Chapter 3 – Altered Cellular and Tissue Biology I

PATHOPHYSIOLOGY Name

Chapter 3 – Altered Cellular and Tissue Biology I. Cellular Adaptation A. Physiologic vs. Pathogenic – due to normal demand vs. disease process 1. Atrophy – decrease or shrinkage in cell and organ size. Example – skeletal muscle deprived of innervation. 2. Hypertrophy – increase in the size of cells and organ. Example – skeletal and cardiac muscle (due to increased workload). 3. Hyperplasia – increase in number of cells due to increased mitosis. Examples – liver if part is removed (enlarges to compensate), breasts due to hormonal signals during pregnancy. 4. Dysplasia – abnormal changes in size, shape and organization of mature cells. This is not a true adaptive change. It is due to persistent severe irritation. Often reversible if stimulus is removed. Example – cervical dysplasia due to human papillomavirus. 5. Metaplasia – reversible replacement of one mature cell type by another cell type (sometimes less differentiated). This can be reversible, or it can progress to dysplasia and neoplasia (cancer). Example – in the bronchi pseudostratified ciliated columnar ep. → stratified squamous ep.

Match each description with one of the processes above. Circle the letter of those that are pathologic. a) Excessive hormonal stimulation causes cells in the ducts of the breast to change their shape, size and arrangement.

b) During childhood, the thymus decreases in size.

c) During puberty, the male and female reproductive organs grow and develop into their mature forms.

II. Cellular Injury  Reversible – cells can recover if injurious stimuli ceases.  Irreversible – cells die due to injury. A. Cellular Injury Mechanisms 1. Hypoxic injury – due to lack of sufficient oxygen  Ischemia – reduced blood supply; if gradual, then adaptation can occur. Example – a growing thrombus which gradually blocks a vessel.  Anoxia – total lack of oxygen. This is not well tolerated by most tissues. Example – an embolus which lodges in a vessel.  Cellular responses: o Decrease in ATP, causing failure of sodium-potassium pump and sodium-calcium exchange – Na+ and Ca++ accumulate inside cells, K+ outside cells o Cellular swelling – due to movement of Na+ into cells. This is reversible if oxygen is restored.

o Vacuolation – if O2 is not restored, vacuoles accumulate in cytoplasm and organelles swell. 2

 Damage is irreversible when there is: o Lack of ATP production due to mitochondrial damage. o Major membrane damage and disturbance of membrane function.

 Reperfusion injury due to oxidative stress – when O2 is restored, reactive oxygen intermediates damage organelles. Can be prevented using antioxidants. 2. Free radicals and reactive oxygen species  Electrically uncharged atom or group of atoms having an unpaired electron that cause damage by: o Lipid peroxidation – damages membranes of cell and organelles, increases permeability. o Alteration of proteins – especially those for ion pumps and transport proteins. o Alteration of DNA – fragmenting of DNA reduces protein synthesis. o Mitochondrial damage – allows liberation of calcium into cytosol. 3. Chemical injury

 Carbon tetrachloride (CCl4) – the liver converts this to a toxic free radical which causes lipid peroxidation → damage to membranes, release of lysozyme, and mitochondrial damage → fatty liver, cellular autodigestion, and decreased ATP production.  Lead – causes neurological problems (interferes with neurotransmitter release), anemia, and renal problems.  Carbon monoxide (CO) – prevents oxygen from binding to hemoglobin → hypoxic injury (cherry red coloring of skin).  Ethanol → acetaldehyde and free radicals in liver → inflammation, fatty liver, membrane damage; depresses CNS by acting on reticular formation which normally inhibits unacceptable behaviors.  Mercury – causes birth defects and brain damage in fetuses and small children.

ACTIVITY 2: Indicate whether each of these is primarily associated with a lack of oxygen (–) or with free radicals and oxidative stress (+). a) CO poisoning c) Cellular swelling e) Formation of vacuoles b) Damage by CCl4 d) Damage to DNA f) Decreased ATP production

B. Unintentional and Intentional Injuries 1. Blunt force injuries – in ER most are from falls and car accidents  Application of mechanical energy to the body resulting in the tearing, shearing, or crushing of tissues  Contusion – “bruise” (release of blood into tissues from damaged vessels without break in skin)  Hematoma – a collection of blood in soft tissues or an enclosed space (subdural space, etc.)  Abrasion – “scrape” (removal of the superficial layers of skin due to friction)  Laceration – a rip or tear of the skin; irregular edges. Avulsion – an extreme laceration. May also occur in internal organs due to blunt impact trauma with no external signs on skin.  Fractures – breakage of bone tissue 2. Sharp injuries  Incised wounds – a cut that is longer than it is deep. 3

 Stab wounds – a penetrating sharp-force injury that is deeper than it is long.  Puncture wounds – caused by pointed objects without sharp edges.  Chopping wounds – caused by axes, hatches, propeller blades, etc. 3. Gunshot wounds  Entrance wounds – usually have an abrasion collar o Contact range entrance wound – muzzle touching skin . Blow-back and muzzle imprint – searing of edges by heat of gun o Intermediate range entrance wound – not touching skin; less than 48 inches away . Tattooing and stippling – fragments of gunpowder driven into skin or cause abrasion o Indeterminate range entrance wound – only bullet hits body; may occur through clothes  Exit wounds – usually are clean without an abrasion collar, except: o Shored exit wound – abrasion around exit wound as skin pushes against something 4. Asphyxial injuries o Caused by a failure of cells to receive or use oxygen  Suffocation – caused by lack of oxygen in environment or blockage of external airways o Choking asphyxiation – blockage of internal airways  Strangulation – caused by compression and closure of blood vessels and air passageways by external pressure; death due to lack of blood flow to brain. o Hanging, ligature, and manual strangulation – due to suspension, cord around neck, or hands  Chemical asphyxiants – prevent delivery or utilization of oxygen in tissues

o Cyanide – CN prevents O2 binding to cytochrome oxidase in mitochondria → cherry red coloring like CO poisoning  Drowning – alteration of oxygen delivery due to breathing fluid into lungs; death occurs more rapidly in warm water than in very cold water. C. Infectious Injury  Pathogenicity of a microorganism  Disease-producing potential depends on an organism’s ability for: o Invasion and destruction o Toxin production o Production of hypersensitivity reactions D. Immunologic and Inflammatory Injury – is caused by:  Phagocytic cells  Release of immune and inflammatory substances o Histamine, antibodies, lymphokines, complement, and proteases  Membrane alterations – cause leakage of K+ out of cell and influx of Na+ and water. o Antibodies can block membrane receptors and intercellular communication. 4

III. Manifestations of Cellular Injury A. Cellular Accumulations (infiltrations) – pathologic accumulations can occur due to: 1) excess production of a normal substance, 2) the substance not being broken down due to lack of an enzyme, or 3) accumulation of harmful exogenous substances.  Water – enters cells due to lack of ATP and failure of Na+/K+ pump, causing cellular swelling. o Oncosis (hydropic degeneration) – water accumulates in endoplasmic reticulum forming vacuoles separate from cytoplasm (vacuolation). The organs appear pale as a result.  Lipids and carbohydrates – accumulate (usually in spleen, liver and CNS) due to metabolic disorders like Tay-Sachs and Niemann-Pick disease. o Fatty change - can be caused by disruptions of normal lipid metabolism; liver appears yellow.  Glycogen – occurs in disorders of glucose and glycogen metabolism, including diabetes mellitus.  Proteins – accumulate during pathological change in renal tubules, and B cells (antibodies)  Pigments – accumulation may be normal or signal pathological changes (melanoma, jaundice) o Melanin (suntan, melanomas) or hemoproteins, hemosiderin and bilirubin (from RBC breakdown)  Calcium – occurs in hypoxic cells due to entry of extracellular Ca2+ into mitochondria  Urate – due to increased levels of uric acid from purine catabolism; causes gout. B. Cellular Death  Necrosis– cellular dissolution o Sum of cellular changes after local cell death and the process of cellular autodigestion  Processes o Karyolysis - nuclear dissolution and chromatin lysis o Pyknosis - clumping of the nucleus o Karyorrhexis - fragmentation of the nucleus C. Necrosis 1. Coagulative necrosis  Occurs in kidneys, heart, and adrenal glands, etc.  Due to protein denaturation - results from hypoxia caused by chemical injury (for example, mercuric chloride intake). 2. Liquefactive necrosis  Occurs in neurons and glial cells of the brain  Due to hydrolytic enzymes – from lysozyme in dying cells. Enzymes digest cell contents.  Can be caused by bacterial infection - staphylococci, streptococci, and Escherichia coli. 3. Caseous necrosis – “cheese-like”  Occurs in a tuberculous pulmonary infection.  Combination of coagulative and liquefactive necrosis – cells disintegrate but are not completely digested. 5

4. Fat necrosis  Occurs in breast, pancreas, and other abdominal organs that have lipase enzyme.  Action of lipases – releases free fatty acids that react with Ca2+, Mg2+ and Na+ → forms soaps 5. Gangrenous necrosis  Death of tissue from severe hypoxic injury – often due to atherosclerosis or trauma o Dry vs. wet gangrene – Dry → coagulative. Wet → liquefactive necrosis (internal organs)  Gas gangrene –bacteria produce hydrolytic enzymes and create gas bubbles in muscles. o Clostridium – the anaerobic bacteria responsible.

ACTIVITY 3: Which type of necrosis would most likely occur in each of the following situations? a) Damage to a tissue rich in hydrolytic enzymes. b) Damage to a tissue rich in lipid digesting enzymes. c) Tissue destruction by a chemical that denatures protein.

D. Apoptosis – death of unnecessary cells due to enzymes produced within cell; genetically programmed.  Programmed cellular death – prevents overgrowth of cells; also occurs during fetal development.  Physiologic (normal) vs. pathologic (due to enzyme deficiencies, viruses, free radicals, etc.)  Apoptosis vs. necrosis o Apoptosis - normal, genetically programmed cell death. . Usually involves individual, scattered cells. . Cellular enzymes cleave key cellular proteins; cells shrink and fragment. . Cellular debris remains bound in a membrane forming apoptotic bodies which are removed by neutrophils and macrophages. . This process does not stimulate the inflammatory response. o Necrosis - due to damage from exogenous injury. . Usually involves many cells in area of injury. . Cell membranes rupture, releasing cell contents into tissue. . Triggers inflammatory response. IV. Aging and Altered Cellular and Tissue Biology  Aging – time-dependent loss of structure and function that proceeds slowly due to accumulated small injuries. Q: At what point does this become disease? There is some overlap.  Disease – abnormal dysfunction due to injury.  Normal life span- across cultures the maximal life span is 80-100 years.  Gender differences – females have a life expectancy about 5 years greater than males. A. Theories and Mechanisms of Aging (none of these are thoroughly proven) 1. Genetic and Environmental-Lifestyle Factors - includes three basic mechanisms:  Programmed aging – cells have a finite lifespan with a finite number of possible divisions, after which the DNA loses the capacity for mitosis. 6

 Somatic mutation hypothesis – repetitive injury to the DNA causes progressive mutations that interfere with the ability of the cell to repair itself and maintain DNA and protein synthesis.  Catastrophic or error-prone theory – the enzymes responsible for transcription and translation become increasingly abnormal, leading to increasing errors in protein synthesis. 2. Alterations of cellular control mechanisms  Neuroendocrine theory – the genetic program for aging is encoded in the brain and is controlled and relayed to peripheral tissues through hormonal and neural signals.  Immune theory - with aging, there is decreased immunity to invaders and cancer and increased autoimmunity (immune system attacks self). 3. Degenerative extracellular and vascular changes –  Binding of collagen – crosslinking, decreased synthesis and increased breakdown of collagen  Free radical effects (oxidative stress) – damage to DNA → malignancies and cell death  Alterations in peripheral blood vessels – decreased vessel integrity and atherosclerosis B. Aging  Cellular aging – characterized by: o Atrophy, decreased function, and loss of cells (through apoptosis).  Tissue and systemic aging – every physiologic process declines in efficiency with age. o Progressive stiffness and rigidity – arterial, pulmonary, and musculoskeletal systems. o Sarcopenia – loss of muscle mass and strength.  Frailty – can be a wasting syndrome of aging. o Decreased mobility, balance, muscle strength, motor activity, cognition, nutrition, endurance and bone density result in increased falls and fractures. o Accompanied by declining hormone levels and increased levels of proinflammatory cytokines.

ACTIVITY 4: What are some lifestyle changes that might slow down the effects of aging? Why might these be beneficial?

V. Somatic Death  Death of an entire person  Postmortem changes – after death, diffuse changes that do not involve the inflammatory response. o Algor mortis – postmortem reduction of body temperature. Body temp drops by 1-1.5 °F per hour. o Livor mortis – purplish discoloration of tissues due to accumulating blood drawn down by gravity. o Rigor mortis – stiffening of muscles due to depletion of ATP; begins after 6 hours and continues until about 36 hours after death. o Postmortem autolysis – digestion of body tissues due to release of lysozymal enzymes causing liquefactive changes and putrification.

ACTIVITY 5: A coroner examines a body at the scene of a murder and takes note of the following: the core body temperature is 95 °F, the surface resting on the ground is purplish, and there is no abnormal stiffening of the muscles. Roughly how long ago did death occur?

Answer Key to Activities

b) During childhood, the thymus decreases in size. Atrophy c) During puberty, the male and female reproductive organs grow and develop into their mature forms. Hyperplasia

ACTIVITY 2: Indicate whether each of these is primarily associated with a lack of oxygen (–) or with free radicals and oxidative stress (+). a) CO poisoning – c) Cellular swelling – e) Formation of vacuoles – b) Damage by CCl4 + d) Damage to DNA + f) Decreased ATP production –

ACTIVITY 3: Which type of necrosis would most likely occur in each of the following situations? a) Damage to a tissue rich in hydrolytic enzymes. Liquefactive necrosis b) Damage to a tissue rich in lipid digesting enzymes. Fat necrosis c) Tissue destruction by a chemical that denatures protein. Coagulative necrosis

ACTIVITY 4: What are some lifestyle changes that might slow down the effects of aging? Why might these be beneficial?

Avoidance of exposure to substances that damage DNA, like ionizing radiation, carcinogens in tobacco smoke and overcooked meat, etc. Eating foods or taking supplements that contain antioxidants to decrease oxidative damage to cells and ones that support the immune system (omega-3 fatty acids, for example). Eating a low fat diet to avoid atherosclerosis. Doing aerobic exercise to improve cardiovascular function, weight bearing exercise to maintain muscle mass and strength, and stretching exercises to prevent crosslinking of collagen and maintain flexibility.

Less than 6 hours (but probably more than 2 hours, since body temp drops by 1-1.5 °F per hour).