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cell injury
Recovery
Normal
72
6.3.5 Nucleic Acid Damage
Nucleic acids, especially the genome composed of DNA, provide the basic code by which all
proteins in the cell are synthesised. Nucleic acid damage can result from free radical cell injury or
the activation of nucleases following increases in cytosolic calcium. Significant damage to the
DNA genome generally activates mechanisms of apoptosis, which end in programmed cell
death(1– 6, 43).
6.4 Responses toCell Injury
As described in Chapter5, understanding normal cell structure and function is essential to studying
cellular responses to injury. The response to cell injury can be reversible (sublethal), with eventual
restoration (i.e. healing) of standard or near- normal cellular structure and function, or irreversible
(lethal) with progression from degeneration to death of the cell (Figure6.1). Irreparable DNA damage
can result in permanent growth arrest (senescence), cell death or malignant transformation(1, 6, 43).
6.4.1 Reversible Cell Injury
Reversible injury is usually mild, and after the negative influences are removed, the cell reverts
to its normal steady state (Figure6.2). At this stage, the injury has not caused severe membrane damage or nuclear dissolution(1– 7, 43). Cell swelling (hydropic degeneration) is the
most crucial event resulting from the influx of water and sodium ions when the sodium–
potassium ion pumps fail.
Normal
cell
Swelling of
endoplasmic
reticulum and
mitochondria
Cell injury
Swelling of endoplasmic reticulum
Swollen mitochondrion with amorphous densities
Reversible
cell injury
Clumping of
chromatin
Membrane blebs
and loss of ribosomes
Myelin figures
Nuclear condensation
Lysosome rupture
of cell
Irreversible
Recovery
Necrosis
Fragmentation
of cell membrane
and nucleus
cell
Cell death
Figure6.2 Normal cell and the changes in reversible and irreversible cell injury. Miller etal.
(43)/with permission of Elsevier.
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6.5 Cell Death
Table6.1 Morphological findings inreversible andirreversible cell injury.
Morphological findings of reversible cell injury
● Cellular swelling (increased influx of water into the cytoplasm and mitochondria)
● Nuclear chromatin clumping
● Ribosomal detachment secondary to decreased protein synthesis
● Membrane blebbing
● Fatty change
Morphological findings of irreversible cell injury
● Plasma membrane damage
● Lysosomal rupture
● Autolysis
● Increased mitochondrial permeability
● Changes in the nuclei include:
– Pyknosis
– Karyorrhexis
– Karyolysis
Source: Lineage Medical, Inc./https://step1.medbullets.com/pathology/106028/cell- injury/last accessed on
03February, 2024.
6.4.2 Irreversible Cell Injury andCell Death
73
Severe cell damage can cause irreversible cell injury and cell death (necrosis) (Figure6.2) (1, 2, 43).
The principal targets of irreversible cell injury are the cell membranes, mitochondria, protein synthesis machinery and DNA. Damage to the nucleus presents in pyknosis, karyorrhexis and karyolysis(2, 3, 43). Pyknosis is characterised by condensation of the chromatin. Karyorrhexis refers to
nuclear fragmentation, the dissolution of the structure of the nucleus and the lysis of chromatin
by enzymes such as DNase and RNase, which marks karyolysis. Multiple cellular abnormalities
resulting from the damage can cause cell death (necrosis) (Table6.1). Cytoplasmic enzymes such
as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase
(LDH) are released from the injured cells(1– 4, 43).
6.5 Cell Death
Cell death may result from several distinct and highly regulated energy- dependent processes
(apoptosis, pyroptosis and autophagy) or energy- independent processes (oncosis/necrosis)(1– 8, 22).
6.5.1 Apoptosis
Apoptosis is a physiological process characterised by programmed cell death. Cells undergoing
apoptosis show typical, well- defined morphological changes. These include plasma membrane
blebbing, chromatin condensation with margination of chromatin to the nuclear membrane and
karyorrhexis and the formation of apoptotic bodies. Apoptosis is generally non- inflammatory and
results in the orderly removal of damaged cells from tissues without inducing collateral damage to
surrounding cells(1– 8, 39, 43).
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6.5.2 Necrosis
Necrosis typically occurs when extensive damage to the cell membrane occurs, and the injury is
irreversible. Morphological characteristic features of necrotic cell death include increased cell volume (oncosis), swollen organelles and plasma membrane rupture, which results in subsequent
loss of intracellular contents. Necrosis occurs when cells are depleted of ATP and lack sufficient
energy to maintain membrane- associated ionic pumps. This leads to swelling and gross calcium
influxes that disrupt the mitochondrial and plasma membranes, including releasing lysosomal
enzymes(1, 2, 44, 45).
6.5.2.1 Types ofNecrosis
Six distinct patterns of necrosis are identifiable: coagulative necrosis, liquefactive necrosis, caseous
necrosis, gangrenous necrosis, fibrinoid necrosis and fat necrosis(1, 2, 44, 45).
Coagulative necrosis occurs when blood flow to cells stops or slows (ischaemia). It can occur
anywhere in the body except the brain. Injury denatures structural proteins and lysosomal
enzymes. This phenomenon blocks the damaged cells’ proteolysis. Coagulative necrosis aims to
preserve the basic outline of the coagulated cell for at least some time(46). Coagulative necrosis
does not have a zone between necrotic cells and viable cells. As most of the structural remnants of
the necrotic tissue remain, labile adjacent to the affected tissue will replicate and replace the cells
killed during the event(47).
Cells constantly undergo mitosis, which can help reform the tissue. In contrast, nearby stable
and permanent cells (e.g. neurons and cardiomyocytes) do not undergo mitosis and will not replace
the affected tissue(1– 7, 47).
Liquefaction or colliquative necrosis is usually associated with bacteria, viruses, parasites or
fungal infections. It is characteristically seen in hypoxic cell death in the brain and suppurative
(pus or abscess- producing) bacterial infections. Liquefactive necrosis forms a viscous liquid mass
as the dead cells are digested. The affected tissue is liquified by the action of hydrolytic enzymes
released from the lysosomes in the brain or released from the neutrophils in the pus/abscess.
Microorganisms can release enzymes to degrade cells and initiate an immune and inflammatory
response(43, 48). The gross appearance of liquefaction necrosis includes a liquid- like layer (pus)
and yellowing, softening, or swelling and softening (malacia) of the tissue. A cystic space is usually
present for tissue resolution. Liquefaction necrosis is common after cell death in lipid- rich tissue
such as the brain (cerebral infarction)(1, 3, 43).
Caseous necrosis occurs when the immune system and body cannot successfully remove
the foreign noxious stimuli, as in pulmonary tuberculosis, where there is an aberrant immune
response to the mycobacteria. The immune system seals the foreign matter using fibroblasts,
lymphocytes, neutrophils, natural killer (NK) cells, dendritic cells and macrophages. A granuloma may form with fibroblast cells creating an encasing layer, leukocytes and the formation of
Langhans giant cells (fusion of epithelioid cells). Gross appearance includes a yellow- white
soft cheesy sphere enclosed by a distinct border. Microscopic appearance consists of a granuloma(1– 7, 43).
Gangrenous necrosis is a form of coagulative necrosis. The term gangrenous necrosis term
generally describes the damage to the tissues where there is severe ischaemia. Two types of gangrene occur: Dry and wet. Dry gangrene is usually seen in the lower limb. It is non- infected ischaemic coagulative necrosis of tissue. It is seen as a complication of atherosclerosis and diabetes
mellitus(1– 7, 30, 43). The affected part is dry, skinny and dark reddish- black. Severe frostbite
injuries can also lead to dry gangrene. When dry gangrene is infected with bacterial (putrefactive)
t.me/Dr_Mouayyad_AlbtousH
infection, it is called wet gangrene. In moist gangrene, the coagulative necrosis of the dry
gangrene is modified by the action of the bacteria into liquefactive necrosis. The limb becomes
foul- smelling and black and starts decomposing. Wet gangrene has a poor prognosis compared
to dry gangrene because the infection can spread to the rest of the body, causing septicaemia
and can be life- threatening. When Clostridium perfringens and other clostridial species cause
wound infection, it is characterised by extensive tissue necrosis and gas production by the fermentative action of the bacteria. This condition is gas gangrene. The gross appearance resembles wet gangrene(1– 7, 43).
Fibrinoid necrosis is associated with vascular damage caused mainly by autoimmunity,
immune- complex deposition, infections and the exudation of plasma proteins such as fibrin.
Fibrinoid is not the same as fibrinous. Fibrinous denotes the deposition of fibrin, which occurs in
inflammation and blood coagulation. The fibrinoid pattern typically occurs due to type 3 hypersensitivity, where an immune complex is formed between an antigen (Ag) and an antibody (Ab).
Fibrin, a non- globular protein involved in blood clotting, is leaked out of the vessels. Creating an
amorphous bright pink fibrin- like (fibrinoid) material in an H&E stain(1– 7, 43).
Fat necrosis can occur from acute inflammation affecting tissues with numerous adipocytes (as
in breast tissue). Damaged cells release digestive enzymes, which break down lipids to generate
free fatty acids. Fat necrosis’s gross appearance includes whitish deposits due to the formation of
calcium soaps. Microscopically, an infiltrate of foamy macrophages adjacent to adipose tissue is a
predominant feature. Multinucleated giant cells, lymphocytes and plasma cells are often present(2– 7, 43, 49). Fat necrosis can be seen in acute pancreatitis (acute inflammation of the pancreas causing necrosis of pancreatic acinar cells and lipase release) or from trauma to fatty tissues.
Disorders of necrosis include myocardial infarction (Coagulative necrosis), cerebral infarction (liquefaction necrosis), pulmonary tuberculosis (caseous necrosis) and gangrene of the lower extremities (gangrenous necrosis).
Some examples of necrotic lesions in oral tissues include irreversible pulpitis, necrotising
ulcerative gingivitis (NUG), necrotising ulcerative periodontitis (NUP) and necrotising ulcerative
stomatitis (NUS)(1– 7, 43).
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6.6 Cellular Adaptations
When exposed to an external or internal insult, a cell can react to this injury differently depending on the circumstances. Cell response can lead to adaptation, apoptosis or necrosis. Adaptation
is a reversible response that can alter cell function and structure, thus attempting to maintain
homeostasis(1– 7, 43). Two types of cellular adaptations occur: Physiological and pathological.
Physiological adaptations represent tissue responses to intrinsic or extrinsic stimuli, such as
normal stimulation by hormones or endogenous chemical mediators, as evidenced in the
enlargement of the uterus and breasts in pregnancy(1– 7, 43). Pathological adaptation represents responses in which tissues modulate their structure and function to escape permanent
injury. Whether physiological or pathological, adaptations include hypertrophy (an increase in
the size of constituent cells and intercellular substance), hyperplasia (an increase in the number
of constituent cells), atrophy (reduction in the size of cells and tissues), metaplasia (a change in
the type of differentiation of a cell or tissue) and dysplasia (abnormal growth refers to individual cell populations in a tissue or organ or the tissue itself). Dysplasia, however, should be
considered a disease state rather than adaptation(1– 7, 43).
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6.6.1 Hypertrophy
Hypertrophy is an increase in the cells resulting in the organ’s size(2, 6). Types of hypertrophies
are known as physiologic or pathologic. Hypertrophy is caused by increased functional demand or
specific hormonal stimulation. It may be a compensatory response to injury when parenchymal
cells are damaged or lost. For instance, cardiac myocytes cannot divide following myocardial
infarction to replace destroyed muscle fibres. Still, residual myocytes enlarge (hypertrophy) to
replace some of the functions of the lost myofibers(1– 8, 22).
6.6.2 Hyperplasia
Hyperplasia is an increase in the number of cells that increases the organ’s size. Hyperplasia differs
from neoplastic cellular proliferation in that hyperplastic cells generally subside if the stimulus is
removed(1– 8). This response can occur only in a cell population capable of cell division (mitosis).
These are called labile cells. Bone marrow haemopoietic cells, epithelial cells of the skin and
mucosae of the mouth, intestine, vagina, cervix and ductal epithelia of exocrine glands, including
those of the salivary glands and epithelia of the uterus and the urinary tract are examples of labile
cells(1– 7, 50, 51).
Cells in these tissues quickly undergo hyperplasia in response to hormonal stimulation, inflammation or physical trauma(1– 7, 43). The liver, kidney and pancreas cells are stable cells with only
a minimal replicative capacity in their normal state. However, these cells can increase in response
to injury or loss of tissue mass. Conversely, striated muscle, cardiac muscle cells and neurons do
not undergo hyperplasia due to their negligible capacity to proliferate. Cells of these tissues, called
permanent tissues, are terminally differentiated and non- proliferative(1– 8, 43).
Hyperplasia can be physiologic or pathologic. Physiologic hyperplasia is divided into two forms:
hormonal hyperplasia and compensatory hyperplasia. Compensatory hyperplasia is the proliferation of cells that maintain their differentiated structure and function(1– 7, 43).
6.6.3 Atrophy
Cellular atrophy is the shrinkage of cell size caused by losing cell substances. Atrophic cells may
have diminished functions. Decreased protein synthesis and increased protein degradation causes
atrophy (1– 8, 22). Atrophic cells exhibit fewer mitochondria and endoplasmic reticulum.
Autophagosomes take up damaged organelles, where their digestion and lysis occur. Undigested
residues remain in the cytoplasm as a lipid- rich brown pigment, as in brown atrophy of the heart
or brown atrophy of the testis(1– 7, 43).
Causes of atrophy may include decreased workload, as in immobilisation of a limb after a bone
fracture (disuse atrophy), loss of innervation, diminished blood supply, inadequate nutrition, loss
of endocrine stimulation and senile atrophy(1– 7, 43).
6.6.4 Metaplasia
Metaplasia is a reversible change in which another adult cell type replaces one adult cell type. It is
not known to occur during embryonic development. Generally, it results from persistent cellular
trauma and is a protective mechanism. Metaplasia may be induced or accelerated by some abnormal stimulus, which includes acid or base (causing a change in pH), hormones, cigarette smoke or
alcohol(1– 4, 52– 54).
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6.7 Cellular Degenerations
6.7 Cellular Degenerations
Non- lethal injury to a cell may cause cell degeneration (retrogressive change), manifested as some
abnormality of biochemical function, a recognisable structural change or a combined biochemical
and structural abnormality(1– 8, 22). Degeneration is reversible but may progress to necrosis if the
injury persists. Cellular degenerations include hydropic degeneration, cellular fatty change, cloudy
swelling, hyaline degeneration, mucoid (myxoid/myxomatous) degeneration, fibrinoid degeneration
and glycogen storage(1– 7, 43).
6.7.1 Hydropic Degeneration/Cloudy Swelling/Vacuolar Degeneration
Hydropic change means water accumulation within the cell’s cytoplasm. Other synonyms used are
cloudy swelling because of the gross appearance of the affected organ and vacuolar degeneration
because of cytoplasmic vacuolation. Hydropic swelling is an entirely reversible change upon
removal of the injurious agent(1– 7, 43).
The common causes of hydropic degeneration include acute and subacute cell injury from various agents such as bacterial toxins, chemicals, poisons, burns, high fever and intravenous administration of hypertonic glucose or saline. Ischaemia and chemical damage are two major stimuli
leading to hydropic change(1– 7, 43). Loss of blood supply due to ischaemia results in decreased
oxygen tension inside the cell and ATP depletion. There is also a loss of oxidative phosphorylation,
causing reduced ATP generation and failure of the Na
cellular sodium, water and extracellular potassium, leading to cellular swelling. Activation of the
anaerobic pathway causes the accumulation of catabolites (phosphates and lactates), causing
increased osmotic load and cellular swelling(1– 8, 22). Hydropic change may also be due to directly
or indirectly acting chemical agents. Chemical agents cause increased cell membrane injury. Some
examples include cyanide poisoning, antineoplastic drugs and tetrachloride. Some agents can
release highly toxic free radicals, causing lipid peroxidation and cell membrane damage with
increased sodium and water influx, causing cellular swelling(1– 7, 43).
+K+
pump. Such a situation increases intra-
77
6.7.2 Cellular Fatty Change (Fatty Degeneration)
Fatty change (or older term fatty degeneration) is the accumulation of neutral fat within parenchymal cells. The term neutral fat is also taken as a synonym for triglycerides. Fatty change is widespread in the liver but may occur in other non- fatty tissues, such as the heart, skeletal muscle and
kidneys. The causes of fatty change in the liver include obesity, diabetes mellitus, alcoholism, starvation, protein- calorie malnutrition, chronic illnesses (e.g. tuberculosis), acute fatty liver in late
pregnancy, hypoxia (due to anaemia, cardiac failure), use of hepatotoxins (e.g. carbon tetrachloride, chloroform, ether, aflatoxins and other poisons), administration of methotrexate, steroids and
halothane anaesthetic(1– 7, 43).
6.7.3 Hyaline Change
The word ‘hyaline’ means glassy (halos=glass). Hyalinisation is a common descriptive histologic
term for the glassy, homogeneous, eosinophilic appearance of proteinaceous material in hematoxylin and eosin- stained sections and does not refer to any specific substance(1– 8, 22). Hyaline
change is seen in heterogeneous pathologic conditions and may be intracellular or extracellular.
Intracellular hyaline is mainly seen in epithelial cells(1– 7, 43).
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6.7.4 Mucoid Degeneration
Mucoid means mucus- like. The mucus is the secretory product of mucous glands and is a
combination of proteins complex with mucopolysaccharides. Mucin, a glycoprotein, is its chief
constituent(1– 7, 43). Mucin is usually produced by epithelial cells of mucous membranes, glands
and some connective tissues, such as the ground substance in the umbilical cord. By convention,
connective tissue mucin is termed myxoid.
6.7.5 Fibrinoid Degeneration
Fibrinoid degeneration is essentially extracellular. Two types of connective tissue degenerations
occur connective tissue fibrinoid and vascular fibrinoid. Connective tissue fibrinoid degeneration
is formed by the breakdown of collagen fibres and the mucopolysaccharide ground substance
between the fibres, resulting in a material with similar staining properties to fibrin(1– 7, 43).
6.8 Pathologic Calcification
Pathologic calcification refers to depositing calcium phosphates (CaP) or other calcific salts at sites
that would not usually have become mineralised. Two distinct types of pathologic calcification are
recognised: dystrophic calcification and metastatic calcification(1– 8, 43). Dystrophic calcification is
characterised by the deposition of calcium salts in dead or degenerated tissues with normal calcium
metabolism and serum calcium levels. Metastatic calcification occurs in normal tissues and is associated with deranged calcium metabolism and hypercalcaemia. Metastatic calcification deposition can
be influenced by releasing excess calcium salts from bone, phosphate concentration, alkaline phosphatase activity and viscera physicochemical conditions under alkalosis(1– 7, 54, 55).
6.9 Summary
When cells are injured, one of the two responses can occur: reversible or irreversible. The former
leads to adaptation of the cells (and tissue), and the latter leads to cell death and tissue damage.
Aetiologies of cell injury include hypoxia, temperature extremes, physical trauma, chemicals,
ischaemia, immunological reactions, toxins, infectious agents, genetic abnormalities, nutritional
imbalances and ageing. Response to a given stimulus depends on the injured cell’s type, status and
genetic makeup. General biochemical mechanisms include loss of energy (ATP depletion, O
depletion), mitochondrial damage, loss of calcium homeostasis, defects in plasma membrane permeability, generation of ROS and other free radicals. The most common morphologically apparent
adaptive changes are hypertrophy, hyperplasia, atrophy and metaplasia. Apoptosis is programmed
cell death. Necrosis is cell death caused by a lack of nutrients or infection. Non- lethal injury to a
cell may cause cell degeneration, manifested as some abnormality of biochemical function, a recognisable structural change or a combined biochemical and structural abnormality. Cellular
degenerations include hydropic degeneration, cellular fatty change, cloudy swelling, hyaline
degeneration, mucoid (myxoid/myxomatous) degeneration, fibrinoid degeneration and glycogen
storage. Pathologic calcification occurs in two types: Dystrophic calcification is the abnormal deposition of calcium phosphate in dead or dying tissue. Metastatic calcification is calcium deposition
in normal tissues as a consequence of hypercalcaemia.
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