GENERAL PATHOLOGY
CELL INJURY
DR. AHMED SAMI JARAD
INTRODUCTION
Pathology is the scienti c study (logos) of disease (pathos). It mainly focuses on the
study of the structural and functional changes in cells, tissues, and organs in disease.
Study of pathology can be divided into:
• General pathology: It deals with the study of mechanism, basic reactions of cells and
tissues to abnormal stimuli and to inherited defects.
• Systemic pathology: This deals with the changes in speci c diseases
In medieval times, diseases were attributed to “evil humors,” “miasma,” and other
equally nebulous and unprovable causes. One of the most fundamental advances in
human biology and medicine was the realization that the cell is the structural and
functional unit of living organisms and abnormalities in cells underlie all diseases:
Individuals are sick because their cells are sick. All diseases share the common feature
that they alter cellular function and structure.
Therefore, the foundation of pathology and medicine is an understanding of how cells are
injured.
OVERVIEW OF CELL INJURY
In response to stress, cells may adapt, may be injured reversibly and recover, or
may be irreversibly damaged and die.
Cells normally maintain a steady state, called homeostasis, despite being constantly
exposed to countless potentially damaging agents. Cells deal with external or internal
stresses by undergoing changes that are grouped into three broad categories.
• Adaptations are alterations that enable cells to cope with stresses without damage.
• Reversible injury refers to structural and functional abnormalities that can be corrected
if the injurious agent is removed. If the injury is persistent or severe, it can become
irreversible and lead to cell death.
• Irreversibly injury (Cell death) is the end result of injury. As we discuss later, there are
two major pathways of cell death, necrosis and apoptosis, and they occur upon exposure
to a variety of injurious agents.
Causes of Cell Injury
ETIOLOGY OF CELL INJURY
The cells may be broadly injured by two major ways:
A. Genetic causes (Genetic abnormalities), including mutations that impair the function of
various essential proteins and other mutations that lead to the accumulation of
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GENERAL PATHOLOGY
CELL INJURY
DR. AHMED SAMI JARAD
damaged DNA or abnormal, misfolded proteins, both of which cause cell death if they
cannot be repaired or corrected
B. Acquired causes
The acquired causes of disease comprise vast majority of common diseases a icting
mankind. Based on underlying agent, the acquired causes of cell injury can be further
categorized as under:
1. Hypoxia and ischaemia Hypoxia (reduced oxygen supply) and ischemia (reduced blood
supply), which are caused by blockage of arteries or loss of blood; both deprive tissues of
oxygen.
2. Physical agents. (Environmental insults, such as physical trauma, radiation exposure,
and nutritional imbalances).
3. Chemical agents and drugs and Toxins, which abound in the environment, as well as
some therapeutic drugs
4. Biological agents Infectious pathogens, which injure cells by producing toxins,
interfering with critical cellular functions, or by stimulating immune responses that
damage infected cells in the course of trying to eradicate the infection.
5. Immunologic agents Immunologic reactions against self antigens (as in autoimmune
diseases) or environmental antigens (as in allergies), which cause cell injury, often by
triggering in ammation.
6. Nutritional derangements
7.Aging, a form of slow, progressive cell injury.
8. Psychogenic diseases
9. Iatrogenic factors
10. Idiopathic diseases.
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.
Cellular adaptations may be part of physiologic cellular responses or may be pathologic.
# 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).
# # Pathologic adaptations are responses to stress that allow cells to modulate their
structure and function and thus escape injury, but at the expense of normal function.
Physiologic and pathophysiologic adaptations can take several distinct forms.
• Hypertrophy is an increase in the size of cells resulting in enlargement of the organ
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GENERAL PATHOLOGY
CELL INJURY
DR. AHMED SAMI JARAD
It can be physiologic or pathologic and is caused either by an increased functional
demand or by hormonal stimulation. For example, physiologic enlargement of the uterus
during pregnancy is caused by increased estrogen levels. Muscle hypertrophy following
weight lifting is an adaptation to increased mechanical stress. Cardiac hypertrophy in
hypertension or aortic valve disease is an example of pathologic hypertrophy resulting
from increased work load.
In all forms, hormones and mechanical sensors activate signaling pathways that lead to
increased protein synthesis and assembly of more organelles, and thus enlargement of
the cell. Although an adaptation to stress, hypertrophy can progress to functionally
signi cant cell or organ injury if the stress is not relieved. For example, cardiac
hypertrophy can cause myocardial ischemia due to relative lack of oxygen delivery, and
eventually give rise to cardiac failure.
• Hyperplasia is an increase in the number of cells in an organ that stems from
increased proliferation, either of less-di erentiated progenitor cells or, in some
instances, di erentiated cells.
- Hyperplasia occurs if the tissue contains cell populations capable of replication and
may occur concurrently with hypertrophy and often in response to the same stimuli.
- Hyperplasia can be physiologic or pathologic and, in both situations, cellular
proliferation is stimulated by hormones and growth factors that are produced by a
variety of cell types.
- Postpartum enlargement of the breast due to increased proliferation of ductular
epithelium is an example of physiologic hyperplasia induced by hormones.
- Growth factors are responsible for stimulating proliferation of surviving cells after death
or removal of some of the cells in an organ (e.g., growth of residual liver following
partial hepatectomy, called compensatory hyperplasia).
- Pathologic hyperplasia is typically the result of inappropriate and excessive stimulation
by hormones and growth factors, as in endometrial hyperplasia resulting from a
disturbed estrogen, progesterone balance.
- It is important to distinguish hyperplasia from neoplasia: Unlike neoplastic growths,
hyperplasia is reversible when the growth signals abate. In some cases, persistent
pathologic hyperplasia, such as that a ecting the endometrium, sets the stage for the
development of cancer because proliferating cells are susceptible to mutations and
oncogenic transformation.
• Atrophy is a decrease in size or function of an organ that occurs under pathologic or
physiologic circumstances. It is caused by decreased protein synthesis (due to reduced
metabolic activity) and increased protein breakdown mediated by the ubiquitinproteasome pathway.
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DR. AHMED SAMI JARAD
- Physiologic atrophy (i) Atrophy of lymphoid tissue with age; (ii) Atrophy of thymus in
adult life; (iii) Atrophy of gonads after menopause; (iv) Atrophy of brain with ageing; and
(v) Osteoporosis with reduction in size of bony trabeculae due to ageing.
- Pathologic atrophy (1) Starvation atrophy; (2) Ischaemic atrophy Gradual diminution of
blood supply due to atherosclerosis may result in shrinkage of the a ected organ; (3)
Disuse atrophy Prolonged diminished functional activity is associated with disuse
atrophy of the organ; (4) Neuropathic atrophy Interruption in nerve supply leads to
wasting of muscles e.g. poliomyelitis; (5) Endocrine atrophy Loss of endocrine
regulatory mechanism results in reduced metabolic activity of tissues and hence
atrophy; and (6) Pressure atrophy Prolonged pressure from tumors or cyst or aneurysm
may cause compression and atrophy of the tissues.
• Metaplasia is a change of one adult cell type to another. It is a response to stress in
which a cell that is sensitive to that stress is replaced by another cell type that is better
able to survive the adverse environment.
- The mechanism is thought to be reprogramming of tissue stem cells to di erentiate
along a new pathway. Examples include squamous metaplasia of the bronchial
columnar epithelium in chronic smokers and columnar metaplasia of the esophageal
squamous epithelium in patients with chronic gastric re ux.
- Also, with the persistence of triggering stimuli, metaplastic epithelium can be the site of
neoplastic transformation, as in the bronchi (squamous cell carcinoma of the lung) and
upper gastrointestinal tract (esophageal adenocarcinoma arising in the setting of
Barrett esophagus).
Other conditions with su x(-asia )
• Dysplasia means ‘disordered cellular development’, often preceded or accompanied
with metaplasia and hyperplasia; it is therefore also referred to as atypical hyperplasia.
Dysplastic changes often occur due to chronic irritation or prolonged in ammation. On
removal of the inciting stimulus, the changes may disappear. In a proportion of cases,
however, dysplasia may progress into carcinoma in situ (cancer con ned to layers
super cial to basement membrane) or invasive cancer.
• Aplasia is failure o f cell production during embryogenesis (e.g., unilateral renal
agenesis).
• Hypoplasia is a decrease in cell production during embryogenesis, resulting in a
relatively small organ (e.g., streak ovary in Turner syndrome).
REVERSIBLE CELL INJURY
Reversible injury is characterized by functional and structural changes in cells that are not
permanent. The earliest changes associated with cell injury mostly a ect cytoplasmic
structures but do not damage nuclei (nuclear damage is usually irreversible) and include
the following:
HYDROPIC SWELLING
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DR. AHMED SAMI JARAD
Hydropic swelling is characterized by a large, pale cytoplasm and a normally located
nucleus. The greater volume re ects an increased water content. Hydropic swelling
re ects acute, reversible cell injury and may result from such varied causes as chemical
and biologic toxins, viral or bacterial infections, ischemia, excessive heat or cold, etc.
- Hydropic swelling is entirely reversible when the cause is removed.
- Hydropic swelling results from impairment of cellular volume regulation, a process that
controls ionic concentrations in the cytoplasm.
- This regulation, particularly for sodium (Na+), involves three components: (1) the
plasma membrane, (2) the plasma membrane Na+ pump and (3) the supply of
adenosine triphosphate (ATP).
- The plasma membrane imposes a barrier to the ow of Na+ down a concentration
gradient into the cell and prevents a similar e ux of potassium (K+) from the cell.
However, the barrier to Na+ is imperfect, and the relative leakiness to that ion permits
its passive entry into the cell. To compensate for this intrusion, the energy-dependent
plasma membrane Na+ pump (Na+/K+-ATPase), which is fueled by ATP, extrudes Na+
from the cell. Injurious agents may interfere with this membrane-regulated process by
(1) increasing the permeability of the plasma membrane to Na+, thereby exceeding the
capacity of the pump to extrude Na+; (2) damaging the pump directly or (3) interfering
with the synthesis of ATP, thereby depriving the pump of its fuel. In any event, the
accumulation of Na+ in the cell leads to an increase in water content to maintain
isosmotic conditions; the cell then swells.
- With persistent or excessive noxious exposures, injured cells pass a nebulous “point
of no return” and undergo cell death. Although there are no de nitive morphologic or
biochemical correlates of irreversibility, it is consistently characterized by three
phenomena: the inability to restore mitochondrial function (oxidative phosphorylation
and ATP generation) even after resolution of the original injury; altered structure and
function of the plasma membrane and intracellular membranes-, and DNA damage and
loss of chromatin structural integrity.
IRREVERSIBLE CELL INJURY
(CELL DEATH)
Necrosis and apoptosis, the two main forms of cell death, di er in causes, mechanisms,
and functional consequences.
Necrosis and apoptosis are usually distinct forms of cell death, with di erent morphologic
changes and other distinguishing features. Necrosis may be thought of as “accidental”
cell death, re ecting severe injury that irreparably damages so many cellular components
that the cells simply “fall apart”. When cells die by necrosis, there is a local in ammatory
response that clears the scene of the “accident.” By contrast, apoptosis is “regulated”
cell death, because it is mediated by de ned molecular pathways that are activated under
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GENERAL PATHOLOGY
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DR. AHMED SAMI JARAD
speci c circumstances and kill cells with surgical precision, without in ammation or the
associated collateral damage.
* In some situations, cell death may show features of both necrosis and apoptosis, or may
start with apoptosis and progress to necrosis, so the distinctions may not be as absolute
as once thought. Nevertheless, it is useful to consider the two forms as largely non
overlapping pathways of cell death because their principal mechanisms and functional
consequences are usually di erent.
Necrosis
Necrosis is the result of severe injury and is a pathologic process in which cells spill their
contents into the extracellular milieu, causing local in ammation.
The hallmarks of necrosis are:
• Dissolution of cellular membranes, including the plasma membrane and lysosomal
membranes, because of damage to membrane lipids and activity of phospholipases
• Leakage of lysosomal enzymes that digest the cell.
• Local in ammation in response to the released contents of dead cells. Some speci c
components of these contents have been called damage-associated molecular
patterns (DAMPs). These released factors include ATP (from damaged mitochondria),
uric acid (a breakdown product of DNA), and numerous other molecules that are
normally contained within healthy cells and whose release indicates severe cell injury.
These molecules are recognized by receptors expressed by macrophages and most
other cell types, and trigger phagocytosis of the debris, as well as the production of
cytokines that induce in ammation. In ammatory cells produce more proteolytic
enzymes that exacerbate the damage and the subsequent reaction, until the necrotic
tissue has been cleared.
The main causes of necrosis include ischemia, exposure to microbial toxins, burns and
other forms of chemical and physical injury, and unusual situations in which enzymes leak
out of cells and injure adjacent tissues (as in pancreatitis). All these initiating triggers lead
to irreparable damage to numerous cellular components, which culminate in membrane
damage, the basis for the subsequent steps in necrosis.
Morphology. Necrotic cells show more di use cytoplasmic eosinophilia compared with
that seen in reversible injury. Nuclei undergo sequential changes, from condensation of
chromatin (pyknosis) to fragmentation of nuclei (karyorrhexis) to their complete
dissolution (karyolysis).
Necrosis from di erent causes is manifested by di erent morphologies, and recognition
of these patterns is helpful for determining the underlying etiology
• Coagulative necrosis, the underlying tissue architecture is preserved, at least for
some time, even though the constituent cells are dead. This form of necrosis is
characteristic of hypoxia-induced cell death, caused most commonly by a loss of blood
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supply (ischemia). The resultant necrosis, called infarction, is seen in most solid
organs, such as the heart and kidneys.
• liquefactive necrosis, the dead cells are digested by released enzymes. This is seen in
necrosis resulting from bacterial and fungal infections and in ischemic infarcts of the
brain.
• Caseous necrosis is characteristic of chronic disease such as tuberculosis and some
fungal infections such as histoplasmosis. The dead tissue breaks down, creating a
cheesy consistency on gross examination. Microscopically, the necrotic focus is a
collection of fragmented or lysed cells with an amorphous granular pink (eosinophilic)
appearance. Cellular outlines cannot be discerned, and there is often a peripheral
collection of macrophages forming & granuloma.
• Gangrenous necrosis is a clinical term used for the death of soft tissue and is often
applied to a limb that has lost its blood supply and has undergone coagulative necrosis
involving multiple tissue layers. It results from ischemia (e.g., from diabetic vascular
disease, a ecting the lower limbs) and is called dry gangrene if the dead tissue
remains intact or wet gangrene if the tissue su ered from liquefaction necrosis or Gas
gangrene.
• Fat necrosis refers to focal areas of fat destruction, typically resulting from the release
of activated pancreatic lipases into the substance of the pancreas and the peritoneal
cavity. This occurs in acute pancreatitis. On histologic examination, the foci of necrosis
contain shadowy outlines of necrotic fat cells surrounded by basophilic calcium
deposits and an in ammatory reaction
• Fibrinoid necrosis is a characteristic microscopic nding seen most commonly in
immune reactions in which complexes of antigens and antibodies and extravasated
plasma proteins are deposited in the walls of blood vessels, where they have a bright
pink, amorphous appearance reminiscent of brin.
* * The laboratory diagnosis of necrosis may be made by detecting an increase in serum
levels of intracellular proteins, which leak out of the necrotic cells because of membrane
damage. This is the basis of measuring serum troponin for diagnosis of myocardial
infarction, transaminases for liver disease, and pancreatic enzymes such as amylase for
pancreatitis.
Apoptosis
Apoptosis is a form of cellular suicide that eliminates cells that are no longer needed or
are damaged beyond repair, without eliciting a potentially harmful in ammatory response.
In this pathway of cell death, enzymes activated by speci c signals dismantle the nucleus
and cytoplasm, generating fragments that are recognized and rapidly cleared by
phagocytes.
Causes of Apoptosis
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GENERAL PATHOLOGY
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DR. AHMED SAMI JARAD
Apoptosis occurs in many physiologic situations and serves to eliminate potentially
harmful cells and cells that have outlived their usefulness. It also occurs as a pathologic
event when cells are damaged, especially when the damage a ects the cell’s DNA or
proteins; thus, the irreparably damaged cell is eliminated.
• Physiologic apoptosis
- Death of cells during the development of organisms, such as cells of primordial tissues
that are replaced by mature tissues
- Death of leukocytes (neutrophils and lymphocytes) after in ammatory and immune
responses have eliminated o ending agents
- Elimination of dysfunctional or auto reactive lymphocytes or lymphocyte precursors,
particularly in the bone marrow and the thymus
- Cell loss that alternates with cell proliferation in hormone-responsive tissues such as
the endometrium
- Elimination of lymphocytes that recognize self antigens
• Pathologic apoptosis
- Severe DNA damage, after exposure to radiation or cytotoxic drugs
- Accumulation of misfolded proteins, giving rise to ER stress
- Certain infectious agents, particularly some viruses such as hepatitis B and C, which
trigger immune responses that destroy infected cells.
Mechanisms of Apoptosis
There are two pathways of apoptosis, the mitochondrial (intrinsic) pathway and the death
receptor (extrinsic) pathway, which di er in their initiation and molecular signals.
• Clearance of apoptotic fragments. When cells undergo apoptosis, they begin to
express a number of molecules that are recognized by receptors on phagocytes.
Phagocytes ingest and destroy the fragments of apoptotic cells, often within minutes,
before the cells undergo membrane damage and release their contents. The
phagocytosis of apoptotic cells is so e cient that dead cells disappear without leaving
a trace, and in ammation is virtually absent. The morphologic appearance of apoptotic
cells is distinctive and di erent from necrosis. In H&E-stained sections, the nuclei
appear pyknotic, because of the condensation of chromatin, and the cells are
shrunken, appearing to lie in vacuoles.
Other Pathways of Cell Death
Although necrosis and apoptosis are the best-de ned pathways of cell death, several
other mechanisms have also been described recently.
• Necroptosis is induced by activation of speci c kinases in response to the cytokine
tumor necrosis factor (TNF), which is produced as part of the host response to
microbes and other irritants. Signals from these kinases lead to plasma membrane
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injury, as in necrosis, but the process is regulated by speci c molecules, like apoptosis,
so it is considered to have features of both.
• Pyroptosis is a form of cell death induced by bacterial toxins in which the dying cell
releases cytokines, such as interleukin-1, that induce local in ammation and fever
(hence pyro in the name).
• Autophagy is a form of “self-eating” (Greek, phagia - to eat) in which cells starved of
nutrients digest their own organelles and recycle the material to provide energy for
survival. In this process, organelles and portions of the cytosol are enclosed within
vacuoles, which fuse with lysosomes, and the contents are destroyed by lysosomal
MECHANISMS OF CELL INJURY AND DEATH
The degree of injury from any injurious stimulus varies depending on the type of the
o ending agent, its severity, and its duration, as well as the adaptive ability and genetic
makeup of the target cell.
Small amounts of a toxin or brief periods of ischemia may cause reversible injury but
larger doses of the toxin or more prolonged ischemia may cause necrosis. Striated
muscle in the leg survives ischemia for 2 to 3 hours, whereas cardiac muscle, with its
higher metabolic needs, dies after 20 to 30 minutes of ischemia. The genetic makeup of
the individual may also determine the reaction to injurious agents. Polymorphisms in
genes encoding members of the cytochrome P450 family a ect the rate of metabolism of
many chemicals and hence the e ects of toxins.
Cell injury results from abnormalities in one or more essential cellular components, mainly
mitochondria, cell membranes, and the nucleus.
The consequences of impairment of each of these cellular organelles are distinct but
overlapping.
• Mitochondria are the sites where ATP, the primary carrier of energy in cells,
is produced by oxidative phosphorylation. Injury due to hypoxia, ischemia, radiation, or
other insults impairs oxidative phosphorylation, leading to the formation of reactive
oxygen species (ROS) and decreased ATP production. Mitochondria also sequester
molecules, such as cytochrome c, whose release into the cytosol is an indicator of
damage and a trigger for apoptosis.
• Cellular membranes are composed of lipids and contain protein and carbohydrate
molecules. They maintain the structure of cells and organelles and serve numerous critical
transport functions such as uid and ion homeostasis. Damage to lysosomal membranes,
by ROS or other agents, leads to release of enzymes that digest the injured cell, the
hallmark of necrosis. Damage to the plasma membrane results in loss of cellular
constituents, the end result of necrosis.
• Nuclei store most of the cell’s genetic material. Nuclear damage disrupts transcriptiondependent cellular functions (i.e., protein synthesis), as well as cell proliferation.
Irreparable damage to DNA triggers apoptosis.
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• Other cellular components that su er damage upon exposure to various injurious agents
include the ER (one site of protein synthesis and post- translation processing) and the
cytoskeleton (the structural sca old and “motor” of cells).
• In addition to cell injury resulting from impairment of these intrinsic structures, cells may
be damaged from the outside, for example, by the products of leukocytes during
in ammatory reactions.
FREE RADICAL INJURY
I. BASIC PRINCIPLES
A. Free radicals are chemical species with an unpaired electron in their outer orbit.
B. Physiologic generation of free radicals occurs during oxidative phosphorylation. 1.
Cytochrome c oxidase (complex IV) transfers electrons to oxygen.
2. Partial reduction of O2 yields superoxide (O2ꜙ), hydrogen peroxide (H2O2 ), and
hydroxyl radicals ( ̇ OH ).
C. Pathologic generation of free radicals arises with
1. Ionizing radiation - water hydrolyzed to hydroxyl free radical
2. In ammation - NADPH oxidase generates superoxide ions during oxygendependent killing by neutrophils.
3. Metals (e.g., copper and iron)-Fe2+ generates hydroxyl free radicals (Fenton
reaction).
4. Drugs and chemicals - P450 system of liver metabolizes drugs (e.g.,
acetaminophen), generating free radicals.
D. Free radicals cause cellular injury via peroxidation of lipids and oxidation of DNA
and proteins; DNA damage is implicated in aging and oncogenesis.
E. Elimination of free radicals occurs via multiple mechanisms.
1. Antioxidants (e.g., glutathione and vitamins A , C, and E) 2. Enzymes
I) Superoxide dismutase (in mitochondria) - Superoxide (O2ꜙ) → H2O2
II) Glutathione peroxidase (in mitochondria) - 2GSH + free radical → GS-SG
and H2O
III) Catalase (in peroxisomes) - H2O2 → O2ꜙ and H2O
3. Metal carrier proteins (e.g., transferrin and ceruloplasmin)
II. EXAMPLES OF FREE RADICAL INJURY A. Carbon tetrachloride (CCl4)
1. Organic solvent used in the dry cleaning industry
2. Converted to CCl3 free radical by P450 system of hepatocytes
3. Results in cell injury with swelling of RER; consequently, ribosomes detach,
impairing protein synthesis.
4. Decreased apolipoproteins lead to fatty change in the liver (Fig. 1.12).
B. Reperfusion injury
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1. Return of blood to ischemic tissue results in production of O2-derived free
radicals, which further damage tissue.
2. Leads to a continued rise in cardiac enzymes (e.g., troponin) after reperfusion of
infarcted myocardial tissue
Cellular Aging
Cells age because of accumulation of mutations, progressively decreased replication, and
defective protein homeostasis.
People age because their cells age. Although much of the public’s attention on aging is
focused on its cosmetic and physical consequences, the greatest danger of cellular aging
is that it promotes the development of many degenerative, metabolic, and neoplastic
disorders. Numerous intrinsic molecular abnormalities are believed to cause the aging of
cells.
- Accumulation of mutations in DNA, which occurs naturally and may be enhanced by
ROS and environmental mutagens.
- Decreased replication of cells because of progressive loss of the enzyme telomerase,
which maintains the normal length of the enzyme telomeres. These short DNA
sequences at the ends of chromosomes protect the ends from fusion and degradation.
Telomeres shorten with every replication but can be maintained by the activity of the
enzyme telomerase. Because most cells (except germ cells) contain little or no
telomerase, telomere shortening is inevitable in dividing cells. With complete loss of
telomeres during cellular aging, the “naked” chromosome ends activate the DNA
damage response, causing the cells to enter a state of replicative senescence.
- Defective protein homeostasis, due to increased turnover and decreased synthesis of
intracellular proteins, together with accumulation of misfolded proteins.
- Altered signaling pathways that may a ect responses to growth factors. There has
been great interest in de ning these pathways, in part because of the intriguing
observation that calorie restriction prolongs life. One possibility is that calorie restriction
reduces signaling by insulin-like growth factor, so cells cycle less and su er fewer DNA
replication-related errors
- In addition to these intrinsic abnormalities, damaged and dying cells induce low-level
in ammation, and chronic in ammation predisposes to many diseases, such as
atherosclerosis, type 2 diabetes, and some types of cancer.
❖In humans, the modest correlation in longevity between related persons, the excellent
concordance of life span among identical twins and the presence of heritable disease
associated with accelerated aging (progeria) lend credence to the concept that aging is
in uenced by genetic factors.
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PATHOLOGIC ACCUMULATIONS IN CELLS
• Cells may accumulate abnormal amounts of various substances, which may be
harmless (e.g., carbon particles in the lungs and mediastinal lymph nodes of city
dwellers) or may cause varying degrees of injury.
• The substance may be located in the cytoplasm, within organelles (typically lysosomes),
or in the nucleus, and it may be synthesized by the a ected cells or it may be produced
elsewhere.
• The main pathways of abnormal intracellular accumulations are inadequate removal and
degradation or excessive production of an endogenous substance, or deposition of an
abnormal exogenous material.
Some examples are described in the following.
Fatty change (steatosis).
- Steatosis is the accumulation of lipids, most often in the liver following prolonged
alcohol consumption or in obese individuals as a component of nonalcoholic fatty liver
disease.
Cholesterol and cholesteryl esters.
- Phagocytic cells may become overloaded with lipid (triglycerides, cholesterol, and
cholesteryl esters) in several di erent pathologic processes, mostly characterized by
increased intake or decreased catabolism of lipids. Of these, atherosclerosis is the
most important example.
Pigments.
Pigments of several types may accumulate in cells.
Exogenous Substances
Anthracosis refers to the storage of carbon particles in the lung and regional lymph nodes
Virtually all urban dwellers inhale particulates of organic carbon generated by the burning
of fossil fuels. These particles accumulate in alveolar macrophages and are also
transported to hilar and mediastinal lymph nodes, where the indigestible material is stored
inde nitely within macrophages. Although the gross appearance of the lungs of persons
with anthracosis may be alarming, the condition is innocuous.
Tattoos are the result of the introduction of insoluble metallic and vegetable pigments
into the skin, where they are engulfed by dermal macrophages and persist for a lifetime.
Endogenous pigments
- Lipofuscin is a brownish, granular material composed of lipids and proteins that is
produced by free radical-mediated lipid peroxidation. Its accumulation in cells is a sign
of free radical-mediated injury, so it is often seen in older individuals and in atrophic
tissues.
- Hemosiderin is a hemoglobin-derived brown pigment that accumulates in phagocytes
and other cells in conditions of increased red cell breakdown or iron overload.
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- Melanin is an insoluble, brown-black pigment found principally in the epidermal cells of
the skin but also in the eye and other organs. It is located in intracellular organelles
known as melanosomes and results from the polymerization of certain oxidation
products of tyrosine. The amount of melanin is responsible for the di erences in skin
color among the various races, as well as the color of the eyes. It serves a protective
function, owing to its ability to absorb ultraviolet light. In white persons, exposure to
sunlight increases melanin formation (tanning).
Glycogen.
- Excessive intracellular deposits of glycogen are associated with abnormalities in the
metabolism of either glucose or glycogen. Glycogen may accumulate in poorly
controlled diabetes or in glycogen storage diseases.
Calcium.
Calcium salt deposits are seen in a variety of disease states.
- Dystrophic calci cation occurs in the setting of normal serum calcium and is the
deposition of calcium salts in injured tissue (e.g., in areas of caseous necrosis and in
advanced atherosclerosis). Dystrophic calci cation can have functional consequences,
as in calci c stenosis of the aortic valve causing left ventricular hypertrophy due to
pressure overload .
- Metastatic calci cation occurs in the setting of hypercalcemia, which is seen in states
of hyperparathyroidism , or increased bone destruction, as in cancers involving the
bone. Metastatic calci cation occurs widely throughout the body but principally a ects
the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa. It usually
does not cause clinical dysfunction.
Amyloid.
- Amyloid consists of one of many di erent proteins that assume a brillar conformation
and are deposited in extracellular tissues, where they may interfere with the normal
functions of organs. Amyloid deposition is often related to immune processes.
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