3. Cell Injury and Death Flashcards
Relevance of Cell Injury to Disease
• Disease is a manifestation of ____ (initiated by etiologic agents and progresses by pathogenic mechanisms):
– ____ are the result of changes in the ____ of cells/tissues/ organs resulting from injury
– clinical signs and symptoms of disease are the result of changes in ____ of cells/tissues/organs resulting from injury
cellular injury
lesions
structure
function
Causes of Cell Injury
Hypoxia (____ deficiency)
- inadequate oxygenation of blood (e.g. cardiovascular failure; insufficiency)
• loss of oxygen carrying capacity (e.g. ____, CO)
• loss of blood supply (____)
____ agents:
• mechanical trauma, pressure, UV and ionizing radiation, electric shock, extremes of temperature
• Toxins: • Environmental • Drugs • Chemical agents (exogenous, endogenous): –\_\_\_\_ toxicity (e.g. HgCl2, cyanide) –\_\_\_\_ chemicals converted to toxic metabolites(carbon tetrachloride, acetaminophen) –Innocuous
oxygen
anemia
ischemia
physical
direct
inactive
Causes of Cell Injury • Infectious agents • \_\_\_\_ • \_\_\_\_ • Genetic derangement: • malformations •errors of metabolism
- Metabolic and Nutritional imbalance:
- deficiency (protein, caloric, vitamins)
- excess (lipids—____; obesity)
- ____ imbalance, enzyme defects
- diet composition
• Cellular Aging
inflammation
immunity
artherosclerosis
hormone
Causes of cell injury
Most common cause of injury > ____ (anoxia = tissue with no oxygen); there are three mechanisms for loss of oxygen; ____ lethality because it binds to hemoglobin and prevents distribution of oxygen; ____ refers to a decrease in perfusion (decrease of blood flow into tissue) > more common reason is ____ of major arteries (plaque develops and expands into lumen and preventing BF, or forms a thrombosis and forms a clot)
Cigarette smoke = ____; HgCl2 is a component of ____ (direct toxicity)
____ acts as a two-edged sword; both protective and destructive (not detrimental in skin, but in brain, much more of a larger issue)
Errors of metabolism not observed in gross lesions but in ____ abnormalities > ____ > one mutation results into a complex assortment of problems; cellular aging = ____ process
hypoxia
CO
artherosclerosis
environmental toxin
amalgam
inflammation/immunity
functional
down syndrome
physiologic
Cell Injury – basic principles
• Cell injury occurs when
– cells are stressed beyond ability to adapt
– cells are exposed to damaging agents
• Is a result of functional and biochemical alterations in one or more essential cellular components
• Limited number of cellular responses to injury vs wide range of injurious events
• Cellular response to/and consequences of injury influenced by:
– type, ____ and severity of injury
– type, status, ____ and genetic makeup of the cell
duration
adaptability
Cell Injury - basic principles
Oxygen plays a major role:
• ____ (e.g. ischemia)
• ____ production
Limited number of responses to cell injury:
- Cell ____
- –Suppression of protein, RNA and DNA synthesis
-Activation of degradative enzymes and ubiquitin- proteasome system ---Proteolytic digestion of cell constituents ---Cell atrophy ---\_\_\_\_
deprivation
free radical
shut-down
autophagy
Biochemical Mechanisms of Cell Injury
- ____ depletion
- ____ damage
- Intracellular accumulation of ____
- Accumulation of ____
- Defects in ____ permeability/integrity
- Plasma membrane
- Mitochondrial membranes
- Lysosomal membranes - ____ stress
ATP mitochondrial calcium free radicals membrane ER
1. ATP Depletion •Loss results in rapid shutdown of critical homeostatic pathways •Cell \_\_\_\_ •\_\_\_\_ •\_\_\_\_ synthesis •Basic metabolic pathways
•Tissues with greater ____ have an advantage (e.g. liver)
osmolarity
transport
protein
glycolytic capacity
ATP Depletion
Glucose is broken down in two stages > breakdown to ____ (2 mols of ATP net generated) > pyruvate into mitochondria > broken down in aerobic respiration in Krebs cycle > and then ultimately utilized in ox phos (1 mol of glucose > ____ mol of ATP)
Warburg effect > cancer cells uses ____ metabolism to generate ATP (because of lack of innervation)
Hypoxia occurs as a result of ____ > tissue deprived of ____ (the mitochondria); exposure of cells to ____ (ATPases) > either process results in a total loss of ATP > when a cell loses control of ATP synthesis > ____ pumps (normal cell: more Na+ ____ than ____) get shut down resulting in a Ca2+ and Na+ ____, (Na+ bringing water inside and swelling of cell) and ____ efflux (a lot of enzymes requires)
The swelling of the cell is NOT ____; in case of specialized cells (microvilli) > you lose these ____; this is ____ initially > blebs break off, mitochondria swell resulting in juxtaposition of ox phos which can result in ____
Because of low oxygen > cells adapt by ____ > pH drops due to formation of ____ > effect on nucleus resulting in ____ (liver can prolong hypoxic effects more so than the brain)
Loss of ATP > detachment of ribosomes from ____ > decrease protein synthesis
pyruvate
anaerobic
ischemia oxygen toxins Na+ intracell extracell influx potassium
hypertrophy
PM modifications
reversible
ROS
anaerobic metabolism (glycolysis)
lactate
nuclear clumping
RER
2. Increase in intracellular calcium: • Causes: – \_\_\_\_ – Loss of \_\_\_\_ – \_\_\_\_ • Consequences: – Activation of protein kinases, \_\_\_\_ and proteases – Membrane and Nuclear damage, \_\_\_\_ disassembly and further reductions in ATP
Cell maintains ____ levels of free intracellular calcium; most is pumped out of the cell and those that are retained are sequestered
Mitochondria and SER receive signals to release Ca2+ > elevating levels > acts on enzymes (acts as a ____) > phospholipases (breakdown phospholipids > ____) > proteases (disrupt both ____ proteins and membrane proteins) > endonucleases (breakdown ____) > ATPase (____, further contributing to decrease in ATP); direct effect on mitochondria (increasing ____, ETC becoming disrupted)
ischemia ATP toxins phospholipases cytoskeletal
low
coenzymes membrane damage cytoskeletal DNA endogenous permeability
3. Mitochondrial damage: • Consequences: – Decreased \_\_\_\_ – Increased \_\_\_\_ – \_\_\_\_ release – In some instances, release of \_\_\_\_ factors
Leakage of ____ as a result of increased mito membrane permeability
ATP ROS Ca proapoptotic cytochrome c
- Accumulation of Free Radicals
• Free radicals are highly active atoms or molecules that carry an ____ electron
• Examples of oxygen free radicals are toxic intermediates formed by incomplete reduction of oxygen:
• ____ anion (O2-•)
• ____ (H2O2)
• ____ anion (OH•)
- Formation may be initiated by:
- ____ energy
- enzymatic metabolism of drugs and chemicals
- ____ reaction
- Inflammation (PMN and macrophages)
- ____ aging
- normal metabolic processes
• ____ produced by inflammatory cells
When energy transfers do not involved ox metabolism > oxygen free radicals are generated; O2 and OH most ____, H2O2 broken down ____ by cell
____ injury > free radicals
Fenton reaction is in presence of ____ metals (iron) that takes H2O2 and turns into ____ anion
Normal metabolism > free radicals are always around; most cells have generated a way to protect themselves; only when in high amounts are they detrimental
unpaired
superoxide
hydrogen peroxide
hydroxyl anion
radiant
fenton
cellular
reperfusion
heavy
OH
Free Radical Injury: oxidative stress
•lipid peroxidation–> attack ____ membrane fatty acids leading to membrane damage (e.g. change in permeability plasma membranes, mitochondrial and lysosomal membranes)
- protein damage –> attacks ____ (causes ____ and abnormal folding (e.g. damage to enzymes)
- DNA strand breaks: leads to ____, breaks and/or impairs protein synthesis
- deplete mitochondria of ____–>liberation of Ca++
- Associated with: chemical and radiation injury, cellular aging, inflammation-induced injury, ischemia-reperfusion injury
Change in permeability of PM > ____ to the cell
Proteins modified by free radicals > attacking thiol groups > abnormal folding results in changed ____ > protein is no longer functional or structurally functional
Mutation in functional gene is carried on upon ____
unsaturated (double bonds) thiol groups cross-linking mutations NADPH secondary, tertiary, quaternary generations
Removal/scavenging of free radicals
• SOD (in ____) converts ____ to ____
• Glutathione peroxidase (in
____ and____)
converts ____ to ____ and ____ to water
- Catalase (in ____) converts ____ to ____ and ____
- Antioxidants (e.g. ____)
Antioxidants > ____ to free radicals and shut them down (glutal thiol can also conduct in a similar mechanism)
mitochondria
O2-
H2O2
mitochondria cytoplasm OH H2O2 H2O2
peroxisomes
H2O2
H2O
O2
Vit A and C
combine
Lipofuscin
• represents cell membrane lipids that have undergone ____
• ____ pigment
• Increases with ____ in cells of heart and liver
Present in cells in small ____ pigments
peroxidation
“wear and tear”
age
brown
