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Cellular Reactions to Injury

by
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


die.
External and Internal Stresses

Homeostatic Cells Injury

Adaptation Injury Death Neoplasia

Inflammation and Repair

Fluid & Hemodynamic Changes


Objectives
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
element
• 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
environment
• Feedback mechanisms
Causes of Cell Injury

• Hypoxia and ischemia


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

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


athereosclerosis

• 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
Equilibrium

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
pathological
Morphologic Expressions of Cell Adaptation
Hypertrophy
- increase in cell and organ size
- increase nuclear DNA and cytoplasmic organelles
Morphologic Expressions of Cell Adaptation
Hypertrophy
- increase in cell and organ size
- increase nuclear DNA and cytoplasmic organelles
Hypertrophy
Hyperplasia

• 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
Atrophy

• Decrease in cell size by autophagy and organ size


• Decrease in cell number by apoptosis
• Increase connective tissue
Metaplasia
• 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
Atrophy

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

Homeostasis Disturbed
Metaplasia
Homeostasis Restored

Adaptive
or reversible
change may be
irreversible
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
Injury
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
Inclusions

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

2. Proteins
3. Carbohydrates
Hemosiderin

Causes: idiopathic, hemolytic, & blood transfusion


Necrosis

• 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
enzymes
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
Liquefactive/Caseous
Necrosis
Apoptosis

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
Apoptosis
2. Programmed cell death
3. Increased cytosolic calcium/degradation of
cytoskeleton
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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