3. Cell Adaptation, Injury, and Death Pts. 2 and 3

Define hypoxia.

Oxygen deficiency

What are the most common causes of hypoxia?

Deficient blood supply

Reduced oxygen-carrying capacity of the blood

Interference with respiratory chain/oxidative phosphorylation

What is the physiologic consequence of hypoxia?

Impairment of oxidative respiration

Why is oxidative respiration important?

Energy production

What is ischemia?

Deficient blood supply

What causes ischemia?

Impeded arterial flow OR reduced venous drainage

What is the equation that commonly leads to ischemia?

Hypoxia + decreased delivery of nutrients + decreased removal of metabolites

What is an infarction?

Localized area of ischemic necrosis

What tissues are most prone to ischemic damage?

Kidney and heart

What can cause a reduced oxygen-carrying capacity in the blood?

Anemia or hemoglobin dysfunction

What is anemia?

Reduction in numbers or volume of RBCs or the quantity of hemoglobin

How is hemoglobin abbreviated in the medical field?

Hb

What can cause Hb dysfunction?

Nitrite or carbon monoxide poisoning

What does nitrite poisoning lead to?

Methemoglobinemia

What does carbon monoxide poisoning lead to?

Carboxyhemoglobinemia

Nitrite converts ___________ into __________ which cannot bind or transport oxygen leading to hypoxia.

Ferrous → Ferric

What is the physiological effect of cyanide poisoning?

Blockage of cytochrome C oxidase that leads to blockage of oxidative phosphorylation

What are the most common causes of physical agent cell injury?

Direct mechanical trauma

Temperature extremes

Radiation

Electrocution

Sudden changes in atmospheric pressure

What are common groups of chemicals/drugs/toxins that can cause cell injury?

Inorganic poisons

Organic poisons

Manufactured chemicals

Physiologic compounds

Plant toxins

Animal toxins

Bacterial toxins/Mycotoxins

What are examples of inorganic poisons?

Lead, copper, arsenic, selenium, etc.

What are examples of organic poisons?

Nitrates and nitrites, oxalate, hydrocyanic acid, etc.

What are examples of manufactured chemicals?

Drugs, pesticides, herbicides, etc.

What are examples of physiologic compounds that can cause cell injury?

Salt/water, glucose, oxygen, etc.

What are some examples of plant toxins?

Ragwort, Sweet clover, bracken fern, etc.

What are examples of animal toxins?

Snake/spider venom, tick toxin, etc.

What are examples of bacterial toxins/mycotoxins?

Botulinum toxin, aflatoxin, etc.

What are the infectious agents that can cause cell injury?

Viruses (+ prions)

Bacteria

Fungi

Protozoa

Metazoan parasites

What are immunologic reactions that can cause cell injury?

Immune/Inflammatory response

Hypersensitivity reaction

Autoimmune

What is the immune/inflammatory response?

Cells are damaged as “innocent bystanders”

What is a hypersensitivity response?

Anaphylactic (allergic) reaction

What is an autoimmune disease?

Reaction to self-antigens

What are some genetic abnormalities that can cause cell injury?

Cytogenetic disorders

Mendelian disorders

Multifactorial inheritance

What is a cytogenetic disorder?

Chromosomal abnormality

What are examples of cytogenetic disorders?

Down’s Syndrome and equine Turner’s syndrome

What are Mendelian disorders?

Mutant genes

What are examples of enzyme defects in Mendelian disorders?

Lysosomal storage disease

What are examples of structural/transport protein defects in Mendelian disorders?

Collagen dysplasia, cystic fibrosis, anemia, etc.

What is multifactorial interitance?

Combination of environmental factors and 2 or more mutated genes.

What are examples of multifactorial inheritance disorders?

Neoplasia, hypertension, coronary artery disease, etc.

You can only have nutritional imbalances by deficiency.

False, also by over-nutrition

What are some common nutritional deficiencies?

Protein-calories

Vitamin A-E

Minerals (iron, copper, selenium, etc.)

What are the over-nutritional possibilities?

Excess lipids or calories

What diseases are commonly associated with over-nutrition?

Obesity, diabetes, atherosclerosis, etc.

What is “white muscle disease”?

Nutritional myopathy

What is nutritional myopathy a result of?

Deficiency of Vitamin E or selenium

What is represented in the image?

White muscle disease (Nutritional myopathy)

What does the mnemonic device “Double MINT” help to remember?

Malformation

Miscellaneous

Infectious

Immune

Nutritional

Neoplastic

Trauma

Toxicity

What are the 9 causes of cell injury?

Hypoxia

Physical agents

Chemicals/drugs/toxins

Infectious agents

Immunologic reactions

Genetic abnormalities

Nutritional imbalances

Adaptation to workload imbalances

Aging

What is the cellular response to injurious stimulus dependant on?

Type

Duration

Severity

Which is typically compatible with low doses and brief durations of injurious stimuli?

Reversible cell injury

Which is typically compatible with high doses or longer intervals of injurious stimuli?

Irreversible injury and cell death

What are the consequences of an injurious stimulus dependant on?

Type

Current status of the cell

How long do neurons typically have when experiencing hypoxia before irreversible cell injury occurs?

3-5 minutes

How long do cardiac myocytes, hepatocytes, and the renal epithelium typically have when experiencing hypoxia before irreversible cell injury occurs?

30-60 minutes

How long do fibroblasts, keratinocytes, and skeletal muscle typically have when experiencing hypoxia before irreversible cell injury occurs?

Many hours

What is cyanide known to attack?

Cytochrome oxidase

What is fluoroacetate known to block?

Citric acid cycle

What is Enterotoxigenic E. Coli known to do?

Elaborates toxin causing Cl secretion (leading to Na + water secretion)

What are prions known to do?

Convert PrPc to PrPsc

What is a prion?

Abnormally folded protein that is a misfold of a protein that is usually present within a system

What are the intracellular sites that are particularly vulnerable to injury?

All of these

In regards to cell injury which of the following are we expecting to influx?

1. Na+

2. Cl-

3. H2O

4. K+

1 and 3

What is the pathway showing the interrelationship of structural and biochemical elements?

Impaired aerobic respiration → disruption of energy dependent membrane Na+/K+ pump → ionic and osmotic imbalance → cell swelling

What are the biochemical mechanisms of cell injury?

ATP depletion

Free radical induced injury (oxidative stress)

Intracellular calcium and loss of Ca2+ homeostasis

Mitochondrial damage

Defects in membrane permeability

What is a free radical?

Single unpaired electron in the outer orbit

Free radicals are not normally formed within the body.

False, they are formed via metabolic processes

Which of the following describes free radicals?

All of these

What can combat free radicals if you have enough of them?

Antioxidants

What are the 4 ways to generate free radicals?

Cellular metabolism

Enzymatic metabolism of exogenous chemical

Ionizing & UV Radiation

Divalent Metals

What is the most reactive or damaging reactant in free radical injury?

Hydroxyl radical

What is another common reactive oxygen species involved in free radical induced injury?

Superoxide anion

What is an ROS?

Reactive Oxygen Species

What is the process of lipid peroxidation?

Free radicals steal e- near double binds in unsaturated fatty acids → Lipid peroxides → autocatalytic reactions → rapid widespread membrane and organelle damage

What is the process of free radical damage to proteins?

Protein fragmentation & cross linkage between proteins → damage to structural proteins & enzymes →degradation by proteosomes

What is the process of free radical damage to DNA?

Reaction with DNA → strand breakage & DNA-protein adducts

What does immediate damage to the DNA lead to?

Apoptosis

What does long term damage to DNA lead to?

DNA mutations

What are the protective mechanisms against free radical damage?

Storage and transport proteins

Antioxidants

Enzymes

What storage and transport proteins are known to catalyze ROS?

Fe and Cu

Which of the following is lipid soluble and found in cell membranes?

1. Vitamin A

2. Vitamin C

3. Vitamin E

4. Glutathione

1 and 3

Which of the following is an aqueous phase antioxidant?

1. Vitamin A

2. Vitamin C

3. Vitamin E

4. Glutathione

2 only

Which of the following in its reduced form reaction with hydrogen peroxide or hydroxide to form an oxidized version and water?

1. Vitamin A

2. Vitamin C

3. Vitamin E

4. Glutathione

4 only

What is GSH?

Reduced glutathione

What is GSSG?

Oxidized glutathione

What does the enzyme glutathione peroxidase do?

GSH → GSSG

What does superoxide dismutase do?

Superoxide anion → hydrogen peroxide

What does catalase do?

Break down hydrogen peroxide into oxygen and water

Which cellular compartment is low when there is cell damage due to loss of calcium homeostasis?

Intracellular

What can happen when there is a loss of calcium homeostasis?

Membranes damage/ischemia or certain toxins cause increased cytosolic calcium due to influx from the ECF/ER/mitochondria

All cells are dependent of oxidative metabolism for long term survival regardless of glycolytic activity.

True