Lecture 1 Flashcards
Causes of cell stress and injury
physical injury; trauma, heat, cold, radiation, electricity, and oxygen deprivation.
chemical injury; ph extremes, free radicals, low or high oxygen concentration, poisons, drugs
biological causes; factors arising from micro organisms, damaging factors released during immune responses, nutritional imbalances, lack of growth factors.
immunological injury; autoimmune disorders
genetic derangements range from severe congenital malformations to subtle variations in the genetic makeup that influence the susceptibility of cells to injury.
nutritional imbalances range from severe malnutrition in third world countries or anorexia nervosa to excess intake of lipids and cholesterol predisposing to atherosclerosis
Effects of reduced energy production on individual cells
reduces energy available for enzymes to repair damaged DNA and proteins.
reduces energy available for ATP-driven membrane pumps. these pumps control the ionic and osmotic homeostasis of the cell and its organelles. reduced activity of plasma membrane sodium pumps leads to an accumulation of na and water inside cell ad organelle swelling. reduced plasma membrane calcium pumps leads to influx of ca into the cytosol, which damages numerous cellular components by inappropriately activating destructive ca dependent enzymes.
depleted ATP reduces the energy available for protein synthesis and causes detachment of ribosomes from the rough ER.
Effects of damage to cell membranes on individual cells
May occur directly (due to free radicals), following hypoxia, due to membrane targeting bacterial toxins (clostridium perfringens) or following failure of the plasma membrane ca pump.
- loss of cellular contents, loss of osmotic balance and influx of fluids and ions, as well as loss of proteins, enzymes, co enzymes
- transmembrane pumps can be injured directly or their function can be reduced due to available ATP
- injury to lysosomal membranes results in leakage of their enzymes into cytoplasm and digestion of cellular components-autolysis
- decrease in membrane phospholipids. due to activation during cell injury of phospholipase that degrade them and reduced synthesis due to lack of ATP
- mitochondrial membrane damage results in formation of nonselective high conductance channels in the inner mitochondrial membrane known as mitochondrial permeability transition, removes transmembrane potential required for oxidative phosphorylation. allows leakage of cytochrome C into cytosol, can prime apoptosis and hinders oxidative phosphorylation and energy production.
Effects of cytosolic calcium concentration on individual cells
activates destructive calcium dependent enzymes such as
- ATPases (hastening ATP depletion)
- phospholipase (cause damage to lipid components of membranes)
- proteases (breakdown both membrane and cytoskeletal proteins
- endonuclease (responsible for DNA and chromatin fragmentation)
Effects of damage due to free radicals
occurs as secondary form of injury in cells exposed to various injurious agents.
free radicals are reactive molecules with a single unpaired electron in an outer orbit (O2-, H2O2,OH-)
they can release energy through reactions with adjacent molecules. accumulation of free radicals is known as oxidative stress
they are generated by ionising irradiation (targets water to generate OH-), enzymatic metabolism of chemicals and drugs and oxygen toxicity.
cause damage by attacking double bonds in unsaturated fatty acids in membranes, oxidising a/a residue side chains in proteins, and reacting with thymine in nuclear and mitochondrial DNA
cells have defines systems to protect against free radicals. vitamin E and A in membranes (antioxidants) and enzymes such as catalase, superoxide dismutases and glutathione peroxides.
Effects of damage to proteins on individual cells
may be damaged directly (eg. free radicals)
Also protein synthesis is reduced as a consequence of reduced ATP availability. proteins may also be damaged by glycation (addition of sugar residues) eg. in diabetes, neurodegenerative disorders and cataracts.
Effects of damage to nuclear or mitochondrial DNA on individual cells
ionising radiation (eg, x rays and gamma rays) may cause DNA strands to break
UV radiation causes structural changes in DNA bases that may eventually lead to cell death
chemical agents and free radicals
genetic causes- mutations in the ATM gene reduce DNA repair after damage and predispose to cancer
nutritional deficiencies of Vit. B12 or folate affect DNA synthesis
DNA is continually damaged by the agents described above, cells have evolved DNA repair enzymes to repair this damage as it occurs
Most types of cell stress and injury are accompanied by activation of…
Heat shock factors.
transcription factors that specifically induce the expression of heat shock proteins, these are molecular chaperones which assist in the repair of damaged proteins in the cell or arrange degradation of the cell.
stress kinases.
eg. p38 MAP kinase and Jun N-terminal kinase pathways. initiate signalling cascades that co ordinate a cells response to injury
specific types of damage accompany the activation of specific signalling proteins. for example…
p53.
senses DNA damage and initiates either a halt to cell division to allow repair or cell death by apoptosis
BMF.
involved in the response to damage to the actin cytoskeleton
Bim.
involved in the response to microtubule damage
Bad.
involved in cell stress due to inadequate stimulation by growth factor
Adaptive responses to mild injurious agents such as chronic irritant
hypertrophy and hyperplasia.
cells respond to increased functional demand by hyperplasia (increased number) or hypertrophy (increased size). in hyperplasia may result from division of stem cells that reside locally in the tissue or the division of stem cells that emigrate into the adapting tissue from the bone marrow.
Atrophy
reduced functional demand, reduced supply of nutrients and growth factors by cell shrinkage. involves proteolytic systems including lysosomes (contents digested known as autophagy)
Metaplasia
cells respond to continuous mild damage by reversibly changing from one adult cell type to another. results from reprogramming of stem cells that reside in normal tissues. these reprogrammed stem cells then differentiate along a new pathway.
In what way the increase in cell number that occurs during tumour growth is different from hyperplasia
hyperplasia is in response to many stimuli in growth factors. tumours have an unregulated division due to up regulation of genetic factors that are unresponsive to normal regulatory proteins.
Necrosis (oncosis) pattern of cell death
passive form of cell death in which cells are killed.
often affects large numbers of cells in a tissue.
does not require energy.
often accompanied by lysosomal rupture and leakage leading to autolysis.
cytosolic contents also leak across damaged plasma membrane into extracell. space. leakage induces an inflam response.
uncontrolled messy process.
cytoplasm of necrotic cells is featureless due to denaturation and digestion of proteins. nuclei show fragmentation of chromatin.
within days debris is removed by phagocytosis.
if it is not promptly removed can causes dystrophic calcification
pyknosis, karyorrhexis, and karyolysis
pyknosis
chromatin shrinks into a dense mass at the margin of the nucleus.
karyorrhexis
nuclei show fragmentation of nuclei
karyolysis
fading of chromatin
Apoptosis pattern of cell death
controlled suicide of a cell
although the cell is irreversibly damaged, it still has the time and the energy to execute suicide programme
due to requirement of energy first step is destroying cellular machinery that uses a lot of energy such as DNA repair enzymes
common after DNA damage, mild hypoxia or damaged proteins
plays a role in eliminating unwanted or wrongly placed cells in embryogenesis, neoplastic cells and cells infected with virus
chromatin is cleaved and condenses and membrane bound blebs contain cytosolic contents and organelles break off the cell and are phagocytes by neighbouring cells .
inflammation is not initiated because cytosolic contents don’t leak
capsases activate one another which digest cellular proteins.
The outcome and clinical manifestations of inflammation depend on
the nature, intensity, and duration of the injurious agent and the tissue affected.
