Chapter 1

CELL INJURYCELL DEATH

CELL ADAPTATIONS

M.G.Rajanandh, Dept. of Pharmacy Practice, SRM College of Pharmacy, SRM University.

CONCEPTS IN CELL INJURY

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

• The clinical signs and symptoms are severalsteps removed from the biochemical changesassociated with cell injury.

• Cell injury is common to all pathologic processes.

CONCEPTS IN CELL INJURY

• Cell injury may be reversible, result in cell adaptation, or lead to cell death.

– Biochemical alterations occur prior to morphologic changes.

– The result of cell injury is determined, in part, by the intensity,duration and/or the number of exposures to an etiologic agent.

– The result of cell injury is determined, in part, by the celltype and its physiologic state.

• Injury at one point induces a cascade of effects.

CONCEPTS IN CELL INJURY

• The clinical signs and symptoms are severalsteps removed from the biochemical changesassociated with cell injury.

• Cell injury is common to all pathologic processes.

CAUSES OF CELL INJURY -THE PATIENT’S VIEW

• Hypoxia• Infectious agents• Physical injury• Chemicals/drugs

• Immune response• Genetic derangement• Nutritional imbalance

HYPOXIC INJURY

Cerebral infarction Myocardial infarction

Renal atrophy

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

CONCEPTS IN CELL INJURY

• Divergent factors can act at the same point on the cell to induce cell injury.

CELL INJURY - THE CELL’S PERSPECTIVE

CONCEPTS IN CELL INJURY

• Injury at one point induces a cascade of effects.

• The clinical signs and symptoms are severalsteps removed from the biochemical changesassociated with cell injury.

• Cell injury results from a disruption of oneor more of the cellular components thatmaintain cell viability.

MECHANISMS OF CELL INJURY

• Hypoxia / Ischemia Model

• Generation of Reactive Oxygen Species

• Increased Cytoplasmic Ca++

HYPOXIA - ISCHEMIA MODELBlood Clot

⇓ O2

⇓ Oxidative Phosphorylation

⇓ATP

Impaired function of the plasma membrane

ATP-dependentNa+ pump

⇑ Glycolysis

Detachment ofribosomes

HYPOXIA - ISCHEMIA MODEL

Detachmentof ribosomes

⇑ Glycolysis ⇓pH

⇓ GlycogenStores

⇓ ProteinSynthesis

LipidDeposition

ChromatinClumping

REACTIVE OXYGEN SPECIES

02

Fe+2 Fe+3SODO2 H2O2 OH + OH

2GSHGlutathione GlutathionePeroxidase Reductase

GSSH

H20CELL INJURY

Ca++ INDUCED CELL INJURY

Ca++Ca++ Ca++

⇑Cytoplasmic ionic Ca++

ATPase Phospholipase Protease Endonuclease

⇓ATP ⇓Phospholipids Protein DNADisruption Damage

OTHER CAUSES OF CELL MEMBRANE INJURY

• Complement - C5-C9 MAC• Cytotoxic T Cells - perforin• Virus• Bacterial Endotoxins and Exotoxins• Drugs

CONCEPTS IN CELL INJURY

• Cell injury may be reversible, result in a cell adaptation, or lead to cell death.

– Biochemical alterations occur prior to morphologic changes.

– The result of cell injury is determined, in part, by the intensity,duration and/or the number of exposures to an etiologic agent.

– The result of cell injury is determined, in part, by the celltype and its physiologic state.

• Injury at one point induces a cascade of effects.

OUTCOMES OF CELL INJURY

REVERSIBLE CELL DEATH CELLADAPTATIONS

NORMAL CELL

CELL INJURY / CELL STRESS

ACUTE CHRONIC

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.

NECROSIS• Morphologic types of necrosis

– Coagulative– Liquifactive– Caseous– Enzymatic (fat)

• The type of necrosis is dependent upon patterns of enzymatic degradation of cells and extracellular matrix, the type of necrotic debris, and by bacterial products when present.

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 AND DISEASE

• Too Much Apoptosis

toxin induced liver injury

AIDS

ischemia

neurodegenrative 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

Progressive cell shrinkageChromatin condensation

Plasma membrane blebbingApoptotic bodiesPhagocytosis - no inflammation

MECHANISMS OF APOPTOSIS

NECROSIS VS. APOPTOSIS

NECROSIS APOPTOSIS

Stimuli Pathologic PhysiologicPathologic

Morphology Multiple cellsCell swellingCell lysis

Single cellCell shrinkageChromatinCondensationApoptotic bodies

Host response Inflammation No inflammation

CAUSES OF CHRONIC CELL INJURY

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

•Strength of the insult may be minimal.

•Duration of stress is prolongedas compared to acute cell injury.

Alteration in cell differentiation with concurrent alteration of

tissue/organ function.

METAPLASIA

CELLULAR ADAPTATIONS

• Alterations in cell size

• Alterations in cell number

• Alterations in cell differentiation

• Abnormal intracellular accumulations

METAPLASIA

Barrett's Esophagus