patoloji-ders-notlari

Title

Serdar Balcı

General Mechanisms of Cell Injury

Serdar BALCI

Homeostasis

• A happy normal cell
  • Comfortable
    • Suitable environment for function and differentiation
  • Neighbours and neighbourhood
    • Interaction with other cells
  • Good income
    • Available metabolic substrates
  • Can deal with daily problems
    • Physiologic demands
  • No enemy
• A normal cardiac cell
  • Comfortable
    • Suitable environment for contraction
  • Neighbours
    • Can interact with vascular supply, nerves and other cells
  • Good income
    • Oxygen and glucose is readily available
  • Can deal with daily problems
    • Can pump faster if necessary
  • No enemy
    • No organisms (Toxoplasmosis), or autoimmune activity

What if homeostasis is not preserved

Figure 1-1 from Robbins and Cotran Pathologic Basis of Disease 8 th _ ed, _

Adaptations

Reversible

Functional and structural responses

More severe physiologic stresses

Pathologic stimuli

**A new steady state is achieved. **

Continue to function

Type of adaptations

• Hypertrophy
  • Increase in size of the cells
  • Increase in proteins, increase in function
• Hyperplasia
  • Increase in number of cells
• Atrophy
  • Decrease in size and metabolic activity of the cell
• Metaplasia
  • Change in cell phenotype

If cell cannot adapt

If adaptive capability is exceeded

Or the stress is very harmfull

If stress is severe

Persistent

Rapid onset

Irreversible Injury

Cell Death

• Many causes
  • ischemia (lack of blood flow)
  • Infections
  • Toxins
  • Immune reactions
• It is also a “normal” process
  • Remember embriology?
  • GIS epitheium regenerates every week

ALTERED PHYSIOLOGICAL STIMULISOME NONLETHAL INJURIOUS STIMULI

Stimulus	Adaptation
Increased demand, increased stimulation (e.g., by growth factors, hormones)	Hyperplasia, hypertrophy
Decreased nutrients, decreased stimulation	Atrophy
Chronic irritation (physical or chemical)	Metaplasia

Adapted from Table 1-1, from Robbins

REDUCED OXYGEN SUPPLYCHEMICAL INJURYMICROBIAL INFECTION

Stimulus	Injury
Acute and transient	Acute reversible injuryCellular swelling fatty change
Progressive and severe (including DNA damage)	Irreversible injury → cell deathNecrosisApoptosis

Adapted from Table 1-1, from Robbins

##

Stimulus	Response
Metabolic alterations, genetic or acquired; chronic injury	Intracellular accumulations; calcification
Cumulative sublethal injury over long life span	Cellular aging

Cardiac muscle cells

**Increased demand **

to pump more and MORE

Decrease O 2 __ supply__

**Increased demand **

to pump more

Atherosclerosis

ischemia

Muscle adapts

Increases functional units (proteins)

Adapts→hypertrophy

Cell cannot aford the demand

Ischemia

Cell death

Remember!

Adaptation is good. But for a certain time.

Adapted cell is functioning, but not as good as it used to be.

Adapted cell is more vulnerable to injury.

Adaptations

• Physiologic
  • normal stimulation by hormones or endogenous chemical mediators
  • the hormone-induced enlargement of the breast and uterus during pregnancy
• Pathologic
  • responses to stress
  • Escape from injury

CELL INJURY AND CELL DEATH

Cell injury

Occurs;

So severe stress → unable to adapt

Exposed to inherently damaging agents, intrinsic anomalies

Reversible cell injury

Early, mild forms

Reversible when damage is removed

No severe membrane damage

No nuclear dissolution

Cell death

• Irreversible;
• Necrosis
  • Cell killed by external factor/cells
• Apoptosis
  • Cell kills itself

	Necrosis	Apoptosis
Cell size	Enlarged (swelling)	Reduced (shrinkage)
Nucleus	Pyknosis, karyorrhexis, karyolisis	Fragmantation into nucleosome size fragmants
Plasma membrane	Disrupted	Intact, orientation of lipids are altered
Cellular contents	Enzymatic digestion, may leak out of cell	Intact, may be released in apoptotic bodies
Adjacent inflammation	frequent	none
	Pathologic, irreversible cell injury	Physiologic (eliminate unwanted cells) Pathologic (DNA, protein damage)

Necrosis

• Damage to membranes is severe:

  • enzymes leak out of lysosomes
  • enter the cytoplasm,
  • digest the cell
  • necrosis.

• Cellular contents leak into the extracellular space

• host reaction (inflammation)

• always a pathologic process

• reasons:

  • ischemia,
  • exposure to toxins
  • various infections
  • trauma

Apoptosis

nuclear dissolution

**without complete loss of membrane integrity. **

Reasons:

deprivation of growth factors

DNA or proteins are damaged beyond repair

many normal functions and is not necessarily associated with pathologic cell injury

no inflammatory response

CAUSES OF CELL INJURY

Causes of Cell Injury

Oxygen deprivation

Chemical agents

Infectious agents

Immunologic reactions

Genetic factors

Nutritional imbalances

Physical agents

**Aging **

O2 deprivation

• Hypoxia: O 2 __ deficiency, inadequate oxidation of blood__
  • Pneumonia
  • Blood loss anemia
  • CO poisoning
• Ischemia: most common reason for hypoxia
  • Loss of blood supply to tissue
  • Decreased arterial flow
  • Reduced venous drainage

Chemical agents

• Substances in excess: glucose, salt, water
• Poisons:
  • Membrane permeability
  • Osmotic homeostasis
  • Enzyme, cofactor
• Environmental:
  • Air pollutants
  • Insectisides
  • CO
  • Asbestos
  • Ethanol
  • Drugs, therapeutic drugs
  • Excess O 2

Infectious agents

Viruses

Rickettsiae

Bacteria

Fungi

Protozoa

Tape worms, flukes

Immunologic ractions

Autoimmune reactions

Exaggerated reactions

Genetic factors

Defect in proteins

Deficiency

Malfunction

Accumulation

Susceptibility to external stimuli

Nutritional imbalances

• Protein- calorie insufficiency
• Vitamin deficiency
• Obesity
  • Diabetes
  • Atherosclerosis
• Some diets cause susceptibility to cancer

Physical agents

Trauma

Heat

Radiation

Electric

Atmospheric pressure

Aging

Decreased replication, repair and destruction capability

Error accumulation in DNA

Protein accumulation