Chap 1 : Cell Injury, Cell Death, and Adaptations

Dr Lina Haffar

Pr Of Pathology

Chap 1 : Cell Injury, Cell Death, and Adaptations

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Cell Injury, Cell Death, and Adaptations

• Introduction to Pathology• Overview of Cellular Responses to Stress and

Noxious Stimuli • Causes of Cell Injury • Sequence of Events in Cell Injury and Cell Death• Mechanisms of Cell Injury and Cell Death• Cellular Adaptations to Stress• Intracellular Accumulations • Pathologic Calcification • Cellular Aging

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MECHANISMS OF CELL INJURY AND CELL DEATH

• The cellular response to injurious stimuli depends on

the type of injury, its duration, and its severity.

• The consequences of an injurious stimulus also depend on the type, status, adaptability, and geneticmakeup of the injured cell.

• Cell injury usually results from functional and biochemical abnormalities in one or more of a limited number of essential cellular components .

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MECHANISMS OF CELL INJURY AND CELL DEATH

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I- Hypoxia and Ischemia

• Deficiency of oxygen leads to failure of many energy-dependent metabolicpathways, and ultimately to death of cells by necrosis.

• Persistent or severe hypoxia and ischemia ultimately lead to failure of ATP generation and depletion of ATPin cells.

• Reduced activity of plasma membrane ATP-dependent sodium pumps

• The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation, decreased intracellular pH

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I- Hypoxia and Ischemia

• Structural disruption of the protein synthetic apparatus , manifested as detachment of ribosomes from the rough ER (RER) and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis.

• Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes , and the cell undergoes necrosis.

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II - Oxidative Stress

• Oxidative stress refers to cellular abnormalities that are induced by ROS, which belong to a group of molecules known as free radicals.

• Free radical-mediated cell injury is seen in many chemical and radiation injury, hypoxia, cellular aging,……..

• In all these cases, cell death may be by necrosis or apoptosis

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• Oxidative Stress

• ROS are produced by two major pathways :

• ROS are produced normally in small amounts in cells during the reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy generation.

• ROS are produced in phagocytic leukocytes, mainly neutrophils and macrophages, as a weapon for destroying ingested microbes and other substances during inflammation and host defense

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• Cell Injury Caused by Reactive Oxygen Species

• ROS causes cell injury by damaging multiple components of cells :

• Lipid Double bonds in membrane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals.

• Crosslinking and other changes in proteins.

resulting in enhanced degradation or loss of enzymatic Activity

• DNA damage. Such DNA damage has been implicate in apoptotic cell death, aging, and malignant transformation of cells.

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• - Cell Injury Caused by Toxins

• Toxins, including environmental chemicals and substances produced by infectious pathogens

• Different types of toxins induce cell injury by two general mechanism:

• Direct-acting toxins.

Some toxins act directly by combining with a critical

molecular component or cellular organelle.

For example, in mercuric chloride poisoning (as may occur from ingestion of contaminated seafood)

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• Latent toxins. Many toxic chemicals are not intrinsically active but must first be converted to reactive metabolites, which then act on target cells.

Carbon tetrachloride (CCl 4 )—once widely used in the dry cleaning industry but now banned—

and the analgesic acetaminophen belong in this category.

• The effect of CCl 4 is still instructive as an example of chemical injury.

• CCl4 is converted to a toxic free radical, principally in the liver, and this free radical is the cause of cell injury, mainly by membrane phospholipid peroxidation

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III- Endoplasmic Reticulum Stress• Intracellular accumulation

of misfolded proteins may be caused by abnormalities that increase the production of misfolded proteins or reduce the ability to eliminate them.

• Protein misfolding within cells may cause disease by creating a deficiency of an essential protein or by inducing apoptosis.

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III- Endoplasmic Reticulum Stress• The accumulation of

misfolded proteins in a cell lead to cell death by apoptosis.

• During normal protein synthesis, chaperones in the ER control the proper folding of newly synthesized proteins,

• If unfolded or misfolded proteins accumulate in the ER, they first induce a protective cellular response that is called the unfolded protein response

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IV- DNA Damage• Exposure of cells to radiation

or chemotherapeutic agents, intracellular generation of ROS, and acquisition of mutations may all induce DNA damage, which if severe may trigger apoptotic death.

• Damage to DNA is sensed by intracellular sentinel proteins, which transmit signals that lead to the accumulation of p53 protein.

• p53 first arrests the cell cycle (at the G1 phase) to allow the DNA to be repaired before it is replicated

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• V- Inflammation

• A common cause of injury to cells and tissues is the inflammatory reaction that is elicited by pathogens, necrotic cells, and dysregulated immune responses, as in autoimmune diseases and allergies.

• In all these situations, inflammatory cells, including neutrophils, macrophages, lymphocytes, and other leukocytes, secrete products that evolved to destroy microbes but also may damage host tissues.

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CELLULAR ADAPTATIONS TO STRESS

• Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment.

Two types of adaptations :

• Physiologic adaptations

• Pathologic adaptations

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• Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormone-induced enlargement of the breast and uterus during pregnancy), or to the demands of mechanical stress (in the case of bones and muscles).

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• Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury, such as squamous metaplasia of bronchial epithelium in smokers.

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• Hypertrophy

• Hyperplasia

• Atrophy

• Metaplasia

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• Hypertrophy• Hypertrophy is an increase in the size of cells resulting in an

increase in the size of the organ. • In contrast, hyperplasia is an increase in cell number. • In pure hypertrophy there are no new cells, just bigger cells

containing increased amounts of structural proteins and organelles.

• Hyperplasia is an adaptive response in cells capable of replication, whereas hypertrophy occurs when cells have a limited capacity to divide.

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• Hypertrophy

• Hypertrophy and hyperplasia also can occur together, and obviously both result in an enlarged organ.

• Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by growth factor or hormonal stimulation.

• The massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen-stimulated smooth muscle hypertrophy and smooth

muscle hyperplasia

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• An example of pathologic hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease

-Myocardium adapts by undergoing hypertrophy to generate the required higher contractile force.

-If, on the other hand, the myocardium is subjected to reduced blood flow (ischemia) due to an occluded coronary artery, the muscle cells may undergo injury.

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• Hyperplasia• Hyperplasia is an increase in the number of cells

in an organ that stems from increased proliferation, either of differentiated cells or, in some instances, less differentiated progenitor cells.

• Hyperplasia takes place if the tissue contains cell populations capable of replication; it may occur concurrently with hypertrophy and often in response to the same stimuli.

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• Hyperplasia• Hyperplasia can be physiologic or

pathologic; in both situations, cellular proliferation is stimulated by growth factors that are produced by a variety of cell types

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• Hyperplasia• The two types of physiologic hyperplasia are

(1) hormonal hyperplasia, exemplified by the proliferation of the glandular epithelium of the female breast at puberty and during pregnancy, and

(2) compensatory hyperplasia, in which residual tissue grows after removal or loss of part of an organ.

For example, when part of a liver is resected, mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal size.

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• Atrophy• Atrophy is shrinkage in the

size of cells by the loss of cell substance.

• When a sufficient number of cells are involved, the entire tissue or organ is reduced in size, or atrophic .

• Although atrophic cells may have diminished function, they are not dead.

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• Atrophy

• Cellular atrophy results from a combination of decreased protein synthesis and increased protein degradation.

• Protein synthesis decreases because of reduced metabolic activity.

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• Metaplasia

• Metaplasia is a change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type.

• In this type of cellular adaptation, a cell type sensitive to a particular stress is replaced by another cell type better able to withstand the adverse environment.

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• Metaplasia• Metaplasia is thought to arise by

the reprogramming of stem cells to differentiate along a new pathway rather than a phenotypic change (trans differentiation) of already differentiated cells.

• Epithelial metaplasia is exemplified by the change that occurs in the respiratory epithelium of habitual cigarette smokers, in whom the normal ciliated columnar epithelial

cells of the trachea and bronchi

often are replaced by stratified

squamous epithelial cells .32

• Metaplasia

• not always occur in the direction of columnar to squamous epithelium; in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium.

• The influences that induce metaplastic change, if persistent, may predispose to malignant transformation.

• In fact, squamous metaplasia of the respiratory epithelium often coexists with lung cancers composed of malignant squamous cells.

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INTRACELLULAR ACCUMULATIONS

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• The main pathways of abnormal intracellular accumulations are inadequate removal and degradation or excessive production of an endogenous substance, or deposition of an abnormalexogenous material .

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• Fatty change

• Cholesterol and Cholesteryl Esters.

• Proteins.

• Glycogen.

• Pigments.

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• Fatty Change :

• also called steatosis, refers to any accumulation of triglycerides within parenchymal cells.

• It is most often seen in the liver, since this is the major organ involved in fat metabolism, but also may occur in heart, skeletal muscle, and other organs.

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• Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, or anoxia.

• Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations.

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Cholesterol and Cholesteryl Esters.

• Cellular cholesterol metabolism is tightly regulated to ensure normal generation of cell membraneswithout significant intracellular accumulation.

• However, phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and cholesteryl esters) in several different pathologic processes, mostly characterized by increased intake or decreased catabolism of lipids.

• Of these, atherosclerosis is the most important.

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• Proteins.

• Morphologically visible protein accumulations are less common than lipid accumulations;

• they may occur when excesses are presented to the cells or if the cells synthesize excessive amounts.

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• Proteins.

• In the kidney, for example, trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules.

• However, in disorders with heavy protein leakage across the glomerular filter (e.g., nephrotic syndrome), much more of the protein is reabsorbed, and vesicles containing this protein accumulate, giving the histologic appearance of pink, hyaline cytoplasmic droplets.

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• Glycogen.• Excessive intracellular deposits of glycogen are

associated with abnormalities in the metabolism of either glucose or glycogen.

• In poorly controlled diabetes mellitus DM, the prime example of abnormal glucose metabolism, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans

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• Pigments.

• Pigments are colored substances that are either exogenous, coming from outside the body, such as carbon, or are endogenous, synthesized within the body itself, such as lipofuscin, melanin, and certain derivatives of hemoglobin.

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• Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow granular intracellular material that

accumulates in a variety of

tissues (particularly the

heart, liver, and brain) with

aging or atrophy

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• Melanin is an endogenous, brown-black pigment that is synthesized by melanocytes located in the epidermis and acts as a screen against harmful UV radiation

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• Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron.

• Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles.

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CELLULAR AGING

• Individuals age because their cells age.

• Although public attention on the aging process has traditionally focused on its cosmetic manifestations, aging has important health consequences, because age is one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease.

• Cellular aging is the result of a progressive decline in the life span and functional activity of cells.

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CELLULAR AGINGSeveral abnormalities contribute to the aging of cells

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CELLULAR AGING

• 1- • Accumulation of mutations in DNA.

• A variety of metabolic insults over time may result in damage to nuclear and mitochondrial DNA.

• ROS induced by toxins and radiation exposure contribute to DNA damage associated with aging.

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CELLULAR AGING

• 2 - Decreased cellular replication.

• Normal cells (other than stem cells) have a limited capacity for replication, and after a fixed number of divisions, they become arrested in a terminally nondividing state, known as replicative senescence.

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• Replicative senescence occurs in aging cells because of progressive shortening of

telomeres, which ultimately results in cell cycle arrest.

• Telomeres are short repeated sequences of DNA present at the ends of chromosomes that are important for ensuring the complete replication of chromosome ends and for protecting the ends from fusion and degradation.

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• When somatic cells replicate, a small section of the telomere is not duplicated, and telomeres become progressively shortened.

• As they shorten, the ends of chromosomes cannot be protected and are sensed in cells as broken DNA, which signals cell cycle arrest.

• Telomere length is maintained by nucleotide addition mediated by an enzyme called telomerase.

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• Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes.

• Telomerase is expressed in germ cells and is present at low levels in stem cells, but absent in most somatic cells

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• Therefore, as mature somatic cells age, their telomeresbecome shorter and they exit the cell cycle, resulting in an inability to generate new cells to replace damaged ones.

• Conversely, in immortalized cancer cells, telomerase is usually reactivated and telomere length is stabilized, allowing the cells to proliferate indefinitely.

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Chap 1 : Cell Injury, Cell Death, and Adaptations