cell injury and degenerations

CELL INJURY, ADAPTATIONS AND DEGENERATIONS

Dr Neha MahajanMD Pathology

PATHOLOGY

Pathos (suffering)Logos

PATHOLOGYETIOLOGY (“Cause”)PATHOGENESIS (“Insidious development”)

MORPHOLOGY (ABNORMAL ANATOMY)

CLINICAL EXPRESSION

ETIOLOGYCause

vs.

Risk Factors

PATHOGENESIS“sequence of events from the initial stimulus to the ultimate expression of the disease”

MORPHOLOGYAbnormal Anatomy

GrossMicroscopicRadiologicMolecular

Most long term students of pathology, like myself, will strongly agree that the very best way for most minds to remember, or identify, or understand a disease is to associate it with a morphologic IMAGE.This can be gross, electron microscopic, light microscopic, radiologic, or molecular.

In MOST cases it is at the LIGHT MICROSCOPIC LEVEL.

CELL INJURY, DEFINITIONS When the cell is exposed to an injurious

agent or stress, a sequence of events follows that is loosely termed cell injury.

Cell injury is reversible up to a certain point If the stimulus persists or is severe enough

from the beginning, the cell reaches a point of no return and suffers irreversible cell injury and ultimately cell death.

Cell death, is the ultimate result of cell injury

NORMAL CELL

ADAPTATIONS REVERSIBLE CELL INJURY

IRREVERSIBLE CELL INJURY

Severe,persistent stressMild to moderate stress

Altered functional demand

Atrophy,HypertrophyHyperplasia,Metaplasia,Dysplasia

Degenerations, Subcellular alterations,Intracellular accumulations

NORMAL CELL RESTORED

REPAIR AND HEALING

IRREVERSIBLE CELL INJURY

CAUSES OF CELL INJURY Hypoxia Direct physical action Ionizing radiation Toxic molecular injury Microbes Inflammatory & immune reactions

CAUSES OF CELL INJURY 1) Oxygen Deprivation (Hypoxia). It is a

common cause of cell injury and cell death. -Hypoxia can be due to :A- inadequate oxygenation of the blood due to

Cardiorespiratory failureB- loss of the oxygen-carrying capacity of the

blood, as in anemia or carbon monoxide poisoning, heart diseases, lung diseases

Depending on the severity of the hypoxic state, cells may adapt, undergo injury, or die.

CAUSES OF CELL INJURY CONT.2) Physical Agents : - Mechanical trauma, - Burns, - Deep cold - Sudden changes in atmospheric pressure, - radiation, and electric shock

CAUSES OF CELL INJURY CONT.3) Chemical Agents and Drugs - oxygen, in high concentrations- poisons, such as arsenic, cyanide, or

mercuric salts- environmental and air pollutants- insecticides, herbicides, industrial and

occupational hazards- alcohol and narcotic drugs and therapeutic

drugs

CAUSES OF CELL INJURY CONT. 4) Infectious Agents e.g. bacteria, fungi,

viruses and parasites. 5) Immunologic Reactions. Hypersensitivity reactions, Anaphylactic reactions Autoimmune diseases 6) Genetic Derangements. 7)Aging 8) Nutritional Imbalances

PATHOGENESIS OF CELL INJURY The following principles apply in

pathogenesis of most forms of cell injury by various agents:

1.Type,duration & severity of injurious agent2.Type,status & adaptability of target cell3.Underlying intracellular phenomenom4.Morphologic consequences

MECHANISM OF CELL INJURY 1.DEPLETION OF ATP 2.MITOCHONDRIAL DAMAGE 3.INFLUX OF INTRACELLULAR CALCIUM

& LOSS OF CALCIUM HOMEOSTASIS 4.ACCUMULATION OF OXYGEN-DERIVED

FREE RADICALS (OXIDATIVE STRESS) 5. DEFECTS IN MEMBRANE

PERMEABILITY

MECHANISM OF CELL INJURY1.DEPLETION OF ATP: . ATP depletion and decreased ATP synthesis

are associated with both hypoxic and chemical (toxic) injury.

. ATP is required for many synthetic and degradative processes within the cell.

MECHANISM OF CELL INJURY CONT. ATP is produced in two ways.A- The major pathway is oxidative

phosphorylation of adenosine diphosphate. B-The second is the glycolytic pathway, which

generate ATP in absence of oxygen using glucose derived from body fluids or from glycogen

Myocardium, neurons of CNS, proximal tubules of kidney- Aerobic respiration

MECHANISM OF CELL INJURY CONT.

Effects of depleted ATP a) The activity of the plasma membrane

energy-dependent sodium pump is reduced. It causes sodium to accumulate intracellularly and potassium to diffuse out of the cell causing cell swelling, and dilation of the endoplasmic reticulum.

MECHANISM OF CELL INJURY CONT.b) If oxygen supply to cells is reduced, as in

ischemia, oxidative phosphorylation ceases and cells rely on glycolysis for energy production (anaerobic metabolism) resulting in depletion of glycogen stores.

Glycolysis results in the accumulation of lactic acid which reduces the intracellular pH, resulting in decreased activity of many cellular enzymes.

MECHANISM OF CELL INJURY CONT.c) Failure of the Ca2+ pump leads to influx of

Ca2+, with damaging effects on numerous cellular components

d) Ribosomes detach from the RER and polysomes breakdown into monosomes, leading to reduction in protein synthesis. Ultimately, irreversible damage to mitochondrial and lysosomal membranes occurs, and cell undergoes necrosis

MECHANISM OF CELL INJURY CONT. e) In cells deprived of oxygen or glucose,

proteins may become misfolded, and trigger the unfolded protein response leading to cell injury and even death.

MECHANISM OF CELL INJURY CONT.

2- Mitochondrial Damage: Mitochondria are important targets for all

types of injury, including hypoxia and toxins. Mitochondrial changes are seen as vacuoles

in the mitochondria and deposit of amorphous calcium salts in mitochondrial matrix

MECHANISM OF CELL INJURY CONT.Mitochondria can be damaged by :A- Increases of cytosolic Ca2+ B- Oxidative stressC- Breakdown of phospholipids, and byD- Lipid breakdown products.

MECHANISM OF CELL INJURY CONT.. Mitochondrial damage results in the

formation of a high-conductance channel, called mitochondrial permeability transition, present in the inner mitochondrial membrane. In the initial phase it is reversible but once mitochondrial permeability transition is irreversble it becomes a deathblow to the cell.

Mitochondrial damage can also be associated with leakage of cytochrome c into the cytosol.

MECHANISM OF CELL INJURY CONT.3.INFLUX OF INTRACELLULAR CALCIUM & LOSS

OF CALCIUM HOMEOSTASIS. . Ischemia causes an increase in cytosolic calcium

concentration. Increased Ca2+ in turn activates a number of enzymes, e.g.

- ATPases (thereby hastening ATP depletion), -Phospholipases (which cause membrane

damage), - Proteases (which break down both membrane

and cytoskeletal proteins), and -Endonucleases (which are responsible for DNA

and chromatin fragmentation).

MECHANISM OF CELL INJURY CONT.4. ACCUMULATION OF OXYGEN-DERIVED

FREE RADICALS (OXIDATIVE STRESS) - Small amounts of partially reduced reactive

oxygen forms are produced as a byproduct of mitochondrial respiration.

- Some of these free radicals can damage lipids, proteins, and nucleic acids.

- They are referred to as reactive oxygen species.

MECHANISM OF CELL INJURY CONT. - Cells have defense systems to prevent

injury caused by these products. - An imbalance between free radical-

generating and radical-scavenging systems results in oxidative stress causing cell injury.

MECHANISM OF CELL INJURY CONT.Free radical-mediated damage are seen in 1. chemical and radiation injury2. ischemia-reperfusion injury3. cellular aging, and4. microbial killing by phagocytes.

MECHANISM OF CELL INJURY CONT.- Free radicals are chemical species that have

single unpaired electron in an outer orbit. - They are initiated within cells in several

ways:

a) Absorption of radiant energy (e.g., ultraviolet light, x-rays).

b) Enzymatic metabolism of exogenous chemicals or drugs .

MECHANISM OF CELL INJURY CONT.c) The reduction-oxidation reactions that occur

during normal metabolic processes. During normal respiration, small amounts of toxic intermediates are produced; these include superoxide anion radical (O2-), hydrogen peroxide (H2O2), and hydroxyl ions (OH).

d) Transition metals such as iron and copper e) Nitric Oxide (NO), an important chemical

mediator generated by various cells, can act as a free radical.

MECHANISM OF CELL INJURY CONT. -The main effects of these reactive species are Lipid peroxidation of membranes: result

in extensive membrane, organellar, and cellular damage.

Oxidative modification of proteins. resulting in protein fragmentation.

Lesions in DNA. This DNA damage has been implicated in cell aging and malignant transformation of cells

MECHANISM OF CELL INJURY CONT.-Cells have developed multiple mechanisms

to remove free radicals and thereby minimize injury.

1- Antioxidants. Examples vitamins E and A and ascorbic acid.

2- Enzymes which break down hydrogen peroxide and superoxide anion e.g. Catalase, Superoxide dismutases,and Glutathione peroxidase.

MECHANISM OF CELL INJURY CONT.

5. Defects In Membrane Permeability:

- In ischemic cells, membrane damage may be the result of ATP depletion and calcium-modulated activation of phospholipases.

- It can also be damaged directly by certain bacterial toxins, viral proteins etc.

MECHANISM OF CELL INJURY CONT.The biochemical mechanisms which contribute

to membrane damage are: Accelerated degradation of membrane

phosholipid Mitochondrial dysfunction Cytoskeletal abnormalities Reactive oxygen species Lipid breakdown products

Cellular and biochemical sites of damage in cell injury.

Functional and morphologic consequences of decreased intracellular ATP during cell injury.

REVERSIBLE AND IRREVERSIBLE CELL INJURY Within limits, the cell can compensate for

these derangements and, If the injurious stimulus is removed the

damage can be reversed. Persistent or excessive injury, however,

causes cells to pass the threshold into irreversible injury.

REVERSIBLE AND IRREVERSIBLE CELL INJURY

Irreversble injury is marked by :- severe mitochondrial vacuolization,- extensive damage to plasma membranes, - swelling of lysosomes and- the appearance large, amorphous densities in

mitochondria..

REVERSIBLE AND IRREVERSIBLE CELL INJURYTwo phenomena consistently characterize

irreversibility. 1) The inability to reverse mitochondrial

dysfunction (lack of oxidative phosphorylation and ATP generation) even after removal of the original injury.

2) Profound loss in membrane function

PATHOGENESIS OF ISCHAEMIC & HYPOXIC INJURY

Hypoxia/Ishaemia

ATP loss

Decresed PH( cytosol) Damaged sodium pump

(membrane)Decreased Protein synthesis(RER)

Ultastuctural/functional changes

Reversible cell injury

Reversible cell injury

1.Decresed generation of cellular ATP 2Reduced intracellular PH 3.Damage to plasma membrane sodium

pump 4.Reduced protein synthesis 5.Functional consequences 6.Ultrastructural changes

Reversible

Ireversible

Ultrastructural changes

IRREVERSIBLE CELL INJURY

1.Mitochondrial dysfunction 2.Membrane damage 3.Hydrolytic enzymes Serum estimation of liberated enzymes

ISCHEMIA-REPERFUSION INJURY

Restoration of blood flow to ischemic tissues can result in recovery of cells if they are reversibly injured.

Ischemia-reperfusion injury is a clinically important process in such conditions as myocardial infarction and stroke.

ISCHEMIA-REPERFUSION INJURY New damaging processes are set in motion

during reperfusion, causing the death of cells that might have recovered otherwise New damage may be initiated during reoxygenation by increased generation of oxygen free radicals from parenchymal and endothelial cells and from infiltrating leukocytes

Reactive oxygen species can further promote the mitochondrial permeability transition,

ISCHEMIA-REPERFUSION INJURY Ischemic injury is associated with

inflammation as a result of the production of cytokines and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells.

These agents recruit circulating polymorphonuclear leukocytes to reperfused tissue; the ensuing inflammation causes additional injury.

Activation of the complement pathway may contribute to ischemia-reperfusion injury.

FREE RADICAL MEDIATED INJURYRole of free radical injury:1.Ischaemia reperfusion injury2.Ionisation radiation by causing radiolysis of

water3.Chemical toxicity4.Hyperoxia5.Cellular ageing6.Killing of exogenous biologic agents7.Inflammatory damage8.Destruction of tumor cells9.Chemical carcinogenesis

CHEMICAL /TOXIC INJURY Chemicals cause cell injury Mechanism- free radical mediated injury Examples:Eg: Mercuric chlorideCyanide poisoningAcetaminophenCCL4

PHYSICAL INJURYIonising Radiation

H20

0HProliferating cells(epithelial cells)

Non proliferating cells(neurons)

DNA damage Lipid peroxidation

Cell membrane damage

NECROSIS

Genetic damage Inhibition of DNA replication

MUTATIONS APOPTOSIS

CLASSIFICATION OF MORPHOLOGIC FORMS OF CELL INJURY

Mechanism of cell injury

Nomenclature

Reversible cell injury Retrogressive changes

Irreversible cell injury Cell death-necrosis

Programmed cell death Apoptosis

Residual effect of cell injury

Subcellular alterations

Deranged cell metabolism Intracellular accumulation of lipd,protein,carbohydrates

Altered effects of necrosis Gangrene,pathologic Calcification

MORPHOLOGY OF REVERSIBLE CELL INJURY DEGENERATIONRETROGRESSIVE CHANGES

1.Cellular Swelling/Cloudy change/ Hydropic degeneration

2.Hyaline change

3.Mucoid change

4.Fatty change

1.Cellular Swelling/Cloudy change/ Hydropic degeneration

Commonest & earliest form of cell injury from almost all causes

Causes: Bacterial toxins, chemicals, poisons, burns

Impaired regulation of cellular volume esp sodium

GROSS FINDINGS Affected organ (Kidney, Liver or heart)

enlarged due to swelling Cut surface- bulges outwards and is slightly

opaque MICROSCOPIC FINDINGS： 1.    Cell swelling, cytoplasm contains coarse

granules, microvasculature compressed 2.Small clear vacuoles seen in

cells(VACUOLAR DEGENERTION)

Cloudy Kidney (Microscopic examination)

HYALINE CHANGE Glassy, eosinophilic, homogenous in H & E Hyaline change : Intracellular & ExtracellularINTRACELLULAR HYALINE: ( epithelial

cells)Hyaline droplets in proximal tubular epitheliumZenkers degenerationMallory hyalineRussels bodiesNuclear cytoplasmic hyaline inclusions

EXTRACELLULAR HYALINE (connective tissue)

Hyaline degeneration of uterus (Leiomyoma)Hyalinised old scar of fibrocollagenous tissueHyaline arteriosclerosis in renal vessels in HT&

DMHyalines glomeruli in CGNCorpora amylacea seen in elderly, in brain

spinal cord of old age, old infarcts in lung

Hyaline degeneration

MUCOID CHANGE

Mucin- mucus glands, Epithelial and connective tissue Epithelial mucin PAS + Connective tissue mucin PAS-Epithelial mucin: Catarrhal inflammation of mucus

membranes( resp tract,GIT,Uterus)Obstruction of duct leading to mucocoele in

oral cavity and gall bladderCystic fibrosis of pancreasMucin secreting tumors

Connective tissue mucinMucoid or myxoid degeneration in some

tumors eg myxomas,neurofibromasDissecting aneurysms of aortaMyxomatous change of dermis in myxedemaMyxoid change in synovium in ganglion on the

wrist

INTRACELLULAR ACCUMULATIONS Abnormal intracellular accumulations can be

divided in to 3 groups1.Accumulation of constituents of normal

cell metabolite produced in excess:Accumulation of lipid(fatty change,cholestrol

deposits) proteins and carbohydrates,amyloid

2.Accumulation of abnormal substances due to abnormal metabolism/lack of enzymes:

Storage disorders or inborn errors of metabolism

3.Accumulation of pigments

FATTY CHANGE/STEATOSIS Intracellular accumulation of neutral fat

within parenchymal cells Commonest- liver, others- heart, skeletal

muscle,kidneyFATTY LIVER

Liver- commonest site of accumulation of fatEtiology:Alcohol,

Starvation,malnutrition,obesity,diabetes mellitus, chronic illnesses, drugs,reyes syndrome

Diet Adipose tissue

Free Fatty acids

Fatty acids

Triglyceride

Lipoproteins

Plasma Lipoprotein

Cholestrol esters

Phospholipids

Ketone bodies

Acetate

1

2

3

4

5

6

Pathogenesis

GROSS- enlarged, with tense glistening capsule and rounded margins.Cut surface-bulges slightly,pale yellow, greasy

Microscopy showing numerous lipid vacuoles in hepatocytes

SUMMARY Cell InjuryTypesMechanismReversible & Irreversible InjuryHypoxic injuryFree radical InjuryChemical & Physical Injury Degenerations CloudyFattyHyalineMucoid