203 L6 Flashcards
Cell injury and reversible effects on cells
Physical damage to DNA
Ionising radiation
—– rays have sufficient —— to break ——- bonds.
The main target of ionising radiation in cells is ——, which undergoes —— (radiation cleaving water) to form a ———– radical and a ——— radical.
This can cause DNA strand ——– (a single one can kill a cell).
Responses to ionising radiation
——- - Cells ——– rejoin the DNA strand ——- (ideal response)
——– - incorrect rejoining of ——– strands causes chromosome ——–. This is potentially dangerous because it can produce —–
——— - leads to damage to ——- ———- cells. When ——— cells die, surrounding tissues may undergo ——–, ——- or ——-. (shrinkage).
X rays have sufficient energy to break chemical bonds.
The main target of ionising radiation in cells is water, which undergoes radiolysis (radiation cleaving water) to form a hydrogen radical and a hydroxyl radical.
This can cause DNA strand breaks (a single one can kill a cell).
Responses to ionising radiation
Repair - Cells enzymes rejoin the DNA strand breaks (ideal response)
Misrepair - incorrect rejoining of DNA strands causes chromosome translocation. This is potentially dangerous because it can produce cancer
Toxicity - leads to damage to vascular endothelial cells. When endothelial cells die, surrounding tissues may undergo ulceration, fibrosis or atrophy. (shrinkage).
Physical damage to DNA
Ultraviolet radiation
Damages DNA ———.
Adjacent ———– (—, —-) become —– by a 4 membered ——– ring. They normally have a ——– bond where it is joined to ——-
Responses
——— - rejoining of DNA strands
——— generates —- to —– mutations, contributing to —– development.
———- - Excessive ——- leads to death of ———— (peeling sunburn).
Damages DNA bases.
Adjacent pyrimidines (C, T) become linked by a 4 membered carbon ring. They normally have a double bond where it is joined to DNA
Responses
Repair - rejoining of DNA strands
Misrepair generates C to T mutations, contributing to cancer development.
Toxicity - Excessive damage leads to death of keratinocytes (peeling sunburn).
Chemical damage of DNA
——— ——- (AFB1) can react directly with — and ——. (accumulates in poorly stored food).
Response - Covalently reacts with
——— - ———- to cause —– injury (aflatoxicosis), acutely, at high doses;
Misrepair - —— , leading to — to —- mutations and ——- cancer, chronically, at low doses.
Repair
Aflatoxin B1 (AFB1) can react directly with DNA and proteins. (accumulates in poorly stored food).
Response - Contently reacts with
Toxicity - Proteins to cause liver injury (aflatoxicosis), acutely, at high doses;
Misrepair - DNA , leading to G to T mutations and liver cancer, chronically, at low doses.
Repair
Biological Damage - Dietary deficiency
Vitamin —- and —- are needed for —— synthesis and —–.
In autoimmune ——-, lack of ——– factor prevents ——- absorption, leading to —— deficiency and megaloblastic ——- (abnormal bone marrow cell production). This can cause abnormal —- synthesis and —–.
Vitamin B9 and B12 are needed for DNA synthesis and repair.
In autoimmune gastritis, lack of intrinsic factor prevents B12 absorption, leading to B12 deficiency and megaloblastic -anemia (abnormal bone marrow cell production). This can cause abnormal DNA synthesis and repair.
Lipids have ——— that maintain compartments within cells, and provide the ——— between cells and the external environment
Lipids have membranes that maintain compartments within cells, and provide the boundary between cells and the external environment
Physical damage to lipids: Crystals
Cells ———— crystals – silica, asbestos, monosodium urate (MSU), cholesterol, and hydroxyapatite (calcium phosphate from bone fragments) – into ———-.
Crystals puncture ——— membranes, releasing hydrolytic ———. These activate ———— (sensors of danger signals) to generate damaging ———-.
Cells phagocytose crystals – silica, asbestos, monosodium urate (MSU), cholesterol, and hydroxyapatite (calcium phosphate from bone fragments) – into lysosomes.
Crystals puncture lysosomal membranes, releasing hydrolytic enzymes. These activate inflammasomes (sensors of danger signals) to generate damaging inflammation.
Chemical damage to lipids: oxidants
Free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS) participate in oxidative reactions.
Superoxide (O2 -• ) is stable, and is detoxified by superoxide dismutase to O2 and H2O2 (hydrogen peroxide).
Hydrogen peroxide is detoxified by catalase to O2 and water.
Hydroxyl radical (OH• ) is highly destructive, damages any biological molecule, and underlies many types of injury
Membrane damage occurs in chain reactions involving carbon-centred radicals, lipid peroxyl radicals, and lipid hydroperoxides.
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ROS injure cells under conditions of
Premature babies who are born with premature lungs need extra ——– so that they get adequate ——– blood. But the babies lungs are also immature with respect to their ———- defenses, so the oxygen can also be ——– causing a cascade of damaging reactions.
Inflammation
Damaged mitochondria
UV radiation
These three generate ——–.
Ionising radiation - produce OH*
Premature babies who are born with premature lungs need extra oxygen so that they get adequate oxygenated blood. But the babies lungs are also immature with respect to their antioxidant defenses, so the oxygen can also be toxic causing a cascade of damaging reactions.
Inflammation
Damaged mitochondria
UV radiation
These three generate superoxide.
Ionising radiation - produce OH*
Biological: lipases
Acute hemorrhagic pancreatitis arises from damage to exocrine cells (that produce digestive enzymes) or from blockage of the ducts that deliver these enzymes to the duodenum.
Activated enzymes (phospholipases, lipases) are released and digest cell membranes and triglycerides.
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Physical damage to proteins
Heat
Proteins are ——–, leading to the production of —— shock proteins.
Chemical damage to proteins: glycation
Glycation is the non- ——— addition of ——- to proteins
The glycation reaction generates:
Reversible early-stage Schiff bases;
irreversible rearrangements to Amadori products (are stable)
Further rearrangements to advanced glycation end products, AGE (continue to stay reactive).
AGE injure cells by
Inhibiting protein ——–;
cross-linking and precipitating ———- (blocking axonal transport in neurons);
Generating ——
Binding to receptors of AGE called ——, on ——– and ————-cells, reducing ——– flow and causing ———–.
AGE accumulate during ageing, diabetes (increased levels of glucose=increased glycation= blood vessel damage), and chronic inflammation. They promote cardiovascular disease (including retinopathy and nephropathy), neurodegeneration, and cataracts formation.
Proteins are denatured, leading to the production of heat shock proteins.
Chemical damage to proteins: glycation
Glycation is the non-enzymatic addition of sugars to proteins
The glycation reaction generates:
Reversible early-stage Schiff bases;
irreversible rearrangements to Amadori products (are stable)
Further rearrangements to advanced glycation end products, AGE (continue to stay reactive).
AGE injure cells by
Inhibiting protein function;
cross-linking and precipitating proteins (blocking axonal transport in neurons);
Generating ROS
Binding to receptors of AGE called RAGE, on vascular and inflammatory cells, reducing blood flow and causing inflammation.
AGE accumulate during ageing, diabetes (increased levels of glucose=increased glycation= blood vessel damage), and chronic inflammation. They promote cardiovascular disease (including retinopathy and nephropathy), neurodegeneration, and cataracts formation.
Biological damage: proteases
Proteolytic cleavage of ———- matrix proteins occurs during ———–:
o ——– in arthritis;
o ——- in emphysema;
o —— during cancer invasion
Proteolytic cleavage of extracellular matrix proteins occurs during inflammation:
o collagen in arthritis;
o elastin in emphysema;
o laminin during cancer invasion
Injury may be ———–, in which case cells adapt and recover.
Severe injury may lead to ——- damage (cell death
Injury may be reversible, in which case cells adapt and recover.
Severe injury may lead to irreversible damage (cell death
Acute intracellular oedema (hydropic change - swelling)
Cell injury may compromise the ability of cells to regulate ion ———– in the ——–.
This may happen because;
plasma membranes become permeable to —– (carries water with it);
the —— ——- is damaged;
——– synthesis is disrupted and the ——– ——- is inhibited.
As a result, —— leaks out of the cell, and —– leaks in.
Cells and organelles swell osmotically.
Cell injury may compromise the ability of cells to regulate ion concentrations in the cytoplasm.
This may happen because
plasma membranes become permeable to Na+ (carries water with it);
the Na+/K+ ATPase is damaged;
ATP synthesis is disrupted and the Na+/K+ ATPase inhibited.
As a result, K+ leaks out of the cell, and Na+ leaks in.
Cells and organelles swell osmotically.
Abnormal storage
If cells cannot process components normally, products such as fat and glycogen may accumulate.
During fatty change in liver cells, triglycerides accumulate when;
normal liver cells are unable to metabolise increased concentrations of fatty acids arriving from adipose tissue (diabetes);
abnormal liver cells have a reduced ability to oxidise fatty acids (alcohol damage), or to export triglycerides complexed with lipid-acceptor proteins as VLDL (kwashiorkor, severe malnutrition).
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Adaptive responses
Cells may actively adapt to stress through a variety of mechanisms, involving;
the activation of transcription factors
their binding to response elements in gene promoters;
the transcription of genes encoding protective proteins.
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