Lecture 27 Flashcards
Mechanisms of Cell Injury and Adaptations of Cell Growth
1
Q
principle intracellular targets of injurious stimuli
A
- mitochondria
- cell membranes
- machinery of protein synthesis and secretion
- DNA
pg 669
2
Q
cellular mechanisms of injury
A
- hypoxia/ischemia, radiation -> mitochondria -> decreased ATP, decreased energy-dependent functions OR increased ROS, damage to lipids, proteins, NAs -> cell injury -> NECROSIS
- ROS -> cellular membranes -> damage to lysosomal membranes, leakage of enzymes OR damage to plasma membrane, impaired transport functions, leakage of cellular contents -> NECROSIS
- radiation, mutations -> nucleus -> DNA damage, cell cycle arrest or activation of caspases -> APOPTOSIS
pg 670
3
Q
mitochondria as intracellular targets of injurious stimuli
A
- increased cytosolic calcium ions
- generation of reactive oxygen species (ROS)
- oxygen deprivation
pg 671
4
Q
three major consequences of mitochondrial damage
A
- ATP depletion (associated with both hypoxic and chemical (toxic) injury)
- reduction in activity of plasma membrane energy-dependent sodium pumps
- alteration of cellular energy metabolism
pg 671
5
Q
role of mitchondria in cell injury and death
A
- ATP required for all synthetic and degradative processes within the cell -> membrane transport, protein synthesis, lipogenesis, and the deacylation-reacylation reactions necessary for phospholipid turnover
- depletion of ATP to 5%-10% of normal levels has widespread effects on critical cellular systems
- ATP generated through: oxidative phosphorylation (MOST) and glycolysis
pg 672
6
Q
reversible cell damage early responses
A
includes injury to one of more vital cell systems
- mitochondria -> leading to inability to produce energy in the form of ATP
- cell membranes -> causing loss of fluid and ion homeostasis and accumulation of free radicals
- first ultrastructural evidence of sublethal cell damage is swelling of membrane-bound organelles (ER and mitochondria)
pg 674
7
Q
reduced activity of plasma membrane energy-dependent sodium pumps
A
- causes sodium ions to enter and accumulate inside cells
- intracellular potassium ion concentration falls
- cell swelling and ER dilation occurs due to osmotically-driven water accumulation
pg 675
8
Q
cellular energy metabolism is altered by mitochondrial injury
A
- supply of oxygen to cells is decreased as ischemia develops and oxidative phosphorylation stops
- adenosine monophosphate levels increase (AMP)
- conditions stimulate the use of glycogen to generate ATP and rapidly deplete glycogen levels
- anaerobic conditions increase as glycogen metabolism increases lactic acid levels and inorganic phosphates
- intracellular pH decreases and causes decreased activity of many cytosolic enzymes
pg 675
9
Q
machinery of protein synthesis and secretion is disrupted
A
- prolonged or worsening depletion of ATP leads to structural disruption of the protein synthetic apparatus occurs
- results in detachment of ribosomes from the rough ER and dissocation of polysomes
- consequent reduction in protein synthesis
- injurious effects caused by increased protein misfolding
pg 676
10
Q
irreversible damage to mitochondrial and lysosomal membranes -> cell undergoes necrosis
A
- incomplete oxidative phosphorylation also leads to formation of ROS, which have many deleterious effects
- leakage of mitochondrial proteins due to channel formation by pro-apoptotic BAX and BAK is the initital step in apoptosis by the intrinisic pathway
- this action of BAX and BAK is specific to mitochondrial membranes only and leads to damage of other organelles indirectly
pg 676
11
Q
mechanisms of membrane damage in cell injury
A
- decreased oxygen
- increased cytosolic calcium ions
- reactive oxygen species, often produced on reperfusion of ischemic tissues
pg 677
12
Q
cytoskeletal abnormalities
A
- cytoskeletal filaments anchor the plasma membrane to the cell interior
- proteases activated by cytosolic calcium may damage these tethers
- cell swelling, particularly in myocardial cells, may lead to detachment of the cell membrane from the cytoskeleton causing the cell to be susceptible to stretching and rupture
pg 677
13
Q
membrane damage
A
- early loss of selective membrane permeability, leading ultimately to overt membrane damage is a consistent feature of most forms of cell injury (except apoptosis)
- membrane damage may affect the integrity and functions of all cellular membranes
- in ischemic cells, membrane defects may be the result of ATP depletion and calcium-mediated activation of phospholipases
- plasma membrane can also be damaged directly by bacterial toxins, viral proteins, lytic complement components, and a variety of physical and chemical agents
- mitochondrial membranes are damaged by the opening of a mitochondrial permeability transition pore that leads to decreased ATP generation and release of proteins that trigger apoptotic death
pg 678
14
Q
plasma membrane damage
A
- results in loss of osmotic balance, influx of fluids and ions, and loss of cellular contents
- leakage of metabolites, such as glycolytic intermediates, that are vital for replacing lost ATP
pg 679
15
Q
injury to lysosomal membranes
A
- results in leakage of lysosomal enzymes into the cytoplasm
- activation of acid hydrolases, which degrade RNA, DNA, proteins, phosphoproteins, and glycogen (work together to cause membrane damage)
- drives the cell into necrosis
pg 679
16
Q
damage to DNA
A
- damage to nuclear DNA activates sensors that trigger p53-dependent pathways (p53 important for tumor suppression)
- DNA damage may be caused by: exposure to radiation, chemotherapeutic drugs, ROS, or may occur spontaneously as a part of aging
pg 680
17
Q
DNA damage activates p53
A
arrests cells in the G1 phase of the cell cycle and activates DNA repair mechanisms
- if these mechanisms fail to correct the DNA damage, p53 triggers apoptosis by the mitochondrial pathway
- the cell dies rather than survive with abnormal DNA that has the potential to induce malignant transformation
- mutations in p53 that interfere with its ability to arrest cell cycling or to induce apoptosis are associated with numerous cancers
pg 680
18
Q
pathologic effects of free radicals
A
affects of ROS and other free radicals are wide-ranging
- lipid peroxidation in membranes
- oxidative modifications of proteins
- lesions in DNA
pg 681
19
Q
lipid peroxidation in membranes
A
LOW HANGING FRUIT: in the presence of molecular oxygen (O2), free radicals may cause peroxidation of lipids within plasma and organellar membranes
- oxidative damage is initiated when the double bonds in UFA of membrane lipids are attacked by O2 derived free radicals
- lipid-free radical interactions yield peroxides, which are unstable and reactive
- an autocatalytic chain reaction follows (called propagation) that can result in extensive membrane damage
pg 682
20
Q
oxidative modification of proteins
A
- free radicals promote: oxidation of amino acid side chains, formation of covalent protein-protein crosslinks (disulfide bonds), and oxidation of the protein backbone
- oxidative modifications may also damage the active sites of enzymes, disrupt the conformation of structural proteins, and enhance proteasomal degradation of unfolded or misfolded proteins -> leads to severe disorder in the cell
pg 683
21
Q
lesions in DNA
A
- free radicals are capable of causing single and double strand breaks in DNA, crosslinking DNA strands, and forming adducts
- oxidative DNA damage has been implicated in cell aging and in malignant transformation of cells
pg 683
22
Q
pathologic effects of calcium homeostasis disturbance
A
ischemia and certain toxins cause an excessive increase in cytosolic Ca2+ (initially bc of release from intracellular stores and later due to increased influx across the plasma membrane)
- accumulation of Ca2+ in mitchondria results in opening of the mitochondrial permeability transition pore and failure of ATP generation
- increased cytosolic Ca2+ abnormally activates: phospholipases, proteases, endonucleases, and ATPases
- phospholipases: cause membrane damage
- proteases: break down both membrane and cytoskeletal proteins
- endonucleases are responsible for DNA and chromatin fragmentation
- ATPases hasten ATP depletion
pg 684
23
Q
ER stress
A
The accumulation of misfolded proteins in the ER can stress adaptive mechanisms and trigger apoptosis. If unfolded or misfolded proteins accumulate in the ER, they trigger a number of alterations that are collectively called the unfolded protein response.
pg 685-686
24
Q
Unfolded Protein Response
A
- activates signaling pathways that increase the production of chaperones
- enhances proteasomal degradation of abnormal proteins
- slows protein translation, thus reducing the load of misfolded proteins in the cell
- if this cytoprotective response is unable to cope with the accumulation of misfolded proteins, the cell activates caspases and induces apoptosis
- protein misfolding is thought to be the causative cellular abnormality in several neurodegenerative diseases
pg 685-686
25
diseases caused by misfolding of proteins
* cystic fibrosis: loss of CFTR leads to defects in chloride transport
* familial hypercholesterolemia: loss of LDL receptor leads to hypercholesterolemia
* Tay-Sachs disease: lack of the lysosomal enzyme leads to storage of GM2 gangliosides in neurons
* α1-antitrypsin deficiency: storage of nonfunctional protein in hepatocytes causes apoptosis, absence of enzymatic activity in lungs causes destruction of elastic tissue giving rise to emphysema
* Creutzfeldt-Jacob disease: abnormal folding of prions (PrPsc) causes neuronal cell death
* Alzheimer disease: abnormal folding of αβ peptides causes aggregation within neurons and apoptosis
## Footnote
pg 687
26
**_hypoxia and ischemia_**
**ULTRA LOW HANGING FRUIT: ischemia is the most common cause of cell injury in clinical medicine and results from hypoxia induced by reduced blood flow (often due to a mechanical arterial obstruction)**
* ischemia can also occur due to reduced venous drainage
* ischemia compromises the delivery of substrates for glycolysis (blood flow has stopped)
* *ischemia causes more rapid and severe cell injury and tissue injury than hypoxia*
* hypoxia maintains blood flow and energy production by anaerobic glycolysis can continue
* in ischemic tissues, aerobic metabolism ceases and anaerobic energy generation also fails after glycolytic substrates are exhausted or _glycolysis is inhibited by the accumulation of metabolites_ which otherwise would be washed out by flowing blood
## Footnote
pg 688
27
cellular adaptation
* cellular injury is reversible up to a certain point
* if severe enough, cell injury can lead to cell death
## Footnote
pg 689
28
mechanisms of ischemic cell injury
* the sequence of events following hypoxia or ischemia reflects many of the biochemical alterations in cell injury
* as intracellular oxygen tension falls, oxidative phosphorylation fails and ATP generation decreases
* loss of ATP results initially in reversible cell injury and later in cell death by necrosis
* decrease in oxidative phosphorylation -> decreased ATP -> eventually: ER swelling, cellular swelling, loss of microvilli, blebs, clumping of nuclear chromatin, decreased protein synthesis
## Footnote
pg 690
29
ischemia-reperfusion injury
* restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured but can also paradoxically exacerbate (increase) cell injury and cause cell death
* as a consequence, reperfused tissues may sustain loss of viable cells in addition to those that are irreversibly damaged by the ischemia
* this process of ischemia-reperfusion injury is clinically important because it contributes to tissue damage during myocardial and cerebral infarction following therapies that restore blood flow
## Footnote
pg 691
30
chemical (toxic) injury
* chemical injury remains a frequent problem in clinical medicine and is a major limitation to drug therapy
* many drugs are metabolized in the liver, making the liver a major target of drug toxicity
* toxic liver injury is often the reason for terminating the therapeutic use or development of a drug
## Footnote
pg 693
31
direct toxicity
Some chemicals injure cells directly by combining with critical molecular components
Examples:
* in *mercuric chloride poisioning*, mercury binds to the sulfhydryl groups of cell membrane proteins, causing *increased membrane permeability and inhibition of ion transport*
* cyanide poisions mitochondrial cytochrome oxidase and thus inhibits oxidative phosphorylation
* many antineoplastic chemotherapeutic agents and antibiotics also induce cell damage by direct cytotoxic effects
## Footnote
pg 693
32
conversion to toxic metabolites
* 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*
* modification is usually accomplished by the *cytochrome P-450 mixed function oxidases* in the smooth ER of the liver and other organs
* *membrane damage and cell injury* occur mainly by *formation of free radicals and subsequent lipid peroxidation*
examples:
* carbon tetra-chloride (CCl4) is converted by cytochrome p-450 into a highly reactive free radical (carbon tri-chloride radical) which causes lipid peroxidation and extensive cellular structural damage
* acetaminophen is convered to a toxic product in the liver, leading to cell injury
## Footnote
pg 694
33
hypertrophy
increase in size of cells resulting in an increase in size of the organ
## Footnote
pg 695
34
pathologic hypertrophy
* most common stimulus for hypertrophy of skeletal and cardiac muscle is increased workload
* muscle cells respond by synthesizing MORE PROTEIN and increasing the number of microfilaments per cell; this increases the amount of force each cell and generate
* classic example: pathologic hypertrophy of the heart in response to pressure overload usually results from either hypertension or valvular disease
## Footnote
pg 696
35
physiologic hypertrophy
increase in amount of protein in cells
Classic Example 1:
* massive physiologic growth of the uterus during pregnancy due to estrogenic hormonal stimulation, leading to hypertrophy of smooth muscle fibers
Classic Example 2:
* bulging muscles of bodybuilders engaged in "pumping iron" results from enlargment of individual skeletal muscle fibers in response to increased demand
## Footnote
pg 696
36
hyperplasia
An increase in the number of cells within an organ or tissue in response to a stimulus; can happen at the same time as hypertrophy
* only takes place in tissues that contain cells capable of dividing (increase in cell number)
* physiologic hyperplasia: due to action of hormones or growth factors, when there is need for... increased functional capacity (female breast development at puberty and pregnancy) OR compensatory increase after damage or resection (liver regeneration after a liver lobe transplant)
* most forms of pathologic hyperplasia are caused by excessive or inappropriate actions of hormones or growth factors
## Footnote
pg 698-700
37
forms of pathologic hyperplasia
* endometrial hyperplasia: due to relative or absolute increases in the amount of estrogen
* benign prostatic hyperplasia: induced by abnormal response to androgens
* certain viral infections: papillomavirus can cause skin warts and mucosal lesions composed of masses of hyperplastic epithelium
* hyperplasia can regress if the hormonal stimulation is eliminated
## Footnote
pg 700
38
pathologic hyperplasia
if growth control mechanisms become deregulated (genetic abberations), hyperplasia can progress to cancerous growth:
* endometrial carcinoma
* prostatic carcinoma
* squamous cell carcinoma (papilloma virus)
## Footnote
pg 701
39
metaplasia
* reversible change in which one differentiated cell type is replaced by another cell type
* most commonly columnar to squamous epithelium (in response to habitual smoking)
## Footnote
pg 702
40
atrophy
reduction in size of an organ or tissue due to a decrease in cell size and number; two types of atrophy
* physiologic: common during normal embryonic development or decrease in size of uterus after giving birth
* pathologic: local or generalized
* causes: decreased workload (atrophy of disuse), loss of innervation, diminished blood supply, inadequate nutrition, loss of endocrine stimulation, pressure
## Footnote
pg 703
41
mechanisms of atrophy
* decreased protein synthesis -> decreased metabolic activity
* increased protein degradation (by ubiquitin-proteasome pathway)
* nutrient deficiency
* ubiquitin ligases attach ubiquitin to cellular proteins, which targets the proteins for degradation in proteasomes
* often accompanied by increased autophagy
## Footnote
pg 704
42
causes of cell injury
* oxygen deprivaiton (hypoxia)
* physical agents
* chemical agents & drugs
* infectious agents
* immunological reactions
* genetic derangements
* nutritional imbalances
## Footnote
pg 705
43
reversible features of cell injury
* cellular swelling: cells become unable to maintain ionic and fluid homeostasis due to failure of energy-dependent ion pumps in the plasma membrane
* fatty change: due to hypoxic injury, various forms of toxic or metabolic injury; lipid vacuoles appear in the cytoplasm
* plasma membrane alterations: blebbing, blunting, loss of microvilli
* mitochondrial changes: swelling, appearance of small amorphous densities
* dilation of the ER: detachment of polysomes, intracytoplasmic myelin
* nuclear alterations: disaggregation of granular and fibrillar elements
## Footnote
pg 706
