- it forms transmembrane channels that disrupt the phospholipid bilayer of target cells → to cell lysis & death
Summary: Mechanisms of Cell Injury
- Mitochondrial Damage
- Ca2+ Influx
- Membrane Damage
- Protein Misfolding/DNA Damage
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