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5 Cellular Structure andFunction
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6
Cell Injury: Causes, Mechanisms andResponses
S. R. Prabhu
School of Dentistry, University of Queensland, Brisbane, Queensland, Australia
6.1 Introduction
Cell survival depends on several factors. Constantly available energy, intact cell plasma membrane,
genetic integrity, directed cell division, homeostasis and cell safety and function are important factors determining cell survival. Severe disruption of these factors can lead to cellular damage.
Regardless of the injury, cells are injured through a series of interdependent essential biochemical
pathways. A slight disruption of basic biochemical processes allows cells to survive and recover.
However, an often irreversible event, such as cell death, occurs when these biochemical processes
are severely disrupted. Cells, tissues and whole organs can adapt if they are placed under continuous, non- lethal stress. Adaptation enables tissues to function despite changed conditions(1– 5).
6.2 Causes ofCell Injury
Most tissue and organ injuries begin at the cellular level. Many processes and factors can cause
cellular injury, including hypoxia, ischaemia, reperfusion injury, heat shock, ionising radiation,
shock, chemicals, medical and illegal drugs, infectious diseases, malnutrition, genetic and metabolic diseases, immunity and ageing(1– 5). These causes are briefly explained below.
6.2.1 Injury Dueto Hypoxia, Ischaemia andReperfusion
Hypoxia: A lack of oxygen reaching the tissues is the cause of hypoxia. When there is no oxygen at
all, it is called anoxia. These are the most common causes of cell injury. In some cases, the cause of
hypoxia is simply an insufficiency of the total amount of oxygen in the blood. For example, hypoxemia is when the partial pressure of oxygen in arterial blood is too low. Arterial blood may have a
normal oxygen tension, but in conditions such as anaemia, the circulating blood oxygen cannot be
transported adequately due to very little haemoglobin. In other cases, when the blood does not
perfuse tissues properly, the rate of tissue oxygenation decreases significantly. Such a situation is
often seen in shock when the heart fails, and oxygenated blood can no longer circulate(1, 2, 6, 7).
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Edited by S. R. Prabhu, Syed Ali Khurram,
Omar Kujan and Merva Soluk Tekkesin.
© 2025 John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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Ischaemia: The lack of blood supply to tissues due to blocked blood vessels is ischaemia, which can
result in a lack of oxygen and nutrients in the tissues. A blood vessel can narrow when it becomes
blocked due to thrombosis or, more commonly, embolism. Acute local declines in blood pressure may also occur due to a haemorrhaging artery. In the event of shock, blood pressure may
decrease, causing ischaemia. Ischaemic injury can also cause cellular acidosis more rapidly and
more severely than pure hypoxic injury because, in the absence of a blood supply, byproducts of
cellular metabolism (e.g. lactic acid from glycolysis anaerobic) are collected locally(2, 8– 10).
Reperfusion: Restoration of the flow of blood to an organ or tissue is called reperfusion(1– 7).
Sudden reperfusion of ischaemic tissue can lead to the development of cellular injury. Ischaemic
cells suffer severe damage in their membrane permeability. When blood flow is restored, fluid
with a high level of calcium occurs, thus potentially enhancing cytosolic calcium derangement.
Viable ischaemic cells also suffer severe damage to their mitochondrial function. When oxygen
and nutrients are restored, excessive amounts of reactive oxygen species (ROS) are produced by
mitochondria, causing cellular damage from free radicals(1, 9, 11– 13).
6.2.2 Mechanical Injury
Vehicular accidents are one of the most common causes of tissue injuries. External and internal
injuries are common in serious accidents. Mechanical force can cause many types of damage(1– 4).
6.2.3 Injuries Dueto Temperature Extremes
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Excesses of heat (hyperthermia, thermal burns) and cold (hypothermia, cryogenic burns) are
important causes of cell and tissue damage(1– 4). Flames, hot liquids, solid objects and vapours
cause excessive heat- related burns. Severe burns can destroy the epidermis with loss of skin
appendages. Low- intensity burns can damage blood vessels, accelerate specific cellular reactions
or stop the reaction of temperature- sensitive enzymes. Extreme heat (thermal burns) denatures
enzymes and other proteins(1– 7).
Excessive cold causes vasoconstriction, limiting blood supply to cells and tissues. Cryogenic
burns, on the other hand, create ice crystals in the cytosol and destroy cell membranes. Causes of
cryogenic burns include contact with frozen metal, dry ice, frostbite or liquid nitrogen(1– 7, 14).
6.2.4 Ionising andNon- ionising Radiation Injury
Radiation has two forms: electromagnetic (EM) and particle (PR). EM radiation is a form of electric and magnetic waves that radiate energy, and PR consists of accelerated, fast- moving particles
such as electrons and protons(1– 7, 15). Electromagnetic (EM) radiation can be divided into ionising and non- ionising. Both types can occur in clinical or environmental settings, and exposure can
affect cells and tissues positively or negatively(2, 15– 18).
6.2.4.1 Ionising Radiation
Ionising radiation exists in natural environmental sources. In clinical practice, ionising radiation
is used in cancer treatment, diagnostic imaging and as diagnostic or therapeutic radioisotopes(1– 7,
19). Ionising radiation can damage cells by producing water or molecular oxygen free radicals.
Ionising radiation is mutagenic, carcinogenic and teratogenic(15– 18). Ionising radiation damages
DNA, causing mutations and neoplastic transformation of cells(20, 21). Ionising radiation can
also cause vascular damage, causing ischaemic necrosis of parenchymal cells(15– 18).
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6.2.4.2 Non- ionising Radiation Injury
Non- ionising radiation is a type of radiation that does not provide enough energy per quantum
(photon energy) to ionise an atom or molecule. Near ultraviolet, visible light, infrared, microwaves,
radio waves and low- frequency radio frequencies (long waves) are examples of non- ionising radiation(20). Ultraviolet radiation can cause skin and lip cancer in fair- skinned outdoor individuals
exposed to chronic sunlight(15– 18).
6.2.5 Electrical Shock Injury (Electrical Burns)
Heat is generated as an electric current passes through tissues, causing electrical burns. The type
of injury and the severity and extent of burns depends on the amperage and path of electric current
within the body(1– 7, 14). Once the current enters the body, it is conducted through tissues of least
resistance, especially the nervous system. Disruption of impulses in brainstem respiratory centres,
the cardiac conduction system, or neuromuscular junctions occur, resulting in indirect injury to
cells and tissues(2, 14). The term ‘electrocution’ refers only to a person killed due to electricity
exposure. This term is not used for someone exposed to electricity and survives.
6.2.6 Chemical Injury
A wide variety of chemicals can cause cellular injury. Any chemical in a gaseous, liquid or solid
form that has the potential to cause injury is called a hazardous chemical. Chemicals pose many
health risks, including irritation, sensitivity, carcinogenicity, flammability, corrosion and explosiveness(1– 7, 19). Chemicals sometimes directly affect cell plasma membranes or mitochondria(4, 19).
In other cases, the drug is metabolised into a toxic compound, notably by xenobiotic- metabolising
enzymes in the liver. Metabolic manipulation of these chemicals often produces reactive intermediates that can cause cell damage through free radicals. Free radical attacks usually result in reactions
between the attacked molecules, which no longer can fulfil their biological functions. Interference
of lipids in the plasma or mitochondrial membrane can affect selective permeability (1– 7). Free
radicals can attack nucleic acids and trigger the apoptotic pathway(1, 2, 19).
Chemical damage can be broadly divided into acid burns and alkali burns. Other less common
injuries include phosphorous burns and chemical injections. Acid burns cause coagulative necrosis. The alkaline solution causes saponification and then necrosis by liquefaction. Chemical damage causes tissue damage through necrosis due to the coagulation of tissue proteins(1– 7, 19).
Toxic substances include pollutants, pesticides, asbestos and ethanol. When concentrated
enough, even harmless substances such as glucose or salt can disrupt the osmotic environment
and damage cells. Chemicals labelled as toxic can cause significant cellular damage by altering
membrane permeability(1– 4, 19). Polycyclic hydrocarbons and nitrosamines found in cigarettes
are potent carcinogens(1– 5, 19). Alcohol contains a substance called ethanol (also called ethyl
alcohol).
6.2.7 Therapeutic andIllicit Drug Injury
Therapeutic Drug Injury: Most medications (therapeutic drugs) are chemical compounds.
Administration of the therapeutic drug to susceptible individuals or administered excessively or
inappropriately may cause cell damage(1– 7). These reactions are called adverse drug reactions
(ADR)(21). Adverse effects can be acute or chronic. Several prescription and over- the- counter
medications, herbs or poisons taken systemically can cause hepatotoxicity. Mitochondria are the
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main target of toxicity(1, 4, 19, 20, 22). Toxicity can occur either directly or indirectly through
the formation of reactive metabolites.
Mitochondrial dysfunction, oxidative stress, the imbalanced production and degradation of bile
acid and inflammatory responses are involved in the occurrence and development of druginduced liver injury (DILI)(1, 19– 22). Drugs also are a common source of acute kidney injury.
Chemotherapeutic agents used in cancer treatment can damage normal cells. Some other drugs
with adverse effects include high doses of aspirin, barbiturates and long- term oestrogen therapy
in postmenopausal women(1– 5, 21).
Illicit Drug Injury: Illicit drugs are substances that either stimulate (e.g. cocaine or amphetamines)
or inhibit (e.g. heroin) the central nervous system or cause hallucinogenic effects (e.g. marijuana). Illicit drugs can occur naturally (e.g. marijuana or cocaine) or can be prepared from naturally occurring substances (e.g. heroin), or they can be synthetic (e.g. amphetamines)(2, 5, 23).
6.2.8 Injury Dueto Infectious Agents
Pathogens that invade the human body can cause cellular injury, often damaging cells and organs.
Pathogenic organisms include bacteria, viruses, fungi, rickettsiae and parasites(1– 7, 24). The type
of death the cell undergoes depends on several factors, including the nature of the pathogen, pathogen load and site of infection. The ability to cause disease (virulence) also depends on host factors
such as age, nutritional status, co- morbid illness and immune status(1, 2, 24). The infection is
considered ‘opportunistic’ when non- pathogenic organisms (such as commensal organisms of the
oral cavity) cause disease in immunocompromised hosts. Some microorganisms are tissue- specific.
For example, hepatitis viruses usually infect liver cells (hepatotropic viruses). Organisms such as
Staphylococcus aureus can cause injury in almost any tissue type(1, 24). Usually, these infections
fall in the category of non- specific infections.
Infectious agents cause cell damage by binding to or entering host cells and causing cell death or
dysfunction. Pathogenic bacteria release endotoxins or exotoxins capable of inducing cell death.
Bacterial endotoxin is a lipo- polysaccharide on the cell wall of gram- negative bacteria released on
bacterial death(1, 4, 24). Bacterial exotoxins, conversely, are secreted proteins; some are bacterial
enzymes, including proteases, hyaluronidases, coagulases and fibrinolysins. Some can damage
blood vessels, causing ischaemic injury(1, 24). Food poisoning is an example of gastrointestinal
cell injury caused by bacteria or viruses found in food. Salmonella, Campylobacter, Listeria and
Escherichia coli cause bacterial gastroenteritis, whereas noroviruses, rotavirus and adenoviruses
can cause viral gastroenteritis.
Most viruses are directly cytopathic(1, 4, 24). They can cause damage by entering cells and
replicating at the host’s expense. An example of a virus that is not directly cytopathic is the hepatitis B virus (HBV). Liver damage in hepatitis B infection is due to the immune response against
hepatocytes. Humoral immune responses induced by some infectious agents can also cause cell
damage. For example, streptococcal infections can form streptococcal antigen- antibody complexes, which, when deposited in renal glomeruli, can cause post- streptococcal glomerulonephritis. Some viruses are oncogenic; they can induce benign and malignant neoplasms(1, 6, 24).
67
6.2.9 Injury Dueto Nutritional Imbalances: Malnutrition andNutritional Deficiencies
Nutritional deficiencies, excesses and imbalances predispose the cell to injury (1, 2, 25).
Malnutrition is a significant cause of immune suppression and increases host susceptibility to
infectious diseases. Malnutrition refers to the imbalance between the nutrient needs of the body
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68
and the nutrients it receives or utilises. Malnutrition can manifest as undernutrition, including
protein- energy malnutrition and micronutrient deficiencies, or overnutrition(1, 25– 29), including obesity and diet- related diseases. Marasmus is a result of severe malnutrition in children due
to caloric deficit. It is associated with muscle atrophy and general growth failure(1– 8). Kwashiorkor
is severe childhood malnutrition resulting from a diet that is very low in protein but high in carbohydrates(1– 8, 30).
On the other hand, nutritional deficiency refers to the lack or insufficiency of one or more essential nutrients in the diet. Nutritional deficiencies have been demonstrated to induce programmed
cell death (apoptosis) in various cell types. Marasmus and Kwashiorkor are prevalent in less developed countries(1, 5, 25– 29).
Vitamins are a group of organic compounds essential for normal physiological functioning(1,
6, 26). The body does not synthesise vitamins endogenously; they are sequestered in small quantities from the diet. The body needs four fat- soluble vitamins (A, D, E and K) and nine water- soluble
vitamins, which comprise thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, cyanocobalamin, folate and vitamin C.
Vitamins participate in the catabolic process of generating energy within cells (1, 2, 26).
Deficiencies of specific vitamins are found worldwide.
Vitamin A is necessary for normal embryonic development and postnatal tissue homeostasis
and affects cell proliferation, differentiation and apoptosis. Retinoic acid, the main biologically
active form of vitamin A, influences the expression of collagens, laminins, entactin, fibronectin,
elastin and proteoglycans; these are significant extracellular matrix components. The extracellular
matrix influences cell behaviour, differentiation and apoptosis. Modifications in vitamin A potentially compromise organ function and may lead to disease(1, 25, 26).
The B vitamins comprise a group of water- soluble vitamins that perform essential, closely
interrelated roles in cellular functioning. They act as co- enzymes in many catabolic and anabolic
enzymatic reactions(3, 25– 27).
Vitamin C (ascorbic acid) is a well- known antioxidant. It plays a central role in the regeneration
of vitamin E and constitutes a strong line of defence in retarding free radical- induced cellular damage(3, 25– 27).
Vitamin D participates in calcium absorption and is critical for controlling systemic inflammation, oxidative stress, mitochondrial respiratory function, and, thus, the human ageing process(2, 27).
Vitamin E (α- Tocopherol) is a vital lipid peroxidation antioxidant in cell membranes. Vitamin E
possesses anti- cancer properties and has also been found to reduce risk factors for arterial clotting
by platelet aggregation and cholesterol(1, 27).
Iron, a vital nutrient, facilitates cell proliferation and growth. It involves critical processes such
as oxygen transport, deoxyribonucleic acid (DNA) synthesis and electron transport. Heme and
non- heme are two forms of dietary iron(2, 28, 29).
6.2.10 Immunologically Mediated Cell Injury
While the immune system is our body’s defence against pathogens, it can also inadvertently cause
cell damage. Immune responses can lead to tissue injury, including allergic (hypersensitivity) reactions to environmental substances (antigens) and autoimmune responses. The immune system
responses are categorised into four types: immediate (Type 1) hypersensitivity, antibody- mediated
(Type II) hypersensitivity, immune- complex mediated (Type III) hypersensitivity and T- cellmediated (Type IV) hypersensitivity(31– 38) (Figure6.1).
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Allergen Fc receptor
for IgE
Allergen-
specific
IgE
Degranulation
Type I Type II
IgE-mediated
hypersensitivity
IgE is bound to mast cells
via its Fc portion. When an
allergen binds to these
antibodies, crosslinking of
IgE induces degranulation.
Causes localised and
systemic anaphylaxis,
seasonal allergies including
hay fever, food allergies
such as those to shellfish and
peanuts, hives and eczema
Antibody-dependent
cellular cytotoxicity
Fc receptor
for IgG
Surface antigen
Complement activation
IgG-mediated cytotoxic
hypersensitivity
Cells are destroyed by bound
antibody, either by activation of
complement or by a cytotoxic
T cell with an Fc receptor for
the antibody (ADCC)
Red blood cells destroyed by
complement and antibody
during a transfusion of
mismatched blood type or
during erythroblastosis fetalis
Cytotoxic
T cell
Target cell
Surface antigen
Immune
complex
Free-floating
immune complex
Complement
activation
Neutrophil
Type III Type IV
Immune complex-mediated
hypersensitivity
Antigen–antibody complexes
are deposited in tissues,
causing activation of
complement, which attracts
neutrophils to the site
Most common forms of
immune complex disease are
seen in glomerulonephritis,
rheumatoid arthritis, and
systemic lupus erythematosus
Antigen
Sensitized
Th1 cell
Cytokines
Activated
macrophage
Cell-mediated
hypersensitivity
Th1 cells secrete cytokines,
which activate macrophages
and cytotoxic T cells and can
cause macrophage
accumulation at the site
Most common forms are
contact dermatitis, tuberculin
reaction, autoimmune diseases
such as diabetes mellitus
type I, multiple sclerosis and
rheumatoid arthritis
Cytotoxic
T cell
Figure6.1 Types of hypersensitivity responses. Rice University/http://cnx.org/content/col11496/
1.6//last accessed on Jun 19, 2013/CC BY 4.0.
Type I hypersensitivity, an immediate reaction, involves the release of antibodies mediated by
immunoglobulin E (IgE) against the soluble antigen. This reaction triggers mast cell degranulation
and the release of histamine and other inflammatory mediators (34). Immediate (Type I)
hypersensitivity can manifest as a local reaction (e.g. hay fever) or a severe, debilitating condition
(e.g. asthma), and in rare cases, it can lead to a systemic disorder, such as anaphylaxis.
Type II hypersensitivity refers to antibody- mediated cytotoxic reactions and engages IgG and
IgM antibodies, leading to complement system activation and cell damage or lysis. Antibodymediated (Type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surfaces of cells or other tissue components(1).
Type III hypersensitivity refers to immune- complex reactions and involves IgG, IgM and
sometimes IgA antibodies. The build- up of these immune complexes results in complement system activation, which leads to polymorphonuclear leukocyte (PMN) chemotaxis and eventually
causes acute inflammation and tissue damage. Antigens in these responses are exogenous
(microbes) or endogenous, such as nucleoproteins(1– 5, 31– 37).
Type IV hypersensitivity is known as a delayed- type hypersensitivity and involves T- cellmediated reactions. T- cells or macrophages are activated due to cytokine release, leading to tissue
damage. Type IV hypersensitivity results from the interaction of T lymphocytes and the specific
antigen to which they have been sensitised. The resulting immune response is mediated by direct
cytotoxicity by CD8+ T lymphocytes or by releasing soluble cytokines from CD4+ lymphocytes,
which act through mediator cells (primarily macrophages) to produce chronic inflammatory
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reactions. Because these responses depend on sensitised T lymphocytes and require 24– 48 hours to
develop, they are also called delayed- type hypersensitivity (DTH). After antigen exposure, leukocytes are attracted by an initial local immune and inflammatory response. Macrophages and
monocytes engulf antigen and present it to the T- cells. This results in the release of cytokines and
chemokines, which can cause tissue damage(1, 3, 35).
6.2.11 Injury Dueto Autoimmunity
Autoimmunity involves the loss of normal immune homeostasis and causes the organism to produce an abnormal response to its tissue. Autoimmune disease results from an interplay between a
genetic predisposition and environmental factors. Any organ system and individuals of any age
can be affected by autoimmune diseases. Females at a much higher risk(1, 2, 36– 38). The hallmark
of autoimmunity is the presence of self- reactive T cells, autoantibodies and inflammation.
6.2.12 Genetic andMetabolic Cell Injury
Genetic defects may cause cell injury because of a deficiency of functional proteins such as
enzymes in inborn errors of metabolism or accumulation of damaged DNA or abnormal proteins
(1– 7). Variations in genetic makeup can also influence the susceptibility of cells to injury by chemicals and other environmental insults(1, 2, 39– 41).
In metabolic disorders, cell injury may be direct or indirect. In diabetes mellitus, for example,
hyperglycaemia can alter the metabolism of liver and kidney cells. Pathologic changes in small
vessels in diabetes (diabetic microangiopathy) also cause damage to tissues receiving blood through
altered blood vessels. Metabolic cell Injury occurs when cells or tissues do not receive sufficient
reactants to perform normal metabolic processes critical for functionality and survival. These reactants include nutrients and oxygen, delivered to cells and tissues by the blood(1, 3, 39– 41).
6.2.13 Cell Damage inAgeing
Ageing is a physiologic change. In humans, this change occurs at different rates(42) and is related
to lifestyle, environment and genetics. Cellular ageing results from a progressive decline in cells’
proliferative capacity and life span(1– 8). Cellular ageing is associated with DNA damage, defective
DNA repair mechanisms, decreased cellular replication, reduced regenerative capacity of tissue
stem cells and progressive accumulation of metabolic damage(1, 4, 42). Cellular ageing includes
complex cellular adaptations. Many events in cellular ageing are irreversible.
6.3 Mechanisms ofCell Injury
Most diseases begin with cell injury. Cells are injured by numerous and diverse causes (aetiologic
agents) from intrinsic and extrinsic sources. The basic mechanisms of cell injury can be categorised as plasma membrane damage, mitochondrial damage, adenosine triphosphate (ATP) depletion, cytosolic calcium derangement and nucleic acid damage(1– 7, 43).
6.3.1 Plasma Membrane Damage
The cellular plasma membrane is the primary physical structure that allows cells to maintain
an intracellular biochemical environment (1– 7, 43). It provides selective permeability to
many molecules and solutes. The plasma membrane requires constant maintenance through
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energy- dependent processes. The deficiency of cellular energy stores will eventually lead to the
breakdown of the barrier. The plasma membrane can be damaged by direct chemical injury or free
radical cell injury, which induces physical modification and, thus, derangement of the molecular
components of the membrane(1– 7, 43). The breakdown of selective membrane permeability is a
critical biochemical event that can lead to severe cellular injury. A breakdown can result in the
influx of potentially toxic chemicals, the release of vital cellular nutrients and proteins and
the elimination of solute gradients across the plasma membrane. These are critical for maintaining cellular life(1, 6, 43).
6.3.2 Mitochondrial Damage
Mitochondria are the essential organelles of cellular respiration and thus provide much of the ATP
for energy- dependent cellular processes. Additionally, various potentially toxic molecules are
sequestered within the mitochondria, including large stores of calcium and Cytochrome C, a key
apoptosis regulator. Many biochemical events can lead to mitochondrial damage, resulting in
physical damage to the mitochondrial membrane. Commonly, mitochondrial damage is due to
increased cytosolic calcium and free radicals damage to mitochondria, resulting in the elimination
of cellular respiration and declines in cellular ATP stores. Additionally, damage to mitochondria
can cause the inappropriate release of Cytochrome C, thus inducing apoptosis pathways, which
can lead to cell death(1– 7, 43).
71
6.3.3 Adenosine Triphosphate (ATP) Depletion
Injurious agents can cause ATP depletion, membrane damage, pathway disruption or DNA damage. Any injury that decreases the supply of oxygen and other nutrients to the cell or damages
mitochondria stops oxidative phosphorylation (2, 3, 43). ATP is a coenzyme that works with
enzymes such as ATP triphosphatase (ATPase) to transfer energy to cells by releasing phosphate
groups. As discussed in this chapter, hypoxia and ischaemia are the most common causes of ATP
depletion(2, 3, 7). ATP depletion results in additional cell damage by causing the failure of energydependent enzymes. The primary site of ATP generation is mitochondria. Mitochondrial injury
results in ATP depletion and increased permeability of mitochondrial membranes. This event
results in the loss of calcium homeostasis and activation of enzymes (such as phospholipases, proteases and endonucleases). It damages mitochondrial and other cell membranes, structural and
enzymatic proteins and nucleic acids(1– 4, 43).
6.3.4 Cytosolic Calcium Derangement
The cytosolic calcium concentration is usually tightly regulated and kept at deficient concentrations compared to the extracellular environment through ATP- dependent mechanisms (1– 7).
Significant increases in cytosolic calcium concentration can activate potent cellular enzymes,
including proteases, phospholipases, endonucleases and ATPases(1– 5, 43). The combined effect of
these proteases is the widespread destruction of intracellular proteins, lipids, nucleic acids and
ATP, which together provide a potent insult to cellular survival(1– 3, 43). The deficiency of ATP
causes slow but steady increases in cytosolic calcium due to an inability to maintain the calcium
concentration gradient with the extracellular space. Additionally, damage to the plasma membrane
can lead to a loss of selective calcium permeability and sharp extracellular calcium influxes(1, 3, 43).
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