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Cellular Reactions to Injury

Emmanuel R. de la Fuente, M.D.
Overview of Cell Injury

Cells actively control the composition of their immediate

environment and intracellular milieu within a narrow range of
physiological parameters (“homeostasis”).

Essentially all body structures are organized such that they help
maintain the automaticity and continuity of life.

Homeostasis is made possible through positive and negative

feedback mechanisms.
Under physiological stresses or pathological stimuli, cells can
undergo adaptation to achieve a new steady state that would be
compatible with their viability in the new environment, or if the
adaptive process is inadequate or has reached its limits can undergo
injury (reversible injury). Both are reversible processes.

If the injury is too severe (“irreversible injury”), the affected cells

External and Internal Stresses

Homeostatic Cells Injury

Adaptation Injury Death Neoplasia

Inflammation and Repair

Fluid & Hemodynamic Changes

Concepts of cell reactions to injury
- Adaptation
- Cell Injury
- Cell Death/Necrosis
“Concept is an idea or mental picture of a group or class of objects,
formed by combining all their aspects.”
Oxford Dictionary

“Object is a thing external to the thinking mind or subject.”

Oxford Dictionary
Anatomic Pathology

3. Definition
4. Lesions
- Etiology
- Pathogenesis
- Morphology
- Pathophysiology
- Clinical manifestations
- Outcome
How do we know the you understand
the concept?
• Recognize the important elements in
a case scenario
• Analyze the components of the
• Synthesizing or organizing these
elements into an acceptable hypothesis
External and Internal Stresses

Homeostatic Cells Injury

Adaptation Injury Death Neoplasia

Inflammation and Repair

Fluid & Hemodynamic Changes

Homeostatic Cell
• Equilibrium
• Steady State
The term homeostasis is used by physiologists to
mean maintenance of nearly constant conditions
(steady state) in the internal environment.
• Internal conditions of the cell in a steady state
• Not subject to dramatic changes despite changes in the external
• Feedback mechanisms
Causes of Cell Injury

• Hypoxia and ischemia

• Chemical agents
• Physical agents
• Infections
• Immunological reactions
• Genetic defects
• Nutritional defects
• Aging

• Hypoxia (oxygen deficiency) and ischemia (blood flow deficiency):


• Chemical agents: including drugs and alcohol

• Physical agents: including trauma and heat, and extreme cold

• Infections: pyogenic infections

• Immunological reactions: including anaphylaxis and loss of immune

tolerance that results in autoimmune disease

• Genetic defects: inherited and acquired

• Nutritional defects: including vitamin deficiencies, obesity leading to

type II DM, fat leading to atherosclerosis

• Aging: including degeneration as a result of repeated trauma, and

intrinsic cellular senescence, metabolic disease

Sublethal and Lethal Reactions

Factors determining cell response to stress
• Capacity to activate cell’s potentials
• Availability of O2 and nutrients
• Capacity to divide
Effects of stress on cell
• Severity
• Duration
• Health of cell
• Type of cell (Genetic make-up)
Cell Cycle

Labile cells
Stable cells
Permanent cells
Mechanisms of Adaptation
• Increasing cellular activity
- size (hypertrophy)
- number (hyperplasia)
• Decreasing cellular activity (atrophy)
• Altering cellular structure (metaplasia)

May be physiological or
Morphologic Expressions of Cell Adaptation
- increase in cell and organ size
- increase nuclear DNA and cytoplasmic organelles
Morphologic Expressions of Cell Adaptation
- increase in cell and organ size
- increase nuclear DNA and cytoplasmic organelles

• Increase in cell size at S phase and organ size

• Increase in cell number after M
• Decrease cell loss
Combined Hypertrophy and Hyperplasia
Hypertrophy is a prelude to hyperplasia

• Decrease in cell size by autophagy and organ size

• Decrease in cell number by apoptosis
• Increase connective tissue
• Change from one type of mature to another type of mature epithelium
• Usually not a direct transformation
• Growth may be altered leading to dysplasia and neoplasia
Cellular Adaptation Summarized
Environmental Stress


Homeostasis Disturbed
Homeostasis Disturbed Hypertrophy
Homeostasis Disturbed Hyperplasia
Homeostasis Disturbed Hyperplasia + Hypertrophy

Homeostasis Disturbed
Homeostasis Restored

or reversible
change may be
Control Mechanisms of Adaptation

Dysplasia or Neoplasia
Control Mechanisms of Adaptation

• Limits of adaptation
- growth factors
- epidermal growth factor
- platelet-derived growth factor
- insulin-like growth factor
- suppressor factors
- contact inhibition
- suppressor factors
Cell Injury and Cell Death

Primary targets
• Cell membrane
• Mitochondria
• Cytoskeleton
• Cellular DNA
Ischemia as a
cause of necrosis
General Biochemical Mechanisms

1. Loss of energy (ATP depletion, O2 depletion)

2. Mitochondrial damage
3. Loss of calcium homeostasis
4. Defects in plasma membrane permeability
5.Generation of reactive oxygen species (O2•,
H2O2, OH•) and other free radicals
Free Radicals

• Free radicals are chemical species with a single

unpaired electron in an outer orbital

• Free radicals are chemically unstable and

therefore readily react with other molecules,
resulting in chemical damage

• Free radicals initiate autocatalytic reactions;

molecules that react with free radicals are in turn
converted to free radicals
Morphologic Manifestations of Cell
Cell Injury
Manifested as cytoplasmic changes
• Cell swelling

• Fatty change

• Inclusions (e.g., pigments)

Cell Swelling
Cell Injury

Causes - ischemia, infections, chemicals

Cell Swelling

Common cause - infections

Fatty Change

Common causes - alcohol, malnutrition, & drugs

Stress Proteins

1. Pigments
- Carbon
- Hemosiderin
- Bilirubin
- Lipofuscin
- Melanin

2. Proteins
3. Carbohydrates

Causes: idiopathic, hemolytic, & blood transfusion


• Death of cell within living tissue

- At what point does the cell die?
• Not synonymous with cell death
• Necrosis is due to the action of
intracellular and/or extracellular
Morphologic Patterns of Necrosis
Coagulative Necrosis

Ischemia most common cause

Liquefactive Necrosis

Ischemia most common cause

Liquefactive Necrosis

Thrombosis most common cause

Caseous Necrosis

Frequently associated with tuberculosis

Cell Injury/Death
Coagulative Necrosis
Coagulative Necrosis

1. Integrated in cell are death inducing and cell survival signals

2. If death signals (inducers) are dominant apoptosis is triggered
- Growth factor withdrawal
- Loss of matrix attachment
- Viruses, free radicals, DNA damage, Fas ligand
3. Apoptosis occurs through so called executioner pathway
(activation of caspases)
Mechanism of Apoptosis

May be started by activation of surface receptor, cell membrane or

mitochondrial damage, unrepairable DNA damage
2. Programmed cell death
3. Increased cytosolic calcium/degradation of
4. Activation of endonuclease/fragmentation of DNA
5. Loss of mitochondrial function
6. Pyknosis
7. Karyorrhesis
8. Cell shrinks retaining an intact membrane
9. Receptor-mediated phagocytosis of apoptotic
cell/apoptotic bodies
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