15.Cell Injury 1

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4.1 Processes involved in cell injury 29

4.2 Cell death 30

Self-assessment: questions 34

Self-assessment: answers 35

4.1 Processes involved in cell

injury

Causes of cell injury

The causes of both reversible and irreversible cell injuryare similar. Many of those listed below may result ini-tially in reversible injury. If the injury is of sufficientseverity, the cell reaches a ‘point of no return’ and irre-versible injury culminating in cell death will occur.

Possible causes include:

q hypoxia, e.g. myocardial ischaemia (reduced bloodflow to, and therefore oxygenation of, the heart) as a

result of coronary artery atherosclerosisq immunological, e.g. thyroid damage caused by

autoantibodies (antibodies produced by the bodyagainst its own tissues)

q infection by micro-organisms, e.g. bacterial, viral,fungal infections (such as tuberculous infection of the

lung or damage to respiratory mucosa by influenzavirus)

q genetic, e.g. Duchenne muscular dystrophy or sicklecell disease

q physical, e.g. radiation (such as sunburn due to UVlight damage to the skin), trauma, heat, cold

q chemical, e.g. acid damage to oesophageal mucosa

(accidental or deliberate).

Mechanisms of cell injury The structure and metabolic function of the cell areinterdependent. Therefore, although an injurious agentmay target a particular aspect of cell structure or func-tion, this will rapidly lead to wide-ranging secondaryeffects. Recognised mechanisms of cell injury include:

q cell membrane damage—complement-mediated lysis via the membrane

attack complex (MAC)—bacterial toxins

—free radicalsq mitochondrial damage leading to inadequate aerobic

respiration

—hypoxia (lack of oxygen)—cyanide poisoning

q ribosomal damage leading to altered proteinsynthesis

—alcohol in liver cells—antibiotics in bacteria

q nuclear damage—viruses—radiation—free radicals.

Free radicals and cell membrane damage

Free radicals are highly reactive atoms which have an

unpaired electron in an outer orbital. They can be pro-duced in cells by a variety of processes, including radia-tion, normal metabolic oxidation reactions and drugmetabolism processes. The most important free radicalsare derived from oxygen, e.g. superoxide and hydroxylions. Free radicals can injure cells by generating chainreactions, producing further free radicals, which cause

Cell injury4

Overview

Cell injury may be reversible (sublethal) or irreversible (lethal).

Many causes may result in reversible injury initially; if severely

injured, the cell may be unable to recover and cell death

(necrosis or apoptosis) follows.

Learning objectives

At the end of this section you should be able to:

q List the main causes of cell injury and give examples.

q

Distinguish reversible from irreversible cell injury.

q Discuss the principal mechanisms of cell injury.

q Describe how the consequences of injury depend on cell-

related factors and on cause-related factors.

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cell membrane damage by cross-linking of proteins and

by critical alterations of lipids.

Ion transporter function and intracellular calcium

A large proportion of a cell’s energy consumption isused by the ion transporter mechanisms (‘membranepumps’). Failure of ATP synthesis (usually because of

hypoxia) can result in failure of these mechanisms.Consequently, there is a rise in intracellular calcium andsodium ions and a reduction in intracellular potassiumions. If the endoplasmic reticulum is damaged,sequestered calcium is released resulting in a furtherincrease in intracellular calcium.

Raised intracellular calcium can have a number of

effects. It may initiate the caspase cascade (see Section4.2) causing apoptosis. It can also activate proteases andphospholipases causing further damage to cellcytoskeleton and membranes, and thus contribute tonecrosis.

Consequences of cell injury The consequences of cell injury depend on both the celland the injurious agent.

Cell features

Certain features of cells make them more vulnerable to

serious sequelae of cell injury.Specialisation Cells that are enzyme rich or have

specialised organelles within the cytoplasm may bemore vulnerable. The presence of specialised proteinswithin the cell may make it prone to certain types ofinjurious agent.

Cell state Cells that have an inadequate supply of

oxygen, hormones or growth factors or lack of essentialnutrients may be more prone to injury.

Regenerative ability The potential of a cell popula-tion to enter the cell cycle and divide is important in theresponse of tissues to injury. Damaged areas in tissuesmade up of cells which can divide may be restored tonormal, while populations of permanent cells will be

incapable of regeneration.

Injury features

In addition, the character of the injury will also affect theseverity of the damage.

Type of injury The injury may be ischaemic, toxic,

chemical, etc. Different cells will be more susceptible tosome injurious agents than others (heart muscle cells are

more susceptible to oxygen depletion than connectivetissue cells).

Exposure time The length of time of exposure to atoxin or reduced oxygen concentration will affect thechance of a cell surviving the insult. Even relatively

resistant cells will be damaged if the duration of expo-sure is prolonged.

Severity The ability to survive an injury will also

depend upon its severity, e.g. is the lack of oxygenpartial (hypoxia) or complete (anoxia).

Irreversible cell injury

When does reversible injury become irreversible? Theexact ‘point of no return’ from reversible to irreversiblecell injury (leading to cell death) has not yet been

defined, although severe mitochondrial damage andcell membrane destruction via free radical generationhave been proposed. The light microscopical changesseen in injured cells are well described:

Early changes These are reversible and include:

q cytoplasmic swelling and vacuolationq mitochondrial and endoplasmic reticulum

swellingq clumping of nuclear chromatin.

Late changes These are irreversible and include:q densities in mitochondrial matrixq cell membrane disruptionq nuclear shrinkage (pyknosis)q nuclear dissolution (karyolysis)q nuclear break up (karyorrhexis)q lysosome rupture.

Death of the cell will follow the development of thelate morphological changes.

4.2 Cell death

There are three main forms of cell death: autolysis,apoptosis and necrosis.

Autolysis

Autolysis is the death of cells and tissues after the deathof the whole organism. It is also seen when tissue is sur-gically removed from the organism. The cells aredegraded by the post-mortem release of digestive

enzymes from lysosomes.

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Cell injury4

Learning objectives

At the end of this section you should be able to:

q Define autolysis, apoptosis and necrosis.

q Describe the features distinguishing necrosis from

apoptosis and give examples of these processes.

q Describe the characteristics of five major types of necrosis.

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Apoptosis

Apoptosis is also known as programmed cell death. Itcan occur in normal tissues, for example as a means ofregulating the number of cells in a tissue or organ, andduring embryological development. It is also seen in

pathological processes.

Examples of physiological apoptosis:q embryogenesis: e.g. formation of digits from the

limb budsq menstrual cycle: endometrial cell lossq breast feeding: reversal of changes in the lactating

breast once breast feeding is finishedq immune cell development: deletion of immune

cells (T cells) that may react with the body’s own

tissues.

Examples of pathological apoptosis:q tumours: the balance between apoptosis and cell

proliferation is disturbed in neoplasiaq atrophy: cell loss in atrophic tissues is by apoptosis

(viral illness: e.g. hepatitis—individual hepatocytescan be seen in apoptotic forms)

q AIDS (acquired immune deficiency syndrome): lossof lymphocytes is by apoptosis.

Apoptosis is brought about by a complex system ofcell signalling pathways and enzyme-induced events.An important group of enzymes is the caspase family,which acts as an enzyme cascade. As seen in otherenzyme cascade reactions, such as the complement sys-

tem (see Ch. 5), this process serves to amplify the initialapoptotic signal. Some caspases activate other

enzymes; others have a direct effect on the structure ofthe cell by breaking down components of thecytoskeleton. Endonucleases break down DNAinto regular fragments at internucleosomal sites, andphospholipases change the configuration of cell

membranes.Morphologically, apoptotic cells shrink and the

nucleus condenses. The organelles and nucleus breakup, and then the cell breaks into fragments called apop-

totic bodies. These express ligands on their surfacemembranes that are recognized by phagocytes, promot-ing their uptake by phagocytes and, uniquely, neigh-

bouring normal cells (Fig. 7).In contrast to necrosis, the cell membrane pumps

remain viable and continue to function until the termi-nal stages of the process. Apoptosis does not provoke aninflammatory response.

The control of apoptosis is crucial in the process ofneoplasia. Some genes involved in cancer formation

(e.g. the bcl-2 oncogene) seem to be able to switch offapoptosis, allowing cells to live forever.

Necrosis

Necrosis is the death of cells in living tissues charac-terised by the breakdown of cell membranes. It is

always pathological. In necrosis, death of a large number of cells in one area occurs, as opposed to the selec-

tive cell death of apoptosis (Fig. 8). These changesoccur because of digestion and denaturation of cellu-lar proteins, largely by release of hydrolytic enzymesfrom damaged lysosomes. In fact, the final appearanceof the necrotic area will depend on the balance

between these two processes. There are several formsof necrosis (see below).

Cell death

Intracellularsignals

Physiological or pathological insulttriggers cell to activate/synthesiseautodestructive enzymes

Triggered enzymes may causechanges in cell morphology

DNA cleavageCell shrinkage

Cell detachment

Surface signal

Receptor

Macrophage

Cell disrupts into ‘apoptoticbodies’ which may beengulfed by neighbouring

normal cells or ‘professional’phagocytes i.e. macrophages

Fig. 7 Apoptosis.

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The results of cell death include:

q cessation of function of a tissue or organq release of cellular enzymes; these can sometimes be

detected in the blood and used as markers of theextent or timing of damage to a particular organ, e.g.

cardiac enzymes after myocardial infarctionq initiation of the inflammatory response (vital

reaction).

Types of necrosis

There are five main types of necrosis (Fig. 9):

q coagulativeq caseousq liquefactionq fatq gangrenous.

Coagulative necrosis Denaturation of intracellularprotein (analogous to boiling the white of an egg) leads

to the pale firm nature of the tissues affected. The cellsshow the microscopic features of cell death but the gen-

eral architecture of the tissue and cell ghosts remain dis-cernible for a short time. Coagulative necrosis is thecommonest type, typically seen in, for example, thekidney and heart, and is usually caused by ischaemia.

Caseous necrosis This cell death is characteristic oftuberculosis (TB) and is seen only rarely otherwise. The

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Cell injury4

A B

NecrosisPro-inflammatory

ApoptosisNon-inflammatory

Alteredblood flow

Cells of tissue/organ

Polymorph neutrophils

Macrophages

Apoptotic cell

Fig. 8 Diagramatic comparison of necrosis and apoptosis.

Caseous (TB) Liquefaction(brain infarct)

Fat necrosis

Gangrenous

Coagulative

NECROSIS

Fig. 9 Types of necrosis.

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creamy white appearance of the dead tissue resembles

cheese and is probably a result of the accumulation ofpartly digested waxy lipid cell wall components of theTB organisms. The tissue architecture is completelydestroyed.

Liquefaction (colliquative) necrosis This is charac-

terised by tissue softening with destruction of architec-ture. The result is an accumulation of semi-fluid tissue.It is usually seen in the brain and spinal cord.

Fat necrosis This can result from direct trauma(common in the fatty tissues of the female breast) orenzyme release from the diseased pancreas. Adipocytesrupture and released fat undergoes lipolysis catalysed by lipases. Macrophages ingest the oily material and agiant cell inflammatory reaction may follow (see Ch. 9).Another consequence is the combination of calcium

with the released fatty acids (saponification).Gangrenous necrosis (gangrene) This life-threatening

condition occurs when coagulative necrosis of tissues isassociated with superadded infection by putrefactive

bacteria. These are usually anaerobic Gram-positiveClostridium spp. derived from the gut or soil whichthrive in conditions of low oxygen tension. Gangrenous

tissue is foul smelling and black. The bacteria producetoxins which destroy collagen and enable the infectionto spread rapidly; it can become systemic (i.e. reach the bloodstream, septicaemia). If fermentation occurs, gas

gangrene ensues. An example is gangrene of the lowerlimb caused by a poor blood supply and superimposed

bacterial infection. This is a life-threatening emergencyand the limb should be amputated.

Sometimes, the word gangrene is used to describe thenecrotic death of part of a limb when there is little or noinfection. In this case, the term ‘dry gangrene’ is usedand the process resembles mummification.

The principal differences between apoptosis and necro-

sis are summarised in Table 4. In many pathologicalcircumstances, both processes may be involved. Forexample, in myocardial infarction the damage at the

centre of the infarct is mainly due to necrosis, but at theperiphery (where the hypoxia is less severe) apoptosismay be more important.

Cell death

Table 4 Apoptosis versus necrosis

Apoptosis Necrosis

Membrane integrity preserved Membranes breachedNo inflammation Inflammatoryresponse

Single cells Contiguous cellsActive process; requires protein Passive processsynthesis and consumes ATP

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Topics relating to cell injury are often asked in multiplechoice questions or vivas. However, necrosis is acommon short answer question—particularly thetypes of necrosis.

Multiple choice questions

1. The following statements are correct:

a. Caseous necrosis is characteristically caused byischaemia.

b. Carbon tetrachloride causes cell injury throughfree radicals.

c. Disaggregation of polyribosomes is anultrastructural feature of reversible cellinjury.

d. The brain is a common site for gangrenous

necrosis.e. Autolysis is characterised by a vital reaction to

dead cells.

2. Apoptotic cells:a. Exclude vital dyes.

b. Provoke an acute inflammatory reaction.c. May be phagocytosed by neighbouring cells.d. Contain enzymatically degraded nuclear

fragments.e. May be seen in areas of tissue necrosis.

3. The following are correctly paired:

a. Gangrene—anaerobic bacteria.

b. Karyorrhexis—reversible cell injury.c. Fatty change—alcohol.d. Free radicals—cell membrane damage.e. Venous infarction—testicular torsion.

Case history

1. What is the likely cause of death?2. At post-mortem, the pathologist found no

morphological evidence of acute myocardial

infarction. Why was this?3. What changes might have been present in the heart

muscle and coronary arteries?4. How do the medical and social history relate to his

terminal event?

Short note question

1. Write short notes on necrosis.

Viva questions

1. Define necrosis. How does this differ from autolysis?2. Describe the main categories of necrosis, with

examples.

3. Define infarction. Give examples.4. What are free radicals and how do they cause cell

injury?

Cell injury4

Self-assessment: questions

A 59-year-old man, a heavy smoker for much of hisadult life, was brought into casualty at 4 a.m. with a

three hour history of crushing, band-like chest pain.

He was seen immediately but died while being exam-

ined. His past medical history included diet-controlled

(Type 2) diabetes mellitus, hypertension and intermit-

tent claudication.He had had several attacks of chest

pain over the five years before his death. A post-

mortem examination was performed.

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Multiple choice answers

1. a. False. Caseous necrosis characteristically occursas a response to TB infection.

b. True. Carbon tetrachloride poisoning is one of theprototypic examples of free-radical-inducedinjury.

c. True. Although electron microscopy is rarely usedto examine cell injury/death in day-to-daypathology, it is important to have a workingknowledge of the ultrastructural appearances of

reversible and irreversible cell injury, if only forexam purposes.

d. False. Gangrenous necrosis characteristicallyoccurs when a tissue/organ that has a residentpopulation of bacteria dies. The organisms then

can invade the tissues; depending upon theamount of liquefaction caused by bacteria, the

gangrene is termed ‘dry’ or ‘wet’.e. False. Autolysis is the process by which post-

mortem tissues liquefy as a result of cellularautodigestion. There is no inflammatory reactionto this process (unlike necrosis). Inflammation(see Ch. 9) can only occur in living and vascularisedtissues.

2. a. True. One of the essential differences between anecrotic and apoptotic cell is that the latterremains ‘alive’ until late on in the process.Therefore, some dyes, which enter dead cells, are

excluded by apoptotic cells. b. False. Apoptotic cells are disposed of by

neighbouring, similar cells or macrophages. Noacute inflammation occurs; therefore tissuedamage does not occur.

c. True. See answer (b).d. True. Soon after apoptosis is triggered, nuclear

material in the apoptotic cell is chopped up byendonucleases.

e. True. The processes of necrosis and apoptosis arenot mutually exclusive; for example, apoptotictumour cells are often seen at the invasion edgeof a cancer where extensive necrosis may also beapparent.

3. a. True. Gangrenous necrosis is caused by infection

of ischaemic necrotic tissues by anaerobic bacteriasuch as the Gram-positive bacillus Clostridium

welchii. The bacteria may produce enzymes suchas collagenases and hyaluronidases which enablethem to spread through tissues planes.

b. False. Karyorrhexis is when the nucleusfragments, denoting severe irreversible cell injury.

c. True. Fatty change is commonly seen in liver cellswhich have been damaged by alcohol. The cellsaccumulate triglycerides as droplets within thecell cytoplasm, rather than exporting themcomplexed to proteins in the form of lipoproteins.Fatty change is reversible.

d. True. Free radicals seem to be one of the final

common pathways of cell damage and affect thecell membrane and the nuclear DNA.

e. True. Torsion (twisting) of the testis on its cordleads to a reduction in the arterial flow to theorgan combined with obstruction to the venousdrainage. The infarct is haemorrhagic and fills thetestis with venous blood. Infarction of the testis

can be prevented if the cord can be untwisted assoon as possible. This is not an uncommonsurgical emergency in young men with suddenpain in the testis. Venous infarction can also beseen in the ovary and the gut.

Case history answer

1. The likely cause of death in this man is ischaemicheart disease caused by coronary arteryatherosclerosis. The chest pain he describes is quite

characteristic of pain owing to an ischaemicmyocardium (heart muscle deprived of bloodsupply and thus oxygen). Severe atherosclerosis(furring up) of his coronary arteries would accountfor this.

2. This is an important point. The macroscopic (nakedeye) and microscopic changes that characterise allforms of necrosis take time to develop. There is asignificant lag, in this and in any case, between theonset of ischaemia and any changes in the

myocardium that can be seen by the naked eye. Thisis not an unusual scenario at autopsy. A patient whohas died instantly from myocardial ischaemia(clinically causing a lethal abnormal heart rhythmsuch as ventricular fibrillation) because of complete blockage of one or more coronary artery will have

no evidence of acute infarction. If, however, thepatient had lived for three to four days after thisevent and then died, established myocardial necrosiswith its attendant inflammatory response would be seen: a pale and haemorrhagic area withtypical microscopic features of cell death andinflammation.

Self-assessment: answers

Self-assessment: answers

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3. The history of previous attacks of chest pain suggest

past ischaemic events and the pathologist may findfibrosis (scarring) of the myocardium (cardiacmuscle cells are permanent cells and regenerationcannot occur). The patient suffered fromhypertension (high blood pressure); therefore

hypertrophy of the myocardium is likely. Thenormal heart weighs about 250–350 g, but in severehypertension the weight can double and much of

this will be because of hypertrophy of the leftventricular myocardium. The coronary arteries will be atherosclerotic (see answers 2 and 4).

4. The pathological process that led to this man’s deathwas atherosclerosis and he had several importantrisk factors for this, namely smoking, hypertensionand Type 2 diabetes mellitus. The fact that hesuffered from intermittent claudication (crampingpains in the calves, usually caused by exertion-induced muscle ischaemia and, therefore, oxygen

lack because of atherosclerotic limb arteries)emphasises the widespread nature of this process.

Short note answer

1. Irrespective of the length or detail of the writtenanswer, always begin by defining the term, in thiscase necrosis. Then outline the classification withexamples of the causes, appearances (naked eye anddown the microscope) and long- term consequences

or complications of the processes.

Viva answers

1. Necrosis is the death of cells within the living body:

q causes: ischaemia, trauma, infection,

immunological injury, chemicalsq types: coagulative, gangrenous, fat, liquefactive,

caseousq consequences: enzyme release, e.g. creatine kinase

(CK) after myocardial infarction—total CK levelsin the blood will start to rise about five hours aftera heart attack and peak at about 36 hours

q inflammatory reaction follows: healing and repair.

Autolysis is the death of cells and tissues after the

death of the whole organism. Autolysis results from therelease of lytic enzymes from lysosomes.

2. There are five main types of necrosis:

q coagulative: denaturation of intracellular protein,

typically seen in the kidney and heart and isusually caused by ischaemia; it is important tonote that there is preservation of cell outlines

q caseous: tissue architecture destroyed with acharacteristic vital reaction around, typicallyincluding multinucleate giant cells; cell outlinesare not apparent

q liquefactive: accumulation of semi-fluid tissuethrough the action of lysosomal enzymes, usuallyseen in the central nervous system

q fat: adipocytes rupture releasing fats that are broken down, the oily material can be ingested bymacrophages to give a foreign body giant cellreaction or combine with calcium; fat necrosis can

result from direct trauma, e.g. in the breast, orfrom pancreatic diseases, e.g. acute pancreatitis

q gangrenous: infection of coagulative necrotic

tissue by putrefactive anaerobic bacteria(Clostridium spp.); toxins destroy collagen orfermentation produces gases leading to systemicinfection; occurs most often in lower limb; if thereis marked liquefaction of the tissues (as a result ofthe bacteria or inflammatory reaction) theappearance is often referred to as ‘wet gangrene’.

3. Infarction is the death of tissue within the living body, due to ischaemia (lack of oxygen supply).Myocardial infarction is the death of cardiac muscle

as a result of occlusion of coronary arteries byatherosclerosis and/or thrombosis.

4. Free radicals are highly reactive atoms which have

an unpaired election. They can injure cells bygenerating a chain reaction of free radicalproduction which causes cell membrane damage bycross linking of proteins and alterations tomembrane lipids.

Cell injury4

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