McCance Chapter 2 - Altered Cellular and Tissue Biology

Irreversible Cell Injury

"Point of no return" structurally when severe vacuolization of mitochondria (no longer able to make ATP) occurs and Calcium moves into the cell, including mitochondrial membrane damage.

Role of ROS in cell injury: three main effects

*1) Lipid peroxidation* = causes MEMBRANE DAMAGE *2) Protein modification* = causes DAMAGE/MISFOLDING *3) DNA Damage* = causes MUTATIONS

Which disease states can be caused from oxidative stress by ROS's?

*Aging Diabetes Autoimmune diseases Cancer Sterility Cardiovascular disease Digestive tract dysfunction Neurologic Disease*

Superoxide Dismutase

*Converts superoxide into H202* (H202 is less damaging than superoxide free radical is)

Sites of ROS generation/sources from cell

*Endoplasmic reticulum* - Misfolded proteins -> ER stress = ROS *Peroxisomes (oxidation of Long Chain Fatty Acids* - the beta-oxidation of LCFA in the peroxisome = ROS *Mitochondrion* - Converts O2 into H202 (oxygen into hydrogen peroxide)

Consequences of Ischemia inside the cell

*Hypoxia* - decrease in mitochondrial oxygenation --> depletion of ATP --> Sodium potassium pump not working --> intracellular Na and Ca INCREASES, extracellular K+ Increases --> INCREASE in H20 --> ACUTE CELLULAR SWELLING

Oxidation VS. Reduction

*Oxidation* - losing an electron *Reduction* - gaining an electron

Enzymes that contribute to the inactivation or termination of free radicals:

*Superoxide dismutase* *Catalase* *Glutathione Peroxidase*

Cocaine and crack

-Crack is more potent than cocaine -Cocaine is widely used as an anesthetic, usually in procedures involving oral cavity -Potent CNS stimulant -Blocks the reuptake of neurotransmitters norepinephrine, dopamine, and serotonin -Increases synthesis of dopamine and norepinephrine -Dopamine induces euphoria -Norepinephrine induces hypertension, tachycardia, vasoconstriction

What happens in the cell following hypoxic injury?

-Decrease in ATP, causing failure of the sodium-potassium pump and sodium-calcium exchange. -Cellular swelling

Methamphetamine (Meth)

-Irritability -Aggressive (violent) behavior -Anxiety -Excitement -Auditory Hallucinations -Paranoia (delusions/psychosis) -Hyperactive behavior -Euphoria, alertness, perception of increased energy Tweaking = Most dangerous stage, user is continually under the influence. *Not sleeping for 3-15 days = extremely irritated and paranoid*

ATP depletion causes

-Loss of mitochondrial ATP and decreased ATP synthesis. - Causes cellular swelling, decreased protein synthesis, decreased membrane transport, lipogenesis --> ALL contribute to loss of integrity of plasma membrane.

What cellular enzymes are activated by Calcium in the cell?

1) ATPase = Decreases ATP 2) Phospolipases + Proteases = Membrane damage 3) Endonuclease = Nucleus Damage

Cellular Damage caused by Radiation

1) Direct toxication : Radiation directly effects DNA. It causes the breakage of double stranded DNA = DNA damage and mutations 2) Indirect Toxication : Radiation causes water (H20) to convert into hydroxyl radical (OH), superoxide (O2-) = which cause damage to nucleic acids and DNA

Late Biological Effects of Radiation

1) Fibrosis: formation of fibrous tissue and permanent scar tissue 2) Vascular changes : blood vessel changes

The Process of Oncosis

1) Hypoxia causes a DECREASE in the production of ATP 2) Na/K Pump is usually sustained by ATP but now it loses function. K moves out, Sodium accumulates inside the cell! 3) Osmotic pressure increases = Water moves inside the cell 4) Cisternae of the ER distend, rupture, and form vacuoles that hold water in the cytoplasm 5) Extensive vacuolization = ONCOSIS OR HYDROPIC DEGENERATION = cellular swelling

Ischemia --> Intracellular Calcium: What does it do inside the cell?

1) Increased cystosolic Ca -> Calcium in mitochondria -> Mitochondrail permeability changes -> Decrease in ATP 2) Increased cystosolic Ca -> Increase in cellular enzyme activity

Primary metabolism of Ethanol

1. Ethanol converted to Acetaldehyde by ALCOHOL DEHYDROGENASE (ADH) 2. Acetaldehyde is converted to Acetate by ALDEHYDE DEHYDROGENASE (ALDH2) 3. Acetate is harmless, found in ketone bodies, fatty acids, and amino acids.

Dysplasia

Abnormal changes in the size, shape, and organization of mature cells. *Not a true adaptive change*

Oxygen and Oxygen Derived Free Radicals cause:

Activated oxygen species (free radicals such as H202, NO, O2- superoxide) CAUSE destruction of cell membranes and cell structures In ischemia, lack of oxygen is key in the progression of cell injury.

Protein Misfolding and DNA damage - what happens in the cell?

Activation of proapoptotic proteins

Marijuana

Active substance: Δ9-Tetrahydrocannabinol (THC) -Alterations of sensory perception -Impairment of cognitive and psychomotor judgments (inability to judge time, speed, distance) -Increase in HR and BP -Increase in susceptibility to laryngitis, pharyngitis, bronchitis, causes cough and hoarseness. -May contribute to lung cancer. -Reduced fertility -Decreased sperm motility FETAL -Low birth weight -Increased frequency of infectious illness -Decreased nausea to cancer chemotherapy -Decreased pain in certain chronic conditions

Hyperplasia

An increase in the number of cells as a consequence of an increase in cell division.

Ionizing Radiation

Any form of radiation capable of removing orbital electrons from atoms -X-rays, Gamma rays, apha and beta particles

Blunt force injuries

Application of mechanical energy to the body resulting in the tearing, shearing, or crushing of tissues

Hematoma

Bleeding in soft tissue or enclosed space (bruise)

Contusion

Bleeding into the skin or underlying tissues

Which enzyme in the cell to converts Hydrogen peroxide (an ROS) into H2O?

CATALASE Catalase converts the ROS H202 -> WATER But if you have too much H202 and ROS, the catalase enzyme can become overwhelmed and not do its antioxidant duties.

Cellular accumulations (infiltrations) : Calcium

Calcium hydroxide and hydroxyapatite

Chemical cell injury: *Lead*

Can cause learning disorders, hyperactivity, attention problems, hemolysis (breakdown of RBS) paralysis, glycosuria, aminoaciduria, hyperphospaturia, nausea, loss of appetite, weight loss, abdominal cramping

Too much acetaldeyhde can:

Can produce ROS, oxidative stress, protein unfolding/DNA damage, lipid peroxidation, liver injury

Asphyxial Injuries

Caused by a failure of cells to receive or use oxygen -Suffocation -Strangulation (hanging, ligature, manual strangulation) -Chemical asphyxiants (cyanide or hydrogen sulfide) -Drowning

Chemical cell injury: *Carbon Monoxide*

Causes hypoxia because carbon monoxide has a 300 times greater affinity for hemoglobin than oxygen does. Headache, giddiness, nausea, tinnitus, weakness, vomiting

What are the susceptible cells affected by radiation?

Cells undergoing division at a rapid rate -Gastrointestinal cells -Fetus -Bone marrow cells -Lymph nodes

Oncosis

Cellular swelling from the shift of extracellular water into the cells.

Intracellular Sources of ROS

Certain enzyme systems in the cell produce ROS *Lipoxygenase Xanthine oxidase Cyclooxygenase Cytochrome P450 monooxygenase Nitric oxide synthase NADPH oxidase* ---> PRODUCE ROS

Late Biological Effects of Radiation - Fibrosis CAUSES

Collagen deposition and the remodeling of the ECM

Mercury

Damage to the CNS and kidney. May be in electronic devices, batteries, cosmetics, dental amalgams, fish, rice, thimerosal (preservative only in inactivated influenza vaccine.

Depletion of ATP as a result of ischemia causes Anaerobic glycolysis and :

Decrease in ATP --> Increase in anaerobic glycolysis --> decrease in glycogen --> increase in Lactate --> decrease in pH === NUCLEAR CHROMATIN CLUMPING

Ischemia --> Decrease in ATP: How does it alter the mitochondrial membrane?

Decrease in HTP --> Altered membrane permeability --> Loss of membrane potential --> Mitochondria CANNOT make ATP --> Necrosis Proapoptic proteins --> APOPTOSIS

Atrophy

Decrease or shrinkage in cell size

Mitochondrial Damage - What happens in the cell

Depletion of ATP (because the mitochondria makes ATP) Increase in Reactive Oxygen Species >-> which cause damage to lipids, proteins, and DNA

Cardiovascular effects of cocaine/crack

Dysrhythmias, sudden death, dilate cardiomyopathy, rupture of descending aorta

Pathologic calcification

Dystrophic and metastatic calcification The release of calcium inside cells or tissues causes deposition of calcium and hardening of tissues. (Dystrophic - organ or tissue wastes away/weakens) (Metastatic - spreading to other parts of the body)

Which form of cell injury causes defects in membrane permeability?

Early loss of selective membrane permeability is found in ALL forms of cell injury

Chemical Liver Injury

Environmental factors/xenobiotic exposure, pathological factors (disease, inflammation), physiologic factors (age/sex), and nutrients/dietary factors CAUSE cell signaling. Cell signaling will cause epigenetic effects (modification of genes, which are turned on/off) = production of protein. Xenobtiotic metabolized -> That protein will be responsible for detoxification OR it will progress to toxification. Toxification will cause bimolecular damage and/or oxidative stress. The cell can undergo homeostasis/adaption OR organelle damage will happen. Organelle damage will cause either necrosis or apoptosis of the liver cells === LIVER INJURY

Catalase

Enzyme that breaks down hydrogen peroxide into water in peroxisomes

Glutathione peroxidase

Enzyme that decomposes OH (hydroxyl) and Hydrogen peroxide

Oxidative stress (by ROS) in Human Pathogensis

Exogenous or endogenous (from hypoxia) ROS cause DAMAGE TO DNA. The DNA repair system (efficient redox system) can become overwhelmed by chronic ROS exposure causing persistent DNA damage and mutations. Accumulation of damaged DNA lesions causes DNA DOUBLE STRAND BREAKS = causes disease onset and progression.

Cellular Injury mechanisms: Free Radicals and Reactive Oxygen Species(ROS)

Free Radicals and ROS: electrically uncharged atom or group of atoms having an unpaired electron. Unstable molecule. To stabilize itself, it gives up an electron or steals one from long chains of phospholipids in the cell membrane = lipid peroxidation Damage it causes inside the cell? *Lipid peroxidation Alteration of proteins alteration of DNA*

Reducing agent/antioxidant that works to reverse the ROS?

GLUTATHIONE - also mediates the ROS But in this process, you can produce hydroxyl radical (OH*) which is a free radical that can cause DNA damage, lipid peroxidation of membrane, and protein damage.

What damage does ionizing radiation cause?

Genetic changes Inflammation Fibrosis and vascular changes Observed in somatic cells (normal), gametes (sex cells), and fetal cells/fetus

Hyperthermic Injury

Heat cramps *Heat exhaustion* - salt and water loss resulting in hemoconcentration (blood volume decreases, hematocrit increase), hypovolemia (liquid portion of blood plasma is too low), hypotension *Heat stroke* - core body temperature rises (above 106 F)

Antioxidants

Help to reverse or inactivate free radicals. They can be endogenous (in the body) or exogenous (something you take in). Block the synthesis or inactivate free radicals MAIN THREE: *Vitamin E, Vitamin C, glutathione*

Gamma rays: Tissue Penetration?

High

Neutrons: Tissue Penetration?

High

X-Rays : Tissue Penetration?

High

Heroin

Highly addictive. Feeling of tranquility and sedation lasts only a few hours. Sudden death as a result of: -overdosage secondary to -respiratory depression -decreased cardiac output -severe pulmonary edema (swelling)

Atrophy Example - Disuse

If you break your leg and have to wear a cast, you will begin to break down/lose muscles in your leg because of disuse - cell shrinkage.

Metaplasia in Cell Linings of the Bronchi

In long term smokers, the normal ciliated columnar epithelium lining (with goblet cells) of their lung bronchi becomes replaced with stratified squamous epithelial cells. The stratified squamous epithelial cells do NOT secrete mucus or have cillia = loss of vital protection. Cells cannot trap pathogens/bacteria/viruses/debris. Bronchial metaplasia can be reversed if the stimulus (smoking) is taken away. If persistent, it can turn into the more severe dysplasia or it can become malignant and cancerous.

Entry of Calcium - Response in cell

Increase in mitochondrial permeability and activation of multiple cellular enzymes Normally, intracellular calcium levels are very low. Ischemia and certain chemicals cause in increase in Ca, which causes damage to the plasma membrane and mitochondrial permeability AND turn on multiple enzymes that shouldn't be on - cause damage to the cell.

Hypertrophy

Increase in the size of cells and the affected organ

Reperfusion Injury

Injury that results from the restoration of oxygen following hypoxic event. Purine catabolites hypoxanthine and xanthine are accumulated during the ishemic period. When oxygen is restored, they generate large amounts of the highly reactive oxygen species hydrogen peroxide (H2O2) and superoxide (O2-). *These ROS cause membrane damage and mitochondrial calcium overload* These changes lead to the leakage of ATP through mitochondrial pores --> thus triggering apoptosis.

Alcohol-Related Neurodevelopmental Disorder

Intellectual disabilities and problems with behavior and learning. Might do poorly in school and have difficulties with math, memory, attention, and judgment, and poor impulse control.

Protons: Tissue Penetration?

Intermediate (between a and B)

The most common cause of hypoxia is:

Ischemia

Intracellular calcium and loss of calcium steady state causes:

Ischemia and certain chemicals cause an increase in cystosolic calcium concentrations. Sustained levels of calcium in the cells continue to increase with more damage to the plasma membrane. Calcium causes intracellular damage by activating a number of enzymes (that shouldn't be activated)

Hypoxia

Lack of sufficient oxygen

Reversible Cell Injury

Loss of ATP, swelling of the cell, detachment of ribosomes, autophagy of lysosomes

Beta particles: Tissue Penetration?

Low

Fetal Alcohol Syndrome Disorders (FASDs) can cause:

Low body weight Poor coordination Hyperactive Behavior Poor Memory Learning Disabilities Speech and language delays Intellectual disability or low IQ Poor reasoning and judgment skills Vision or hearing problems Problems with the heart, kidney, or bones

Cellular accumulations (infiltrations) : Pigments

Melanin, hemoproteins, (hemosiderosis), bilirubin

Methamphetamine - Tweaking Stage

Most dangerous stage, user is continually under the influence. *Not sleeping for 3-15 days = extremely irritated and paranoid*

Intracellular and extracellular Na, K+, Ca, and H20 as a result of ischemia CAUSE

Na/K Pump FAILS as a result of ischemia: -Intracellular Na, Ca increase, extracellular K+ increase -H20 increase = SWELLING CAUSES dilation of the endoplasmic reticulum, detachment of ribosomes, decrease in protein synthesis, and lipid deposition.

Chemical cell injury: *Ethanol*

Nutritional deficiencies of magnesium, B6, thiamine, phosphorus.

Chronic cell injury (subcellular alterations)

Persistent stimuli response may involve only specific organelles or cytoskeleton (e.g. phagocytosis of bacteria)

Membrane damage - what happens in the cell?

Plasma membrane damage = loss of cellular components Lysosomal membrane damage = enzymatic digestion of cellular components that shouldn't normally happen

Late Biological Effects of Radiation - Vascular changes CAUSE

Poor oxygen exchange and hypoxia

Effects on Fetus from use of cocaine/crack

Premature labor Retarded fetal development Stillbirth Hyperirritability

Alcohol-Related Birth Defects (ARBDs)

Problems with the heart, kidneys, or bones, or with hearing. Or a mix of these problems.

Apoptosis

Programmed cell death involving cellular self-destruction for elimination of unwanted cell populations.

Methamphetamine - High Intensity Stage

Psychologically addicted - smokes and injects to achieve faster, stronger high

Three main ROS How are ROS produced?

Radiations, toxins, or reperfusion Superoxide: O2- Hydrogen Peroxide: H202 Hydroxyl Radical: OH Generally, the cellular system using decay and enzymes can remove free radicals or convert free radicals to H20 BUT accumulation/overwhelming amounts of ROS prevent it/overwhelm the cell.

Ischemia

Reduced blood supply

Abrasion

Removal of superficial layers of the skin

Metaplasia

Reversible replacement of one mature cell by another (sometimes less differentiated)

Hypothermic Injury

Slows cellular metabolic processes ROS production

Fentanyl

Synthetic opiod analgesic (pain-reliever) 50-100 times more potent than morphine Associated with a growing number of overdoes and overdose deaths

Laceration

Tear or rip of the skin with jagged edges

Fetal Alcohol Syndrome (FAS)

The most involved end of the FASD spectrum. Individuals with FAS may have abnormal facial features, growth problems, and CNS problems. Can also have problems with learning, memory, attention span, communication, vision, or hearing and may have a hard time in school and trouble getting along with others.

What happens with overconsumption of alcohol?

The problem with overconsumption of ethanol: you overwhelm aldehyde dehydrogenase (ALDH2) and cause too much build up of ACETALDEHYDE = TOXIC

Atrophy Example - Physiological

Thymus - As you mature through fetus into adulthood, your thymus continues to decrease in size and becomes much smaller. Natural, physiological example of decrease/shrinkage in cell size, or atrophy

Anoxia

Total lack of oxygen

Methamphetamine - Low Intensity Stage

User is not psychologically addicted and uses meth by swallowing or snorting

Alpha particles: Tissue Penetration?

Very low

Cellular accumulations (infiltrations)

Water : anaerobic respiration = production or ROS = shutting down Na/K pump = buildup of calcium and sodium intracellularly = WATER FOLLOWS THEM BECAUSE OF OSMOSIS ALSO: Lipids and carbohydrates, glycogen, and proteins

Accumulation or infiltrations - Cell Injury/Response

Water, pigments, lipids, glycogen, proteins may accumulate

Mechanisms of Myocardial Hypertrophy

When the heart is experiencing increased workload (years of hypertension) it will experience mechanical stretch. *Mechanical stretch, agonists/vasoactive agents (substances that combine with a receptor to cause physiological changes, EX: ANGIOTENSIN = vasoconstriction, increase BP), and growth factors all stimulate signal transduction pathways* Transcription factors (GATA4, NFAT, MEF2) are activated from the signal transduction pathways. These transcribe things that will INCREASE the synthesis of heart muscle proteins. *Transcription factors cause the induction of embryonic/fetal genes (cardiac a-actin which increases muscle contraction/pumping), the synthesis of contractile proteins, and the production of growth factors* These three responses INCREASE the size of heart muscle cells (increased growth of adult myocytes) and cause the heart muscle to become thicker. *This INCREASES the mechanical performance of the heart and DECREASES the heart's workload*. Initially, this works well. Over a prolonged period of time, the heart becomes much thicker and more fibrous with scarring and there are changes in its ability to contract properly = heart becomes sick = heart failure/ disease.