Cell Injury and Cell Death

Etiology and Mechanisms of Reversible and Irreversible Injury

Faculty, Biological Sciences Department

Centro Escolar University
Cell Injury

▪ Defined as a variety of stresses a cell encounters as a result of changes in its internal and external
environment.
▪ Results when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to
inherently damaging agents or suffer from intrinsic abnormalities (e.g., in DNA or proteins).
▪ Different injurious stimuli affect many metabolic pathways and cellular organelles.
▪ Injury may progress through a reversible stage and culminate in cell death (irreversible cell injury).

CENTRO ESCOLAR UNIVERSITY FOR INTERNAL CIRCULATION ONLY 2018

Overview of Cellular Responses to Stress and Noxious Stimuli

CENTRO ESCOLAR UNIVERSITY FOR INTERNAL CIRCULATION ONLY 2018

Overview of Cellular Responses to Stress and Noxious Stimuli

Icon

CENTRO ESCOLAR UNIVERSITY FOR INTERNAL CIRCULATION ONLY 2018

 Etiology of Cell Injury

▪ The cells may be broadly injured by two major ways:

▪ By genetic causes (to be discussed in succeeding meetings)
▪ By acquired causes. The acquired causes of disease comprise vast majority of common diseases afflicting
mankind. Based on underlying agent, the acquired causes of cell injury can be further categorized as
under:
▪ Hypoxia and ischemiaPhysical agents
▪ Chemical
Icon agents and drugs Microbial agents Icon

▪ Immunologic agents Nutritional derangements

▪ Aging Psychogenic diseases
▪ Iatrogenic factors Idiopathic diseases
▪ GeneticIcofactors Icon

CENTRO ESCOLAR UNIVERSITY FOR INTERNAL CIRCULATION ONLY 2018

 Etiology of Cell Injury
▪ HYPOXIA AND ISCHEMIA.
▪ Ischemia and hypoxia are the most common causes of cell injury.
▪ Hypoxia is defined as impaired oxygen supply to the tissues (oxygen deficiency)
▪ interferes with aerobic oxidative respiration and is an extremely important and common cause of cell
injury and death.
▪ Ischemia refers to a loss of or diminished blood supply in a tissue due to impeded arterial flow or
reduced venous drainage.
▪ Ischemia is the most common cause of hypoxia

Photo taken from:

https://en.wikipedia.org/wiki/Ischemic_cardiomyopathy

CENTRO ESCOLAR UNIVERSITY FOR INTERNAL CIRCULATION ONLY 2018

 Etiology of Cell Injury

▪ PHYSICAL AGENTS. Physical agents in causation of disease include:

▪ mechanical trauma (e.g. road accidents); thermal trauma
▪ Electricity; radiation (e.g. ultraviolet and ionizing)
▪ rapid changes in atmospheric pressure
Image or icon Image or icon
▪ CHEMICALS AND DRUGS. An ever increasing list of chemical agents and drugs may cause cell injury which
include:
▪ chemical poisons such as cyanide, arsenic, mercury;
▪cause severe damage at the cellular level by altering membrane permeability, osmotic homeostasis, or the
integrity of an enzyme or cofactor
▪ strong acids and alkalis
▪ environmental pollutants; insecticides and pesticides
Image or icon Image or icon
▪ oxygen at high concentrations; hypertonic glucose and salt
▪ social agents such as alcohol and narcotic drugs
▪ MICROBIAL AGENTS.

CENTRO ESCOLAR UNIVERSITY FOR INTERNAL CIRCULATION ONLY 2018

 ▪ IMMUNOLOGIC AGENTS.
▪ hypersensitivity reactions
Image or icon Image or icon Image or icon
▪ anaphylactic reactions
▪ autoimmune diseases
▪ NUTRITIONAL DERANGEMENTS. A deficiency or an
excess of nutrients may result in nutritional imbalances.
▪ Nutritional deficiency diseases may be due to overall
Etiology of Cell Injury deficiency of nutrients (e.g. starvation), of protein
calorie (e.g. marasmus, kwashiorkor), of minerals (e.g.
anaemia), vitamins, or of trace elements.
▪ Nutritional excess is a problem of affluent societies
resulting in obesity, atherosclerosis, heart disease and
hypertension.
 ▪ GENETIC FACTORS
▪ Genetic defects may cause cell injury as a consequence
of deficiency
Icon
of functional proteins, such as enzymes in
inborn errors of metabolism, or accumulation of damaged
DNA or misfolded proteins, both of which trigger cell
death when they are beyond repair.
▪ AGING.
▪ Leads to impaired ability of the cells to undergo
Icon

replication and repair, and ultimately lead to cell death

culminating in death of the individual.
Etiology of Cell Injury ▪ PSYCHOGENIC DISEASES.
▪ There are Icon
no specific biochemical or morphologic
changes in common acquired mental diseases due to
mental stress, strain, anxiety, overwork and frustration
e.g. depression, schizophrenia.
▪ Problems of drug addiction, alcoholism, and smoking
Icon
result in various organic diseases such as liver damage,
chronic bronchitis, lung cancer, peptic ulcer,
hypertension, ischemic heart disease etc.
 Major Biochemical Mechanisms of Cell Injury

▪ Depletion of ATP
▪ Mitochondrial Damage and Dysfunction
▪ Influx of Calcium
▪ Accumulation of Oxygen-Derived Free Radicals
(Oxidative Stress)
▪ Increased permeability of cellular membranes
▪ Damage of DNA and Proteins
Mechanisms of Reversible and Irreversible Injuries
 Depletion of ATP

▪ ATP, the energy store of cells in human cell is derived from 2 sources.
▪ The major causes of ATP depletion are: reduced supply of oxygen and nutrients,
mitochondrial damage the actions of some toxins (e.g., cyanide).
▪ High-energy phosphate in the form of ATP is required for: virtually all synthetic
and degradative processes within the cell, including
▪ membrane transport
▪ protein synthesis
▪ lipogenesis,
▪ deacylation-reacylation reactions necessary for phospholipid turnover
Pathology
Mitochondrial Damage and Dysfunction

Photo taken from:

https://theartofmed.wordpress.com/2015/06/11/
mechanism-of-irreversible-cell-injury/
 Influx of Calcium

▪ The importance of Ca2+ in cell injury was established by the experimental finding that depleting
extracellular Ca2+ delays cell death after hypoxia and exposure to some toxins.
▪ Cytosolic free calcium is normally maintained by ATP-dependent calcium transporters at concentrations as
much as 10,000 times lower than the concentration of extracellular calcium or of sequestered intracellular
mitochondrial and ER calcium.
▪ Ischemia and certain toxins cause an increase in cytosolic calcium concentration, initially because of release
of Ca2+ from the intracellular stores, and later resulting from increased influx across the plasma membrane.
 Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

▪ Free radicals are chemical species with a single unpaired electron in an outer orbital.
▪ Such chemical states are extremely unstable, and free radicals readily react with inorganic and organic
chemicals; when generated in cells, they avidly attack nucleic acids as well as a variety of cellular proteins
and lipids.
 Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)

▪ Reactive oxygen species (ROS) are a type of oxygen-derived free radical whose role in cell injury is well
established.
▪ Cell injury in many circumstances involves damage by free radicals; these situations include:
▪ ischemia-reperfusion
▪ chemical and radiation injury
▪ toxicity from oxygen and other gases
▪ cellular aging
▪ microbial killing by phagocytic cells
▪ tissue injury caused by inflammatory cells
 Free Radical-Mediated Injury

▪ The damage caused by free radicals is determined by their rates of production and removal.
▪ When the production of ROS increases or the scavenging systems are ineffective, the result is an excess of
these free radicals, leading to a condition called oxidative stress.
▪ The generation of free radicals is increased under several circumstances:
▪ The absorption of radiant energy (e.g., ultraviolet light, x-rays). Ionizing radiation can hydrolyze water
into hydroxyl (•OH) and hydrogen (H•) free radicals.
▪ The enzymatic metabolism of exogenous chemicals (e.g., carbon tetrachloride)
▪ Inflammation, in which free radicals are produced by leukocytes.
Free-Radical Mediated Injury
 Photo taken from:
https://scialert.net/fulltext/?doi=rji.2010.129.145
Free-Radical Mediated Injury
Photo taken from: http://mvhospitalfordiabetes.blogspot.com/2010/11/antioxidant-health-benefits-food_6853.html
 Free-Radical Mediated Injury

▪ Cells have developed many mechanisms to remove free radicals and thereby minimize injury. Free radicals are
inherently unstable and decay spontaneously.
▪ Non-enzymatic and enzymatic systems that contribute to inactivation of free radicals.
▪ The rate of decay of superoxide is significantly increased by the action of superoxide dismutases (SODs)
found in many cell types.
▪ Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from
oxidative damage
▪ Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen peroxide (2H2O2 → O2 +
2H2O). It is one of the most active enzymes known, capable of degrading millions of molecules of H2O2
per second.
▪ Endogenous or exogenous antioxidants (e.g., vitamins E, A, and C and β-carotene) may either block the
formation of free radicals or scavenge them once they have formed.
Photo taken from: https://www.howtorelief.com/antioxidant-foods-vitamins/

Photo taken from:

https://flavonjamblog.wordpress.com/2013/11/05/88/
 Defects in Membrane Permeability

▪ Increased membrane permeability leading ultimately to overt membrane damage is a consistent feature
of most forms of cell injury that culminate in necrosis.
▪ The plasma membrane can be damaged by:
▪ ischemia,
▪ various microbial toxins
▪ lytic complement components
▪ variety of physical and chemical agents
 Major Biochemical Mechanisms of Cell Injury: A Summary

▪ Depletion of ATP: failure of energy-dependent functions → reversible injury → necrosis

▪ Mitochondrial Damage and Dysfunction
▪ ATP depletion → failure of energy-dependent cellular functions → ultimately, necrosis; under some
conditions, leakage of mitochondrial proteins that cause apoptosis
▪ Influx of Calcium: Activation of enzymes that damage cellular components and may also trigger apoptosis
▪ Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress): Covalent modification of cellular
proteins, lipids, nucleic acids
▪ Increased permeability of cellular membranes
▪ May affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in
necrosis
▪ Damage of DNA and Proteins: Accumulation of damaged DNA and misfolded proteins: triggers apoptosis
Defects in Membrane Permeability

Photo taken from:

https://theartofmed.wordpress.com/2015/06/
11/mechanism-of-irreversible-cell-injury/
 Damage to DNA and Proteins

▪ Cells have mechanisms that repair damage to DNA, but if this

damage is too severe to be corrected (e.g., after radiation injury
or oxidative stress), the cell initiates its suicide program and dies
by apoptosis.
Sequence of Events in the Pathogenesis of Reversible and Irrversible Cel
Injury Caused by Hypoxia and Ischemia
 Reversible Cell Injury

▪ When the stress is mild to moderate, the injured cell may recover (reversible cell injury) and cells return to a
stable baseline.
▪ In early stages or mild forms of injury the functional and morphologic changes are reversible if the
damaging stimulus is removed.
▪ Although there may be significant structural and functional abnormalities, the injury has typically not
progressed to severe membrane damage and nuclear dissolution.
▪ If the ischemia or hypoxia (the most common causes of cell injury) is of short duration, the effects may be
reversible on rapid restoration of circulation e.g. in coronary artery occlusion, myocardial contractility,
metabolism and ultrastructure are reversed if the circulation is quickly restored.
 Irreversible Cell Injury

▪ Occurs when the injury or stress is persistent and rapid in onset.

▪ The stage at which this point of no return or irreversibility is reached from reversible cell injury is unclear
but the sequence of events is a continuation of reversibly injured cell.
▪ Persistence of ischemia or hypoxia results in irreversible damage to the structure and function of the cell (cell
death).
▪ Two essential phenomena always distinguish irreversible from reversible cell injury:
▪ Inability of the cell to reverse mitochondrial dysfunction on reperfusion or reoxygenation.
▪ Disturbance in cell membrane function in general, and in plasma membrane in particular.
▪ In addition, there is further reduction in ATP, continued depletion of proteins, reduced intracellular pH, and
leakage of lysosomal enzymes into the cytoplasm.
Mechanisms (Biochemical and Ultrastructural Changes) in Reversible an
Irreversible Cell Injuries

REVERSIBLE INJURY IRREVERSIBLE INJURY

▪ Decreased generation of cellular ▪ Calcium influx: Mitochondrial

ATP: Damage by ischemia
versus hypoxia from other
causes.
▪ Intracellular lactic acidosis:
Nuclear clumping.
▪ Damage to plasma membrane
pumps: Hydropic swelling and
other membrane changes.
▪ Reduced protein synthesis:
Dispersed ribosomes
damage
▪ Activated phospholipases: Membrane
damage
▪ Intracellular proteases: Cytoskeletal
damage
▪ Activated endonucleases: Nuclear
damage
▪ Lysosomal hydrolytic enzymes:
Lysosomal damage, cell death and
phagocytosis.
▪ Irreversible damage to the nucleus can be in three forms:
▪ Pyknosis: Condensation and clumping of nucleus
which becomes dark basophilic.
▪ Karyorrhexis: Nuclear fragmentation in to small bits
dispersed in the cytoplasm.
▪ Karyolysis: Dissolution of the nucleus.
ASSIGNMEN
T
Give the major causes of ATP Depletion and Explains why?
SEATWORK
ACTIVITY

Instructions:

• Group your class into 6 groups

• Create a Flow chart of then “Mitochondrial Damage and
Dysfunction”
• Discuss it to your class

NOTE: BE CREATIVE
 QUIZ
1) Refers to a loss of or diminished blood supply in a tissue due to impeded arterial flow or reduced venous
drainage
2) Is defined as impaired oxygen supply to the tissues.
3) Condensation and clumping of nucleus which becomes dark basophilic.
4) Dissolution of the nucleus.
5) Nuclear fragmentation in to small bits dispersed in the cytoplasm.
6) Activation of enzymes that damage cellular components and may also trigger apoptosis
7) Accumulation of damaged DNA and misfolded proteins: triggers apoptosis.
8) Are a family of enzymes whose major function is to protect cells from oxidative damage
9) It is one of the most active enzymes known
10)When the production of ROS increases or the scavenging systems are ineffective, the result is an excess of these
free radicals, leading to a condition called?
11)-13) Physical agents in causation of disease include:
14-15) The cells may be broadly injured by two major ways: