CELL INJURY, CELL DEATH & CELLULAR

ADAPTATIONSLECTURE 1

MR. MASRO BIN MOHAMAD (MBM)

PHAR2262: GENERAL PATHOLOGY

FACULTY OF PHARMACYCUCMS

"Live as if your were to die tomorrow. Learn as if you were to live forever." – Mahatma Gandhi

By the end of this lecture students should be able to:

1. Define cell injury2. List the etiologic agents for cell injury3. Discuss the mechanism of cell death 4. Compare reversible and irreversible injury5. Define apoptosis and necrosis6. Compare apoptosis and necrosis7. Describe cellular accumulation prior to injury8. Discuss the cellular adaptations prior to injury9. Compare atrophy, hypertrophy, hyperplasia and

metaplasia

LEARNING OBJECTIVES

1. CELL INJURY1. Definition2. Etiology of Cell Injury3. Mechanism of Cell Injury

2. CELL DEATH1. Cell response to injury2. Reversible and irreversible injury3. Cell death – apoptosis and necrosis

3. CELLULAR ADAPTATION1. Atrophy, hypertrophy, hyperplasia & metaplasia

LECTURE’S OUTLINES

CELL INJURY1. Cell injury; defined as a variety

of stresses as a result of changes in internal & external environment.

2. Cell injury results from a disruption of one or more of the cellular components that maintain cell viability.

3. Injury at one point induces a cascade of effects.

4. All cells of the body have inbuilt mechanism to deal with changes in environment.

CAUSES OF CELL INJURY -THE PATIENT’S VIEW

• Hypoxia

• Infectious agents• Physical injury

• Chemicals/drugs• Immune response

• Genetic derangement• Nutritional imbalance

IschemiaLocal e.g. embolusSystemic e.g. cardiac failure

HypoxemiaOxygen problems e.g. altitudeHaemoglobin problems e.g. anaemia

Oxidative phosphorylationE.g. cyanide poisoning

HYPOXIC INJURY

Cerebral infarction

Myocardial infarction

Renal atrophy

HYPOXIC INJURY

Fungi, Rickettsia, Bacteria and VirusesE.g. viruses can take over protein translation machinery and subvert it entirely to the production of new virions.

INFECTIOUS DISEASE

INFECTIOUS DISEASE

Primary HerpesCandidiasis

TuberculosisActinomycosis

PHYSICAL INJURY

Causes of physical agents are as below;

I. Mechanical trauma e.g. road accidents

II. Thermal trauma e.g. heat or coldIII. Electricity e.g. electric shockIV. Radiation e.g. ultravioletV. Rapid changes in atmospheric

pressure

PHYSICAL INJURY

Thermal Burn Traumatic ulcer

CHEMICAL / DRUG INJURY

Causes of chemicals & drugs are as below;

I. Chemical poisonsII. Strong acids & alkalisIII. Environmental pollutantsIV. Oxygen at high concentrationsV. Hypertonic glucose & salt

CHEMICAL / DRUG INJURY

GingivalHyperplasia

Asprin Burn

Causes of chemicals & drugs are as below;

i. Hypersensitivity reactions ii. Anaphylactic reactions (Allergy)iii. Autoimmune diseases (SLE)

IMMUNE RESPONSE

IMMUNE RESPONSE

Cinnamon ReactionHemodent Reaction

GENETICS DERANGEMENTS

Congenital malformation Down syndrome

Decreased life of red blood cell Thalassemia, Sickle cell anemia

Inborn errors of metabolism

GENETIC DERANGEMENTS

Down's Syndrome

Ehlers-Danlos

Cancer

NUTRITIONAL IMBALANCES

Protein-calorie deficienciesVitamin deficienciesAnorexia nervosaExcesses of lipids Obesity, Atherosclerosis

Metabolic diseases Diabetes

NUTRITIONAL IMBALANCE

Diabetes

Scurvy

CELL DEATH• Cell death occurs when the strength of the insult cannot be compensated for.

• Necrosis = “cell murder”

• Apoptosis = “programmed cell death or cell suicide”

NORMAL CELL

ADAPTATIONS REVERSIBLE CELL INJURY

IRREVERSIBLE CELL INJURY

ATROPHY, HYPERTROPHY, HYPERPLASIA, METAPLASIA, DYSPLASIA

DEGENERATIONS, SUBCELLULAR ALTERATIONS, INTRACELLULAR ACCUMULATIONS

Increased functional demand

Mild to moderate

stress

Severe, persistent

stress

NORMAL CELL

RESTORED

REPAIR AND HEALING

CELL DEATH

Stress removed Stress

removed

CELLULAR RESPONSES TO CELL INJURY

REVERSIBLE CELL INJURY

• Oftentimes is an acute process.

• Cell injury of short duration and minimal intensity.

• Causes include: ischemia, exposure to toxins, infectious agents, and thermal injury.

• Plasma membrane injury leads to increased intracellular Na+ that leads to an isosmotic gain in water and cell swelling.

• Reversible hypoxic/ ischemic injury

Loss of ATP generation by mitochondria initially results in reversible events:

o Na+/K+ ATPase membrane pump leads to a loss of ionic and osmotic gradient ( ↑edCa+2+ Na+, ↓ed K+ and osmotic gain of water) resulting cell swelling & ER dilatation)

o ↑ed anaerobic glycolysis results in glycogen depletion and lactate accumulation (↓ed pH).

o Reduced protein synthesis due to ribosome detachment from the RER

CELL INJURY AND DEATH

Irreversible hypoxic/ ischemic injury

• These changes are reversible if O2 and flow are reinstated, the transition to irreversible injury depends on the extent of ATP depletion and membrane dysfunction especially of mitochondria.

• ATP depletion results in MPT with loss of the H+ gradient• ATP depletion releases cytochrome c that can induce

apoptosis• ↑edCa+2 activates

o membrane phospholipases with resulting membrane damage

o Intracellular proteases leading to cytoskeletal degradation• Phospholipid degradation products that accumulate are

directly toxic to the cell

CELL INJURY AND DEATH

Reversible injury

Decreased ATP levels

Ion imbalanceSwelling • Decreased pH• Fatty change (liver)

Irreversible injury

Amorphous densities in mitochondria

Severe membrane damage

Lysosomal rupture Extensive DNA

damage

REVERSIBLE VS IRREVERSIBLE CELL INJURY

REVERSIBLE CELL INJURY

Ischemic injury to the kidney.

Pale kidney Hydropic change

12 24 36 48 60 72

Hours After Acute MI

Myoglobin

CK/CK-MB

LD/LD1

cTnI

cTnT

168

Mu

ltip

les

of

UR

L

5

10

15

20

RELEASE OF CELL PROTEINS FOLLOWING CELL DEATH

CONCEPTS - CELL DEATH

• Necrosis = “cell murder”

• Apoptosis = “programmed cell death or cell suicide”

• Cell death occurs when the strength of the insult cannot be compensated for.

NECROSIS – MULTIPLE CELL DEATH IN A TISSUE Definition

Death of groups of contiguous cells in tissue or organ

Patterns Coagulative Liquefactive Caseous Fat necrosis (gangrene) (Infarct)

Red/haemorrhagicWhite

CONCEPTS - CELL DEATH

• Necrosis = “cell murder”

• Apoptosis = “programmed cell death or cell suicide”

• Cell death occurs when the strength of the insult cannot be compensated for.

APOPTOSIS – PROGRAMMED CELL DEATH• Is a distinct reaction pattern

which represents programmed single-cell suicide.

• Cells actually expend energy in order to die.

• Derived from Greek "falling off" (as for autumn leaves)

• Apoptosis is "the physiological way for a cell to die", seen in a variety of normal situations.

APOPTOSIS

MAINTAINS HOMEOSTASIS

• Embryogenesis

• Normal cell turnover– cells with short half-life – tissue involution due to loss of growth

factor stimulation

• Immune function– Elimination of autoreactive T cells– NK and CTL killing

APOPTOSIS IN PHYSIOLOGIC SITUATIONS

Programmed destruction of cell during embryogenesis

Hormone-dependent involution - endometrial cells (menstrual cycle)Cell deletion in proliferating cell

populationDeath of host cells - neutrophilsElimination of self reactive lymphocyteCell death induced by cytotoxic T-cells - viral infected or tumor cells

APOPTOSIS IN PATHOLOGIC CONDITIONS

Cell death produced by injurious stimuli – radiation, cytotoxic drug

Cell injury in certain viral diseases – viral hepatitis

Pathologic atrophyCell death in tumors

APOPTOSIS AND DISEASE

Too Much Apoptosis

toxin induced liver injury

AIDS

Ischemia

neurodegenerative diseases

myelodysplasia

APOPTOSIS AND DISEASE

Inhibition of Apoptosis

various viral diseases - e.g. Herpes, poxvirus, and adenovirus

cancer - e.g. follicular lymphoma, andcarcinomas of the breast, prostate and ovaries

autoimmune diseases - SLE

MORPHOLOGY OF APOPTOSIS

2. Progressive cell shrinkage

1. Chromatin condensation

3. Plasma membrane blebbing4. Apoptotic bodies

5. Phagocytosis - no inflammation

Morphology of Apoptosis

Cell shrinkage

Chromosome condensation

Formation of cytoplasmic blebs

and apoptotic bodies

Phagocytosis of apoptotic cells or

cell bodies

NECROSIS versus APOPTOSIS

NECROSIS APOPTOSIS

Stimuli Pathologic PhysiologicPathologic

Morphology Multiple cellsCell swellingCell lysis

Single cellCell shrinkageChromatinCondensationApoptotic bodies

Host response Inflammation No inflammation

CONCEPTS IN CHRONIC CELL INJURY

• Cells undergo adaptive changes due to persistent (chronic) stress.

• Morphologic changes seldom reflect the type of persistent (chronic) stress.

• Similar responses at the cell level can produce different morphologic changes in different organs.

CAUSES OF CHRONIC CELL INJURY

•Ischemia, hormones, infections, chemicals/drugs, trauma, etc.

•Strength of the insult may be minimal.

•Duration of stress is prolonged as compared to acute cell injury.

Our lives are filled with joys and strife, And what is death but part of life?

Will come the day that we must die,

And leave behind those learning why.

FINAL THOUGHT…

TO BE CONTINUED, CELLULAR

ADAPTATION LECTURE ON

MONDAY

Muscle Hypertrophy