Ch. 2: Cellular Injury, Adaptations and Maladaptive Changes

T or F DNA mutations are common with exposure to high doses of radiation?

TRUE DNA mutations are common with exposure to high doses of radiation. With radiation damage, genes can mutate into oncogenes, which trigger cancerous cell changes. The cancerous cells manufacture cancerous proteins, also called oncoproteins.

What is physiologic hypertrophy?

The enlarged muscle is adequately perfused and supplied with blood flow, oxygen, and nutrients because of angiogenesis. Occurs in response to heavy workload. Example: muscular hypertrophy (weight lifting), removal of diseased kidney, uterus, mammaries with pregnant women In well trained athletes, the heart *physiologically hypertrophies* because of the enlargement of each individual myocardial cell. There is a proportional increase in my- ocardial cell size and enhancement of coronary blood supply of the myocardial cells. Therefore, the enlarged heart in an athlete is supplied with abundant coronary artery blood flow, which delivers large amounts of oxygen and nutrients

injurious immunological cell injury

The immune system is the body's major defense however, the immune system can overreact and attack the body's own cells, causing cell injury and creating disease. • allergy is an adverse immune response • Another example of immunological cell injury occurs in autoimmune diseases such as rheumatoid arthritis (RA). In RA, immune system cells, such as T cells and B cells, are triggered by an unknown antigen to attack the body's own joints.

example of physical cell injury

There are many different physical agents of cell injury. ∙Mechanical trauma from an external force such as a laceration, gunshot wound, or fall ∙Temperature extremes, which can result in such injuries as burns and frostbite; radiation; electrical shock; and extreme changes in atmospheric pressure ∙Sunburn, brought upon by excessive exposure to sunlight ∙Excessive noise is considered a mechanical stressor of the inner ear's delicate organs Hypertension, high pressure within the arteries, acts as a physical force against the endothelial lining of the vasculature. The constant stress of the pulsatile force of blood flow against the arterial endothelium causes a shearing injury.

Dysfunction of the Sodium-Potassium Pump -normal healthy-

Under normal, healthy circumstances, Na+/K+ ATPase expels three sodium ions from the intracellular environ- ment and pumps in two potassium ions. This contributes to the development of membrane polarity in excitable tissues such as muscle cells and neurons. It also main- tains the normal osmotic relationships between ions, with sodium being the major extracellular ion and potassium the major intracellular ion.

nutritional imbalances causing cell injury

What kind of cell injury is this: • high LDL cholesterol deposits on endothelial wall →atherosclerosis • starvation: insufficient proteins leads to cell dysfunction • obesity: excessive fat stores strain the heart (increased work load) → also leads to stress on joints

oxidative stress

free radical generation can overwhelm the mechanisms of removal, in which case a form of cell injury Oxidative stress commonly occurs in cells that undergo transient ischemia and subsequent resumption of circulation, also known as ischemic-reperfusion injury

What is ischemia?

inadequate blood flow

Differentiation

is the process whereby newly growing cells acquire the specialized structure and function of the cells they replace. For example, skin cells that are sloughed daily are replaced by normally differentiated epithelial cells. The new epithelial cells are structurally and functionally exact copies of the sloughed cells.

gangrene

ischemia , infarction, and necrosis of tissue exposed to bacteria that thrive on decaying tissue • clostridium perfringens= emits a gas w/ foul odor associated with _________

infarction

ischemic necrosis (death of cells)

What is angiogenesis?

it is the growth of new blood vessel branches. Exercise stimulates this. Exercise also increases the number of mitochondria in each muscle cell, which in turn increases energy production.

ischemia

lack of circulation (cells not getting enough O₂) Any tissue that sustains prolonged ischemia is susceptible to infarction, but individual cell types have dif- ferent tolerance levels.

histology

microscopic study of tissues and cells

Dysfunction of the Sodium-Potassium Pump -not functioning-

no ATP=cellular physiologic functions are reduced. When this active transport system is not functioning: ∙the normal osmotic balance is altered. ∙The intracellular sodium ion concentration is increased because it is not being adequately removed from the cell. -This increase in intracellular sodium draws in water, leading to cellular swelling.- *osmotic balance altered→intercellular Na⁺ concentration is ↑and not removed from cell = cellular swelling!!!* ∙With a lack of ATP, an energy-dependent calcium pump—which maintains intracellular calcium at extremely low levels—also becomes dysfunctional. As a result, calcium accumulates within the cell and disrupts numerous biochemical processes. ∙Calcium also activates a number of enzymes that further deplete ATP, damage the plasma membrane, disrupt DNA, and induce cell de- generation. Pathological calcification, the deposition of calcium and other minerals within tissues, occurs in a variety of conditions. Calcifications often accumulate in areas of cell injury and cell death

etiology

original cause of a cellular alteration or disease For example: the etiology of a sore throat is commonly streptococcus-a bacterial organism-

apoptosis

programmed cell death no adverse affects • genetically programmed results in cell death • Ex: ovaries undergo __________ around age 55 • Ex: WBCs undergo ___________ after participating in inflammatory reaction In another example, accelerated apoptosis of thyroid epithelial cells results in thyroid gland dysfunction. Hashimoto's thyroiditis is a common autoimmune disease that causes gradual failure of the thyroid gland because of increased apoptotic cell death. FIGURE 2-15. Apoptosis is a geneti- cally programmed step-by-step involutional cellular process. The cell shrinks, deoxyribonucleic acid undergoes orderly fragmentation, and organelles degenerate. The de- generated cells are phagocytosed by white blood cells, do not stimu- late inflammation, and do not have adverse effects on the body

metaplasia

the replacement of one cell type by another cell type. ∙likely a result of the cell's response to a change in environmental conditions. *Commonly, metaplasia occurs in response to chronic inflammation* • in esophagitis, the cells of the lower esophagus change to be able to w/stand with stomach acid, original flat epithelial cells turn to like columnar stomach cells → leads to disease called GERD • barrett's esophagus → can turn into dysplasia ?

pathognomonic changes

unique histological findings that represent distinct disease processes • find where cells originate from Example: an inflamed, crater-like breach in the GI mucosa, as seen on an endoscope exam of the stomach and duodenum, is pathognomonic for peptic ulcer disease.

endothelium

vasoconstrictor recreated by endothelial cells

nitric oxide

vasodilator secreted by endothelial cells

hypertrophy

• *increase in cell size* each individual cell becomes larger It increases the cell's functional components, which leads to a greater metabolic demand and energy needs! • example: increase in cell size in heart in response to hypertension -greater workload- • weight lifters have big muscles -increased workload= ventricular ___________

free radical damage (oxidative stress)

• Free radicals are oxidizing agents with the ability to penetrate the cell's plasma membrane, disrupt internal organelles, and damage the nucleus and its DNA. • they come from env or byproduct of energy making in mitochondria , enter into cells plasma membrane and cause dysfunction COUNTERACT THIS DAMAGE WIT H VIT A, E, C

cell injury

∙occurs when cells are exposed to a severe stress that no longer allows them to maintain homeostasis which results in structural or functional damage ∙can be reversible is the stimulus is removed. ∙If the stress is prolonged→cells reach critical point =organelle disruption and irreversible cell injury.

Neoplastic cells

∙resemble the normal, healthy cells within the tissue where they are found ∙are well-differentiated.

maladaptive changes

derangements of structure or function → not good for homeostasis

Physiologic versus pathological hypertrophy of heart muscle.

(A) In physiologic hypertrophy, the heart muscle is proportionately enlarged and significant coronary blood vessel growth occurs, allowing for sufficient coronary blood flow. (B) In this figure, there is disproportionate enlargement of the left ventricle compared with the remainder of the heart muscle. This is pathological hypertrophy of the left ventricle, which occurs in long-standing hypertension. In pathological hypertrophy, there is lack of growth of coronary vasculature to supply the enlarged cardiac muscle.

Bilirubin, a yellow-pigmented substance, has high affinity for ________?

*elastin* A transient accumulation of the cell breakdown product, bilirubin, occurs in jaundice. Bilirubin, a breakdown product of hemoglobin, can accumulate in the body in liver disorders or conditions of excess hemolysis -red blood cell breakdown- Bilirubin, a yellow-pigmented substance, has high affinity for elastin, a constituent of the sclera of the eye and skin. *Jaundice* the yellow hue of the skin and sclera, diminishes when bilirubin levels are reduced.

With left ventricular hypertrophy, the PMI is displaced to the ___________.

-LEFT- During cardiovascular physical assessment, left chest palpation locates the point of maximal impulse (PMI). The PMI's location correlates with the location of the heart's apex, which is usually located just under the left nipple. However, with left ventricular hypertrophy, the PMI is displaced to the *left.*

Pathological hypertrophy of cells can occur:

1) in disease processes 2) may be a compensatory maladaptation to changed environmental conditions.

Examples of hyperplasia that occur as a maladaptive compensatory mechanism-

A Keloid ∙occurs as a maladaptive compensatory mechanism when it overcompensates by ex- ceeding the cell mass necessary for regeneration. ∙Excessive numbers of cells in a specific tissue or organ can have detrimental effects. *For example, a keloid is a maladaptive hyperplastic accumulation of epithelial cells and connective tissue that can occur in wound healing. It creates an elevated, disfiguring scar that requires cosmetic surgery*

example of infectious agents that cause cell injury

A wide variety of microorganisms, including bacteria, viruses, fungi, and parasites, can cause cellular injury. What kjnd of cell injury is this: • helicobacteria erodes gastric mucosa • H pylori and stomach acid irritate the stomach or duodenum causing ulcers

intracellular accumulation

Accumulated substances may be harmless or toxic to the cell and can be transient or permanently imbedded in the cell. ∙If the accumulation is caused by a problem that can be brought under control, the cellular accumulation may be reversible. ∙However, if accumulation is progressive and continual, cellular injury can occur.

cellular accumulation- coal miners lung

An example of an environmentally derived cellular accumulation occurs in anthracosis, otherwise known as coal miner's lung disease. Individuals who chronically inhale coal dust demonstrate accumulations of this substance within respiratory tract epithelial cells, which leads to blackening of the lung tissues

intracellular accumulation- occurs in familial hypercholesterolemia

Another intracellular accumulation occurs in familial hypercholesterolemia, a condition that causes defective cholesterol metabolism. Xanthomas and xanthelasma are yellow, raised skin lesions that develop because of intracellular accumulation of excess cholesterol within epithelial cells.

As a result of hypertension, the left ventricle undergoes ____________ hypertrophy.

As a result of hypertension, the left ventricle undergoes *pathological* hypertrophy. During cardiovascular physical assessment, left chest palpation locates the point of maximal impulse (PMI). The PMI's location correlates with the location of the heart's apex, which is usually located just under the left nipple. However, with left ventricular hypertrophy, the PMI is displaced to the left.

Skeletal muscle cell atrophy versus hypertrophy.

Atrophy of the arm muscle occurs when skeletal muscle cells revert to a smaller size in response to changes in their environment such as: ∙lack of circulation ∙diminished workload -disuse- ∙decreased neural stimulation. Conversely, hypertrophy of the arm muscle occurs when skeletal muscle cells enlarge in size in response to increased workload.

prolonged ischemia

BASICALLY = INFARCTION • any tissue that sustains prolonged ischemia is susceptible to infarction, but individual cell types have different tolerance levels • brain: 6 minutes • heart: 20 min • skeletal muscle: many hours

why is the amount of oxygen delivered to the tissues decreased in carbon monoxide poisoning.

Carbon monoxide (CO) binds very tightly to the hemo- globin molecule, decreasing its oxygen-carrying capac- ity. This is why the amount of oxygen delivered to the tissues is decreased in carbon monoxide poisoning.

Cell Necrosis

Cell necrosis occurs when cells die because of stressors or insults that overwhelm the cell's ability to survive. Necrosis is an irreversible process

dysplasia

Dysplasia is deranged cellular growth within a specific tissue ∙often as a result of chronic inflammation or a precancerous condition. histological examination ↔ vary in size, shape, and architectural organization compared with healthy cells. Cervical dysplasia -Pap test- is a common example of this cellular change ∙frequent examinations- dysplasia is the classic precursor to cancer of the cervix.

Examples of hyperplasia stimulated by hormonal or compensatory cellular mechanisms-

Example: breast milk glands and tissue mass due to pregnancy Example: Hyperplasia caused by hormonal stimulation occurs in elderly males. As males age, prostate gland cells increase in number because of testosterone stimulation. As a result, a condition known as benign prostatic hyperplasia (BPH) occurs.

Consumption of ___________ can counteract free radical injury?

Individuals can counteract free radical injury through consumption of *antioxidants such as vitamin A, E, C, and beta-carotene*

What is pathological hypertrophy?

Occurs when there is an *increase in cellular size without an increase in the supportive structures necessary for the enlarged cell's in- creased metabolic needs.* For example: in hypertension, blood pressure within the aorta and systemic arterial circulation is elevated: ∙High aortic b/p → higher workload for the left ventricle ∙In response, each cardiac muscle cell undergoes pathological hypertrophy ∙Although each cardiac muscle cell increases in size, in pathological hypertrophy there is no corresponding in- crease in blood vessel growth to supply these muscle cells. As each cardiac muscle cell in the left ventricle undergoes hypertrophy, the whole left ventricle eventually hypertrophies. *cardiac muscles ↑ in size BUT no ↑ in blood vessel growth to supply new cell = whole left ventricle hypertrophy*

On mammography, micro calcifications ofter indicate that the tissue has _________ changes.

On mammography, microcalcifications ofter indicate that the tissue has *cancerous* changes.

What is an example of metaplasia involving GI?

One of the best examples of metaplasia can occur in gastroesophageal reflux disease (GERD). In GERD, the lower esophageal sphincter is weakened and allows stomach acid to reflux into the lower esophagus. The acid irritates the lower esophageal cells, causing inflammation of the esophagus. Without treatment and if prolonged, these lower esophageal cells, which are normally squamous epithelium type cells, transform into columnar stomachlike cells. The stomachlike cells have greater tolerance for the acid reflux

How does protein starvation affect the body?

Protein starvation causes low levels of albumin in the bloodstream, which leads to fluid shifting from the blood into the interstitial spaces. Excess fluid accumu- lation within the peritoneal cavity is most apparent in these starving individuals. The individuals demonstrate wasting of the trunk, bony extremities, and protuberant abdominal swelling.

endothelial cell injury

What kind of cell injury is this: • damage to endothelial cells causes inflammation which leads to→ atherosclerosis The endothelium can be considered the body's largest organ because of its vast area. When it is injured, there are widespread effects. Recognition that the arterial endothelium is an extensive, bodywide, active tissue that is highly vulnerable to injury is key to understanding cardiovascular disease. Endothelial cell injury acts as an initiator of arte-riosclerosis and the fundamental cell change that causes cardiovascular disease.

What would happen if there was a breach in the plasma membrane integrity?

With a breach of membrane integrity, injurious agents can affect any of the organelles. In addition, water can enter the intracellular compartment, causing cellular swelling. The mitochondria can be damaged, which would halt the cell's ability to produce energy. Organelles can swell and deteriorate. The nucleus, which contains the DNA, would be left vulnerable to injury and the cell will be left without regeneration ability

hormone therapy

can use this as an intervention to reverse cell injury for uterine hyperplasia (thickening of uterine wall)

acid suppression

can use this as an intervention to reverse cell injury treat excess gastric acid to treat Barretts esophagus

biopsy

cell sample from an organ or mass of tissue allow for histological examination

failure of apoptosis

cells that fail to do this can give rise to certain cancers, tumors, and can undergo detrimental hyperplasia cells changes Prostate cancer is theorized to arise from cells that lose their apoptotic function. In elderly males, the prostate gland enlarges because apoptosis fails and cells continually multiply. Some of the prostate cells that fail to experience apop- totic cell death undergo cancerous transformation.

atrophy

cellular adaptation in which cells revert to a smaller size in response to changes in metabolic requirements or their environment happens when cell's environment cannot support its metabolic requirements example: shrinking of the skeletal muscle cells in an individual with lower extremity paralysis

cellular hypoxia

• causes the cell to enter anaerobic metabolism → which generates 2 ATP -low amount of energy and pyretic acid which then changes to lactic acid. The inadequate cell energy slows down all metabolic functions and the lactic acid alters cellular biochemical activity. Lactic acid is particularly irritating to muscle cells. Anaerobic metabolism cannot sustain cell life for a prolonged time. • BIGGEST CAUSE OF CELL INJURY ∙Most common cause is diminished circulation= ischemia and its normally due to an obstruction of arterial blood flow. ∙Another cause is anemia because the blood lacks the hemoglobin which is the molecule in the RBC that carries oxygen. Lack of fully oxygenated blood= hypoxia Hypoxia can also be caused by high altitudes, pneumonia, suffocation injury or airway obstruction.

causes of cellular atrophy

• disuse/ diminished workload • lack of nerve stimulation (paralysis) • loss of hormonal stimulation • inadequate nutrition • decreased blood flow • aging

basic changes that occur in cell injury

• dysfunction of Na⁺ / K ⁺ pump • loss of plasma membrane integrity • defects in protein synthesis ability • intracellular accumulations → can lead to cancer • genetic damage

causes of endothelial cell injury

• hypertension: high shearing force against wall • free radicals: disrupt cell integrity • high glucose: in uncontrolled diabetes, glucose attaches to endothelial cells and disrupts their integrity. High-circulating glucose also stimu- lates the endothelium to secrete endothelin, a potent vasoconstrictor, thereby causing arterial narrowing. • hyperlipidemia: LDLs and WBCs combine in endothelial arterial wall to initiate beginnings of atherosclerosis

causes of cell injury

• hypoxic cell injury MOST COMMON CAUSE • free radical • physical agents of injury • chemical injury e..g. meds • infectious agent injury e..g. bacterial/ viral • injurious immunological reactions -immune system attacking itself- • genetic defects -mutated DNA → mutated RNA → mutated protein) • nutritional imbalances

hyperplasia

• increase in the number of cells only occurs in tissues with cells that are capable of mitotic division, such as the epithelium and glandular tissue.

Chapter Summary

∙Cells are vulnerable to many kinds of injurious agents that can cause adaptations, maladaptive changes, and reversible or irreversible damage. ∙Physical trauma, temperature extremes, electrical injury, radiation, free radicals, high circulating glucose in diabetes, and high blood pressure can all damage the plasma membrane and leave cellular organelles vulnerable to injury. ∙Atrophy is the diminished size and growth of tissue, whereas hypertrophy is an increase in the size of each individual cell of an organ or tissue. ∙The most common organ damaged by injurious agents is the endothelium. Endothelial injury initiates arte- riosclerosis, which leads to circulatory obstruction.

intracellular accumulation- can occur in the liver...

∙For example, intracellular accumulation can occur in the liver when exposed to excessive amounts of alcohol. Hepatocytes, which are integrally involved in lipid metabolism, can sustain toxic injury from alcohol and accumulate large quantities of intracellular fat. Fatty liver is a distinctive histological change associated with alcoholism that causes the liver to enlarge and become dysfunctional

*summary*

∙Hypertension, high cholesterol levels, hyperglycemia, and free radicals are major injurious agents of the endothelium. ∙Ischemia is the lack of adequate blood flow to tissues. Ischemia leads to cellular hypoxia, the most common form of cell injury. Prolonged ischemia leads to infarc- tion or death of tissue. ∙Apoptosis is the cell's genetically programmed degeneration. ∙Transplantation may not be the only remedy for nonre- generative organs. ∙Cellular regeneration is under investigation, and stem cells and therapeutic cloning are the methods under intense scrutiny.

Conditions That Cause Pathological Calcification

∙In arteriosclerosis, calcifications accumulate within long-standing plaque. Calcified plaque is hardened, fragile, and likely to break apart into small pieces that can travel in the bloodstream. ∙Aortic sclerosis, a common disorder in elderly individuals, involves a calcified aortic heart valve. Calcification causes thickening and narrowing of the heart valve with consequent blood disruption. ∙On mammography, a breast lesion containing microcalcifications is often indicative of a malignancy. Calcium deposits are seen within the nutrient- deprived cells of a malignant tumor in the breast.

example of chemical cell injury

∙can be caused by either endogenous, biological substances or exogenous, synthetic substances that influence the cell. ∙Chemical agents commonly injure the plasma membrane and gain access to the cell's interior to cause dysfunction of organelles. Imbalances of the body's biological chemical constituents, such as electrolytes, can cause cell injury. ∙For example, high sodium levels in the bloodstream, termed hypernatremia, cause intracellular fluid depletion (cellular dehydration) and reversible cell shrinkage. ∙In uncontrolled diabetes mellitus (DM), hyperglycemia, cause chemical injury of the endothelial cells that line the arteries. High levels of blood glucose can damage the coronary and cerebral arteries, arteries of the kidneys, vessels of the lower extremity, and the retina of the eyes. DM initiate the process of atherosclerosis: coronary artery disease, peripheral arterial disease, and cerebrovascular disease ∙Alternatively, exogenous chemical substances such as drugs, environmental pollutants, or poisons can cause cellular injury in various ways. Many drugs, such as non- steroidal anti-inflammatory drugs (NSAIDs) and antibiotics such as aminoglycosides, can have nephrotoxic side effects. Nephrotoxic drugs have chemically damaging ef- fects on the cells of the kidney's nephron tubules.

Benign neoplasms

∙contain well-differentiated cells, or cells that resemble the healthy cells of the tissue of origin. ∙ cells do not metastasize or break loose from the tissue of origin.

malignant melanoma

∙malignant melanoma (skin cancer) = poorly differentiated, neoplastic epithelial cells, which do not look or act like normal skin cells, replace normal epithelial cells. The cells are arranged in a disorganized fashion so that when viewed with a microscope, the normal cellular arrangement or tissue architecture is altered

neoplasia

∙new growth ∙disorganized, uncoordinated, uncontrolled proliferative cell growth that is cancerous. ∙can be benign or malignant, depending on an differentiation