Mechanisms Of Cell Injury Flashcards
Describe cell injury.
-disruption of cell homeostasis or steady state
-injury from outside/inside cell
-affects 1 or more imp cell structure
-resp of cell to injury:
>adaptation
>degen
>death of cell
-reversible -> healing
-irreversible -> degen or death
Describe the morphology of cell injury.
Depends on:
-what caused the injury
-extent of injury
-duration of injury
-cell type affected
Describe the causes of cell injury.
MOST COMMON:
>oxygen deficiency
>infectious agents common/imp
>immunological dysfunction
-workload imbalance: atrophy, hyperplasia, hypertrophy, metaplasia
-physical agents: heat, cold, crush, friction, UV rad, electrocution
-nutritional imbalance: cal deficiency/excess, vit/mineral deficiency/excess
-genetic derangement: esp selective breeding
-toxins
-aging
Describe oxygen deficiency.
- Hypoxia = partial reduction in O2 delivery to a tissue
- Anoxia = no O2 delivery to a tissue
Describe what causes hypoxia/anoxia.
- Inadequate oxygenation of blood
-heart failure
-respiratory failure - Reduced transport of O2 in blood
-anemia
-CO toxicosis - Reduction in blood supply = ischemia
-thrombosis
-ex: feline aortic thromboembolism ‘saddle thrombus’ (secondary to hypertrophy cardiomyopathy) causes anoxic damage to hind limbs - Blockage of cell respiratory enzymes
-cyanide toxicosis
Describe infectious agents.
- Viruses
-obligate intracellular parasites -> use host cell enzyme system
-cell survival depends on method viruses leave the cell - Bacteria
-toxins
-uncontrolled replication - Fungal (mycosis)
-progressive, chronic inflammatory disease - Protozoan
-replicate in specific host cells -> cell destruction - Metazoan parasites (nematode/cestodes)
-inflammation, tissue distortion, utilization of host nutrients
Describe immune dysfunction.
- IS fails to respond
-congenital defects: severe combined immunodeficiency (SCIDS, Arabian foals) -> antigen receptors (lymphocytes)
-acquired defects (AIDS/HIV)
>can be transient
—results from damage to lymphoid tissue
—viral infections, chemicals, drugs - IS over respond or aberrant reaction
-autoimmune disease
-hypersensitivity reaction
>anaphylaxis, FAD, feline asthma
Describe how workload imbalance can lead to cell adaptation.
- Compensation
-inc workload = hypertrophy, hyperplasia
-dec workload = atrophy, oncotic - Cant compensate
-degen & poss death
Describe the 6 mechanisms of cell injury.
Describe depletion of ATP.
made thru 2 primary metabolic pathways:
1. Aerobic: Krebs cycle
Glu + oxygen -> CO2 + H2O + energy (2900 kJ/mol)
2. Anaerobic: glycolysis
Glu + lactic acid + energy (120 kJ/mol)
both require glu
-ATP needed for almost all synthetic & degradative processes within the cell
-culminates irreversible mitochondrial & lysosomal membrane damage -> cell necrosis
Describe what happens when depletion of ATP is 5%-10%.
- Na/K ATPase pump fail
-cell swell
-ER swell
-PM damage - Altered cell metabolism
-anaerobic glycolysis
>deplete glycogen stores
>inc lactic acid -> dec pH -> loss of enzyme function - Ribosome detachment
-dec protein syn
Describe mitochondrial injury.
- Formation of mitochondrial permeability transition pore (MPTP)
-high conductance channel in mitochondrial membrane
-opened = loss of membrane potential
>failure of oxidative phosphorylation
>progressive depletion of ATP
>cell necrosis - Inc prod of reactive oxygen species (ROS)
- Activation of apoptotic pathways
-proteins activate apoptosis pathway in mitochondria
-leakage of apoptosis activating proteins into cytosol -> cell death
Describe loss of Ca homeostasis - accumulation of Ca2+ sources (3).
- Extrinsic (cell damage)
- Intrinsic: SER & mitochondria
*sets off cascade of events
Describe the accumulation of Ca cascade of intracellular events.
- Opening of MPTP = dec ATP
- Enzyme activation
-phospholipases: membrane damage
-proteases: membrane & cytoskeleton proteins
-endonucleases: DNA & chromatin fragmentation
-ATPases: break down ATP, accelerate ATP depletion
Describe the accumulation of Ca 3 major forms of damage.
- Membrane damage
- Nuclear damage
- ATP depletion
Describe reactive oxygen species (ROS).
-from oxygen
-made during cell respiration by mitochondria
-molecules/atoms w unpaired elections = reactive free radical
-cell quenching/scavenging system neutralize normally
-excess ROS or dec scavenging capacity = oxidative stress -> damage lipid, protein, DNA
Describe the normal metabolic processes of ROS.
-reduction oxygenation reactions
(O2 + 2H2 -> 2 H2O)
-transfer of 4 e-
-sm amt of partially reduced intermediated made
1. Superoxide anion (O2-) 1e-
2. Hydrogen peroxide (H2O2) 2e-
3. Hydroxyl ions (-OH) 1e-
Describe the pathological sources of ROS.
- Inflam
-rapid burst of ROS made by activated WBC (neutrophil) -> gen superoxide anion (O2-) - Transition metals (iron, copper)
-donate/accept free e-
-catalyze free radical formation - Nitric oxide (NO)
-imp chemical mediator
-gen by endothelial cells, macrophages, neurons
-act as free radical
-converted into peroxynitrite anion ONOO-, NO2, NO3 - Absorption of radiant energy
-H2O + ionizing radiation -> -OH + H - Oxidative stress
-cell injury
-cancer
-aging
-degen disease
Describe neutralization of ROS/removal of free radicals.
- Spontaneous decay
-(O2- + H2O -> O2 + H2O2) - Enzymes
-catalase, superoxide dismutase, glutathione peroxidase
>break down H2O2 & O2
>near sites where oxidants formed - Storage & transport proteins
-transferrin, ferritin, ceruloplasmin
-bind reactive metals like Fe & Cu - Antioxidants (VitE & A, glutathione)
-block initiation
-inactivate (scavenge)
Describe the pathological effects of ROS.
- Lipid peroxidation in membranes -> membrane damage
-formation of peroxides -> autocatalytic reaction (propagation)
>dec phospholipid syn
>inc phospholipid breakdown
>cytoskeletal abnormalities
-activation of proteases -> damaged cytoskeleton
-cell stretch & rupture - Oxidative modification of proteins -> damage active sites, change conformation, enhance degradation
-gen by monamine oxidase (MOA) in outer mitochondrial membrane
-PM damage (loss of osmotic balance)
-injury to lysosomal membrane (leak enzyme into cytoplasm & enzymatic digestion) - Lesions in DNA -> cell aging, malignant transformation, mutation
-MOA
Describe membrane damage mechanisms.
- ROS
- Dec phospholipid syn: secondary to defective mitochondrial function/hypoxia
-dec prod of ATP -> dec phospholipid syn
-affect all cell membrane - Inc phospholipid breakdown
-activate Ca dependent phospholipases
-accumulate lipid breakdown products
>detergent effect on membrane
>insert into membranes
—changes in permeability & electrophysiologic alterations
Describe the cytoskeletal abnormalities of membrane damage.
-Inc cytosolic Ca -> activate proteases -> damage cytoskeleton
-in presence of swelling = PM can detach from cytoskeleton -> sus to stretching & rupture
Describe the summary of membrane damage.
-dec O2 & inc cytosolic Ca in ischemia or ROS cause membrane damage
Describe the consequences of membrane damage.
- Mitochondrial membrane damage
-open MPTP -> leak pro apoptotic proteins
-dec ATP - PM damage
-loss of osmotic balance -> influx of fluids & ions
-loss of cell contents & metabolites - Injury to lysosomal membranes
-leak enzymes into cytoplasm: RNases, DNases, proteases, phosphatases, glucosidases
-enzymatic digestion of RNA, DNA, proteins
Describe the clin path of membrane damage.
-chem panels used to determine hepatocellular injury
-alanine aminotransferase (ALT)
>located in cytoplasm of hepatocytes
>converts alanine -> pyruvate
>pyruvate used for gluconeogenesis or Krebs cycle
-when hepatocytes have cell injury ALT is released
>cell necrosis
>membrane blebs w ALT
Describe protein damage.
-misfolded proteins
>mutation
>free radical damage
-repair mech overwhelmed -> protein in ER -> ER stress -> apoptosis
Describe DNA damage: repair, apoptosis, senescence, cancer.
-radiation, cytotoxic anticancer drugs, hypoxia
>direct damage
>free radical damage
-repair mech overwhelmed -> initiate apoptosis
