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CELL INJURY, CELL DEATH & CELLULAR
ADAPTATIONSLECTURE 1
MR. MASRO BIN MOHAMAD (MBM)
PHAR2262: GENERAL PATHOLOGY
FACULTY OF PHARMACYCUCMS
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
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
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
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
Causes of chemicals & drugs are as below;
i. Hypersensitivity reactions ii. Anaphylactic reactions (Allergy)iii. Autoimmune diseases (SLE)
IMMUNE RESPONSE
GENETICS DERANGEMENTS
Congenital malformation Down syndrome
Decreased life of red blood cell Thalassemia, Sickle cell anemia
Inborn errors of metabolism
NUTRITIONAL IMBALANCES
Protein-calorie deficienciesVitamin deficienciesAnorexia nervosaExcesses of lipids Obesity, Atherosclerosis
Metabolic diseases Diabetes
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
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…