Cell Response to Injury & Morphological Changes in Tissues

Cell Response to Injury: Morphological Changes

Aims

• Understand the morphology of sublethal damage, e.g., hydropic degeneration and fatty change.

• Understand the morphology of lethal damage, e.g., necrosis and apoptosis.

• Understand the range of cell vulnerability to injury.

• Understand the differences between lethal and sublethal injury.

Cells are Dynamic

• Cells adapt to limited stress exposure.

• Cells are exposed to constant change.

• If cells were static and rigid, it would lead to disease when the acceptable limit of change is exceeded.

• Reversible change: The limit is not exceeded.

• Irreversible change: The limit is exceeded.

• If change is outside the acceptable limit, it results in disease.

Cell Adaptation

• Reversible functional and structural responses allow cells to achieve a new, altered steady state.

• Physiological structural adaptations:

  • Cell adaptations to environmental change.

  • Change in the normal pattern of growth and detectable structural changes.

How Cells Adapt

• A new altered steady state is achieved, which better equips the cell to survive.

Cell Adaptation - Steady State

• Normal steady state moves towards altered steady states over time due to injury.

• Levels of organizational homeostatic ability degrade towards lethal or sublethal damage, passing a point-of-no-return.

Cell Vulnerability to Injury

• Different cell types have variable susceptibility to damaging stimuli.

• Most sensitive cells (e.g., neurons) die within 2-5 minutes without oxygen.

• Most robust cells are resistant to damage.

• Cell injury results from functional and biochemical abnormalities in one or more essential cellular components.

Why Cells are Variably Susceptible to Injury

• Ability to survive ATP depletion:

  • ATP loss causes failure of biosynthesis and membrane pumps.

• $Ca^{2+}$ influx:

  • Free calcium in the cytosol activates intracellular enzymes, causing destruction.

• Reactive Oxygen Species (ROS):

  • Disturb normal cell function and damage cell components.

Mechanisms of Cell Injury

• The main targets of damaging stimuli are:

  • Mitochondria

  • Cell membranes

  • Cytoskeleton

  • Cellular DNA

• Damage to one system leads to secondary damage to others.

Two Types of Cell Damage

1. Sub-lethal injury

• If damage is minimal, the cell recovers after removal of the damaging stimulus (reversible).

• Associated with reversible structural abnormalities.

• Characteristics:

  • Cell and organelle swelling

  • Blebbing of the plasma membrane (PM)

  • Detachment of ribosomes

• Damaged components are removed by autophagy.

Features of Sub-lethal Injury

1. Hydropic degeneration / cellular swelling

2. Fatty change

• Disruption of ionic and fluid homeostasis.

• Failure of energy-dependent membrane pumps.

• Hypoxic, toxic, or metabolic injury.

• Manifested as lipid vacuoles in cells.

• Two features of reversible cell injury are recognized at the light microscope level.

1) Hydropic Degeneration

• Swelling of organelles leading to cellular swelling.

• Cytoplasm becomes pale.

• Formation of intracellular vacuoles.

• Also called ‘cloudy swelling’.

• Caused by:

  • One of the first signs of cell injury.

Why Does Swelling Occur?

N/A

Hydropic Degeneration in Liver

• Comparison of normal cells vs. injured cells in the liver.

2) Fatty Change

• Caused by:

  • Toxins (e.g., alcohol)

  • Hypoxia

  • Disease

• Accumulation of lipids in cells.

• Affects cells that have a key role in fatty acid (FA) metabolism.

Why do lipids accumulate?

N/A

Characteristics of Fatty Change

• Cells accumulate lipid in cytoplasmic vacuoles.

• Affected organ is enlarged.

• Yellow in color.

• Vacuoles can coalesce to form ‘fatty cysts’.

Fatty Change in Liver

• Vacuolated cells are visible.

Stain to demonstrate lipids in cells

N/A

2. Lethal Injury

• Cell death occurs by two different routes:

  • Necrosis

  • Apoptosis

• Caused by a severe damaging stimulus or prolonged sub-lethal damage (irreversible).

What determines the type of cell death?

N/A

Necrosis

• Necrosis of tissue has distinct patterns.

• Denaturation of proteins and enzymatic digestion.

• Characteristics:

  • Loss of plasma membrane integrity.

  • Enzymatic digestion of cells by autolysis.

  • Leakage of cellular constituents leading to inflammation.

  • Activation of lysosomal enzymes.

Why is the leakage of cellular constituents important?

N/A

Patterns of Necrosis

1) Coagulative

• Architecture and tissue outline are preserved.

• Dead tissue appears firm and pale.

• Causes:

  • Occlusion of arterial blood supply.

• Proteins released from dead cells aid diagnosis (cardiac muscle: Cardiac troponin-T, Creatine kinase - kidney & heart).

Coagulative Necrosis

• Cortical infarct

  • Ghost outline of normal tissue

  • Loss of nuclei

  • Cytoplasm stains darker pink

• Comparison of normal vs. coagulative necrosis.

2) Liquefactive Necrosis

• Result of Dissolution of tissue:

• Describes dead tissue appears: semi-liquid hydrolytic enzymes

• Bacterial/fungal infections Causes:

  • Micro-organisms attract neutrophils.

  • Neutrophils: release hydrolases leading to liquefaction.

Liquefactive Necrosis continued

• Commonly seen in the brain / cerebral infarction

Why does this pattern of necrosis occur in the brain?

N/A

Liquefactive Necrosis Brain with cerebral infarction

• Necrotic brain area is a semi-fluid protein mass.

• No preservation of architecture.

Apoptosis

• Pathway of cell death induced tightly regulated suicide program

• Activation of enzymes degrade:

  • DNA

  • Nuclear / cytoplasmic proteins

• Cells lose contact with neighboring cells

• Cytoplasm shrinks & apoptotic cells breaks into apoptotic bodies

Apoptosis: Apoptotic Bodies

• Apoptotic bodies are phagocytosed by neighboring cells and macrophages.

• Cell contents don't leak out.

Apoptosis: Physiologic situations

• Occurs during development & adulthood

• Purpose:

  • Eliminates aged, unwanted cells or harmful cells

  • Diseased/damaged cells

• Programmed destruction /embryogenesis

• Maintenance of steady cell numbers

• Involution of hormone-dependent tissue after hormone withdrawal

Apoptosis: pathologic conditions

• Removes cells injured beyond repair to limit collateral tissue damage.

• DNA damage: radiation, drugs, hypoxia

  • Directly or via production of free radicals

• Accumulation of misfolded proteins:

  • Leads to ER stress which culminates in apoptosis

• Infection:

  • Loss of infected cells due to apoptosis may be induced by the virus

Apoptosis of epidermal cells

• Round/oval mass

• Intensely eosinophilic cytoplasm

• Dense nuclei

Summary: Cell Response to Injury

• Cell able to adapt vs. cell not able to adapt.

• Mild stimulus leads to sub-lethal damage (cloudy swelling, fatty change) and recoverable change.

• Severe stimulus leads to lethal damage (necrosis) and non-recoverable change, leading to cell death.

• Functional disturbance due to harmful stimulus to the cell or genetic abnormalities can lead to neoplasia (benign/malignant) if the stimulus increases or change in growth pattern occurs.

Summary: Sub-lethal vs Lethal Cell Damage

• Normal cell can undergo changes in sub-lethal cell injury due to mild damaging stimulus; recovery occurs by autophagy, synthesis of new products, and removal of the cause of damage.

• Continued damage or immune/cytokine damage can switch on programmed cell death (pathologic apoptosis) leading to cell death; alternatively, massive damage can lead to instant cell death (coagulated cell) or changes of necrosis.

References

• Core Pathology (3rd edition). A Stevens, JS Lowe & I Scott (2008). Mosby Publishers

• Robbins and Cotran, Pathologic Basis of Disease (7th edition). V Kumar, AK Abbas & N Fausto (2005). Elsevier Saunders

• Basic Pathology (2nd edition). S Lakhani, S Dilly & C Finlayson (1999). Arnold Publishers

AIMS: Adaptive Changes in Tissues

• Understand terms hypertrophy & hyperplasia

• Give examples of increased cellular activity under physiological and pathological conditions

• Understand terms Atrophy, Hypoplasia/Aplasia & Agenesis

• Give examples of decreased cellular activity under physiological and pathological conditions

Cell Division in Tissues

• Cells have different cell division ability

  • Continuous: Labile / Squamous epithelial cells

  • Facultative: Stable / Liver cells

  • Non-dividers: Permanent / Neuronal cells

• Cells adapt to pathological stimuli by altering their pattern of growth

  • Changes in size, number or differentiation of cells

How do cells respond to increased functional demand?

N/A

• Adaptive responses include Hyperplasia, Hypertrophy, and combined Hypertrophy & Hyperplasia.

• Two mechanisms of increase.

Hyperplasia

• ‘hyper + plassein’ : oversized / ‘to mould’

• Increase in cell number caused by increase in cell division

Adaptive response not seen in which cells?

Non-dividers

• Hyperplasia can be physiological or pathological

Physiological Hyperplasia

Bone Marrow Hyperplasia

• Increased functional demand

• Increase in production RBC with high altitude

• Stimulates erythropoietin synthesis

• Increase in erythropoiesis leading to increased No. of erythrocyte progenitor cells

Where is erythropoietin synthesized?

N/A

Glandular Epithelium Hyperplasia

• Occurs during menstrual cycle in endometrial glands

Glandular epithelium hyperplasia occurs in response to?

N/A

Puberty & Pregnancy:

• Hyperplasia female breast epithelial cells & myometrial smooth muscle cells

• Accompanied by hypertrophy

Hyperplasia of Endometrium

• Early proliferative endometrium vs. Secretory phase endometrium

• In response to estrogen:

  • Increase in number of cells in each gland

  • Results in an increased volume fraction gland:stroma

Compensatory Hyperplasia

• Liver:

  • lobe donation for transplantation

  • remaining cells proliferate leading to normal sized organ

• Kidney:

  • removal / loss of function

  • healthy kidney: increase in size & weight

  • enlargement of structures

  • accompanied by hypertrophy

Greek mythology & hyperplasia of Liver

• Prometheus was punished by Zeus for bringing fire to humanity

• Liver was eaten by an eagle but it kept regrowing

How does the Liver regenerate itself?

• Production of:

  • Transforming growth factor-β

  • Interleukin-1

How does the Liver know when to stop?

N/A

Pathological Hyperplasia

Thyroid Hyperplasia (Grave’s Disease)

• increase in secretion TSH stimulation of thyroid gland or

• Auto-Abs against thyroid follicle

• increase in levels of T3/T4 hormones

• Thyroid and thyroid follicles show fleshy enlargement

• Caused by excess of hormones or growth factors

Thyroid Hyperplasia (Grave’s Disease)

• In response increase in Thyroid hormones

• Increase in No. of epithelial cells & are also enlarged

• Edges of colloid appear scalloped, colloid contains thyroglobulin

Benign prostatic hyperplasia

• Induced in response to hormones:androgens

The process remains controlled, why?

N/A

• Causes of hyperplasia

  • Local increase in growth factors / growth factor receptors

  • Or by up-regulation of cell-signaling systems

Hypertrophy

• ‘hyper + trophe’ : oversized / nourishment

• Increase in cell/tissue size as a result of increase in cell size

• Results in increase in functional capacity

How does cell enlargement occur?

• Increase in synthesis of structural components

• Increase in synthesis of RNA & organelles required for protein synthesis

Is an adaptive response seen in which cells?

N/A

• Increase in functional demand on tissues

• Stimulation by hormones / growth factors

Causes of hypertrophy

N/A

Physiological Hypertrophy

Skeletal muscle hypertrophy

• Occurs as a result of increase work load & metabolic demands on the tissue

• Athletes

  • Increase in length & increase in width of muscle fibres

• The increase is in proportion to strength of stimulus

What happens if stimulus ceases?

N/A

Skeletal Muscle Hypertrophy

• Muscle fibres 50 yr old

  • Small, multi-nucleated

• Muscle fibres 50 yr athlete

  • Increase in length & diameter fibres

  • Soleus region

Smooth muscle hypertrophy

Pregnancy

• Hormone induced hypertrophy

How does cellular enlargement occurs?

N/A

• Oestrogenic hormones bind oestrogen receptors

• Results in increase synthesis of smooth muscle proteins & increase size

• Mechanical stimulus

How does increased cell size occur?

N/A

• Hypertrophy is induced by the linked actions of mechanical sensors & growth factors

  • Transforming growth factor - β

  • Insulin like growth factor - 1

  • Fibroblast growth factor

• & vasoactive agents

  • Endothelin-1

  • Angiotensin II

• These stimuli work co-ordinately

Pathological Hypertrophy

Cardiac muscle hypertrophy

• Caused by chronic hemodynamic overload

  • Hypertension or faulty valves

• Results in:

  • Increase synthesis of proteins & increase size myofilaments

  • Increase amount of force each myocyte generates causing:

  • Increase strength & work capacity

Atrophy/Involution

• A - without ; Trophe - nourishment

• Decrease in organ size/tissue by decrease in cell size +/or number

• Adaptive response to decrease requirement

• Associated decrease in cell metabolism & decrease in syn structural proteins

How do different cell types respond?

N/A

Physiological Atrophy / Involution

Loss of Endocrine stimulation

• Hormone - responsive tissues eg.

  • Breast

  • Reproductive organs

• Loss of oestrogen stimulation after menopause

• Atrophy of:

  • Endometrium

  • Vaginal

  • Breast - epithelium

Normal development

Embryonic structures eg.

• thyroglossal duct

Thymus gland:involutes during adolescence

• Thymus / child vs. Thymus / adult

  • Dense cellularity vs. Decrease size / involution

  • Heavily populated by lymphoid cells vs. Replacement by adipose tissue

• notochord &

Pathological Atrophy Decreased workload - atrophy of disuse

• Immobilisation of fractured bone

  • Skeletal muscle atrophy

• Atrophic muscle cells contain

  • Decrease mitochondria

  • Decrease myofilaments

  • Decrease rough ER

• Initial decrease in size is reversible

Loss of innervation - denervation atrophy

• Metabolism & function of skeletal muscle depends on nerve supply

• Damage nerve fibres supplying muscle leading to atrophy

• Normal vs. Denervated muscle

  • Regularly arranged vs. Atrophy of fibres

  • Uniform in size vs. Fibres small & angulated

Lipofusion in cellular atrophy

What are the consequences of atrophy?

• Decrease protein synthesis & increase protein degradation

• Lipofusion accumulation:

  • Brown pigment

  • Degradation products

  • Myocardial fibres of elderly

  • Autophagy of structural elements
    Agenesis

• Absence of tissue/organ

• failure of development

• eg. Renal agenesis

Hypoplasia

• Failure in development of normal size organ

• eg. lung, kidney & bone marrow

Development caused of decreased cell mass

N/A

Aplasia / Hypoplasia

• Haematological condition: aplastic anaemia

• Severe hypofunction of bone marrow

• Failure/suppression of stem cells

Consequence?

Decrease in all blood cell types / pancytopenia

• BM shows decrease in cellularity

• replaced: fat

Adaptive responses resulting in decreased tissue mass

• Stable tissue undergoes abnormal stimulus leading to adaptive response, returning to stable tissue after end of abnormality, and finally back to normal tissue.

• Reduced functional demand leads to Cell Atrophy through reduced cell size; causes include disuse, inadequate nutrients, lack of endocrine stimulation, poor blood supply, denervation, aging.

• Involution involves reduced cell number.

• Cell Atrophy & Involution involve reduced cell size and cell number.
  Restoration of stimulus leads to regrowth!

Adaptive responses resulting in increased tissue mass

• Stable tissue undergoes abnormal stimulus leading to adaptive response, returning to stable tissue after end of abnormality, and finally back to normal tissue.

• Increased functional demand leads to Hypertrophy through increased cell size; causes include increased work demand.

• Hyperplasia involves increased cell number; causes include metabolic demand, excess endocrine stimulation.

• Hypertrophy & Hyperplasia involve increased cell size and cell number; causes include persisting tissue injury.
  Removal of cause leads to reduced cell size and cell number.

References

• Core Pathology (3rd edition). A Stevens, JS Lowe & I Scott (2008). Mosby Publishers

• Concise Pathology (3rd edition). P Chandrasoma & CR Taylor (1998). Lange, Prentice-Hall International

• Muirs Textbook of Pathology, 15th edition, C Simm Herrington (2014). CRC Press

• Basic Pathology (2nd edition). S Lakhani, S Dilly & C Finlayson (1999). Arnold Publishers