Cell Injury, Adaptation, and Death

• Remember to check into the session via Osler

Cellular Adaptations, Cell Injury, and Cell Death

• Presented by Assistant Professor Joan Roehl

Acknowledgement of Country

• Bond University acknowledges the Kombumerri people, the traditional Owners and Custodians of the land
• Bond University pays respect to Elders past, present and emerging

Learning Outcomes for the Week

• Types and mechanisms of cell injury are described
• Cellular adaptation processes to these injuries
• Describe cell death

Session Learning Outcomes

• Identify regenerative capacity of different cell/tissue types
• Know causes/outcomes of cell stress/injury
• Explain the process of cellular adaptation to stress
• Differentiate types of cell damage (reversible vs. irreversible)
• Describe the process of cell/tissue death (apoptosis and necrosis)

Regenerative Capacity of Different Cell/Tissue Types

• Understanding the differences between labile, stable, and permanent tissues is essential

Cell Regeneration

• The human body contains 30 trillion cells
• Most are differentiated 'end' cells, forming body tissues
• Tissues repair themselves partly through proliferative capacity
• Cell populations divide based on regenerative/proliferative capacity: labile, stable, and permanent

Types of Tissue

• Labile tissue continuously divides
  • Cells are constantly lost and replaced in labile tissue
  • Includes hematopoietic bone marrow cells and most epithelia (e.g., skin, gut, respiratory airways, gonads)
• Stable tissue is quiescent and divides only when stimulated to replace injured cells
  • Stable tissue has limited regenerative capacity, replicating slowly
  • Examples include hepatocytes, renal tubular cells, endothelial cells, smooth muscle cells
• Permanent tissue normally only divides in foetus and is terminally differentiated
  • Has very limited regenerative capacity; injury results in scar tissue
  • Includes most neurons, cardiac muscle, and skeletal fibres

Labile Cell Populations

• Constantly divide, experience constant loss of end cells
• Vulnerable to agents preventing or disrupting cell division
• Stem cells differentiate tissues

Stable Cell Populations

• Cells do not constantly divide and may divide in response to cell injury and loss

Permanent Cell Populations

• Cells cannot divide; injury typically results in scar formation
• Examples of permanent cells are Neurons, Skeletal muscle, and Cardiac muscle

Cell Type Examples

• Labile: Haematopoietic stem cells, Skin epithelium, Respiratory epithelium
• Stable: Hepatocytes, Cardiac muscle cells, Endothelial cells, Renal tubule cells
• Permanent: Gut epithelium, Most neurons, Skeletal muscle

Cellular Response to Stress

• What happens to cells if they become stressed?

Cell Response Pathway

• Normal cells maintain homeostasis
• Stress or injurious stimuli can lead to cell injury
• Cell injury can cause either the Adaption, or cell injury pathway will continue
• Mild, transient injuries may cause reversible cell injury
• Severe, progressive injuries may cause irreversible cell injury
• Irreversible cell injury can lead to necrosis or apoptosis

Myocyte Adaptation

• Normal myocyte adapts via hypertrophy in response to increased load
• Cell injury to Normal myocyte leads to reversibly injured myocyte and cell death

Cellular Adaptations to Stress

• How do cells/tissues respond to homeostatic changes (stress)?

Overview of Adaptations

• Changes in size, number, phenotype, metabolic activity, or function
• Cells respond to environmental changes through an active process
• Adaptations can be reversible
  • Atrophy: cell size and number decrease
  • Hypertrophy: cell size increases
  • Hyperplasia: cell number increases
  • Metaplasia: change in cell type

Stressors

• Changes in hormonal stimulation, demand, nutrient supply, and irritation can cause cellular adaptation

Atrophy

• Decrease in organ/tissue size due to decreased cell size and number
• Tissues undergoing atrophy are composed of cells undergoing autophagy and/or apoptosis
• "A-" prefix means "absence of"
• "-trophy" suffix refers to "growth"

Causes of Atrophy

• Decreased workload (disuse atrophy)
• Loss of innervation (denervation atrophy)
• Decreased blood supply (ischaemia)
• Inadequate nutrition (marasmus) (cachexia)
• Loss of endocrine stimulation
• Pressure

Autophagy

• Atrophy is often accompanied by increased autophagy
• Cells "eat themselves" in response to stress, reducing nutrients
• Cytoplasmic materials are delivered to the lysosome for degradation
• This process is implicated in physiologic and pathologic states and can trigger cell death

Senile Atrophy example

• Example: Senile atrophy of the brain includes narrowed gyri and widened sulci

Meningioma Atrophy

• Meningioma is a benign, slow-growing tumour of the meninges

Hypertrophy

• Increase in organ or tissue volume due to enlargement of component cells (increase in cell size)
• "Hyper-" prefix means "increased"
• "-trophy" suffix means "growth"
• Cardiac muscle cells and skeletal muscles only have a limited capacity for division to increase metabolic demands

Hypertrophy Causes

• Increased workload
• Increased hormonal stimulation

Cardiac Hypertrophy Example

• Measuring ventricular free wall thickness shows the difference between Normal Heart vs. Cardiac Hypertrophy

Uterine Hypertrophy

• Physiologic Hypertrophy can cause an increase in size and changes to the cells

Hyperplasia

• An increase in cell number
• "Hyper-" prefix means "increased"
• "-plasia" suffix refers to "development"

Hyperplasia cause

• Increased hormonal/growth factor stimulation

Capabilities

• Hyperplasia can only take place if the tissue contains cells capable of dividing
• Although distinct from cancer, cancerous proliferations may eventually arise

Benign Prostatic Hyperplasia

• Benign Prostatic Hyperplasia creates hyperplastic glands and compressed Urethra

Metaplasia

• A change from one differentiated cell type into another, sometimes less differentiated
  • E.g. most common epithelial metaplasia: columnar to squamous
• "Meta-" prefix: "change"
• "-plasia" suffix says suffix means "development"
• Cellular adaptations result in activation/suppression of genes
  • E.g. epithelium of airways of chronic smokers
  • E.g. oesophageal epithelium in GORD (Barrett oesophagus)
  • Influences that predispose to metaplasia, if persistent, can initiate malignant transformation

Conductive Respiratory Epithelium Metaplasia

• In response to smoking, ciliated columnar Epithelium undergoes metaplasia to Squamous Epithelium

Barrett's Oesophagus

• Squamous to Columnar Metaplasia happens in the oesophagus

Cell Responses to Stimuli

• Liver cells compensate for loss after part of the liver is removed
• Skeletal muscle wastes due to disuse or malnutrition
• Bain shrinks due to ageing
• Weightlifting causes muscles grow
• Prostate enlarges
• Barret's oesophagus develops
• Smoking causes changes to the airway epithelium
• There is small blood supply to the kidneys
• High blood pressure can cause heat cells to enlange
• The Uterine cells get bigger to accommodate growing foetus

Overview of Cell Injury and Death

• What happens to cells if they become injured?

Response Pathway

• Normal cells maintain homeostasis.
• Cell injury arises from stress or injurious stimuli
• Cell injury has three possible outcomes: Adaption, Reversible injury, or Irreversible injury
• Mild injuries can result in Reversible Injury
• Severe progressive injuries result in Irreversible cell injury

Causes and Mechanisms of Cell Injury

• Oxygen deprivation (hypoxia)
• Nutritional imbalances
• Physical injury
• Free radical and reactive oxygen species
• Chemical injury
• Infectious agents
• Immunologic reactions
• Genetic derangements
• The nature of the injury
• Duration/severity
• Cell type
• State/adaptability
• Lack of blood supply = ischaemia
• Lack of oxygen = hypoxia

Microscopic Features of Cell Injury

Reversible Cell Injury: Cellular/Cloudy Swelling

• Cells cannot maintain ionic and fluid homeostasis
• Failure occurs because of energy-dependent ion pumps in plasma membrane

Reversible Cell Injury: Fatty Change (Steatosis)

• Occurs in hypoxic injury and various forms of toxic or metabolic injury
• The appearance manifested by lipid vacuoles in the cytoplasm
• Mainly cells are involved in/dependent on fat metabolism → hepatocytes (liver) and myocardial cells

Irreversible Cell Injury

• Apoptosis vs. Necrosis: What is the process of cell death?

Apoptosis

• Programmed cell death ("cell suicide")
• Removes cells beyond physiological function or are damaged
• Occurs during physiology and pathology

Physiology of Apoptosis

• Embryonic development
• Eliminates unwanted/old cells, e.g., breakdown of endometrium in uterus during menstruation
• Functioning of immune cells

Pathology of Apoptosis

• Defective apoptosis may lead to cancer
• HIV induces increased apoptosis of immune cells
• Some viruses inhibit apoptosis of cells they infect

More on Apoptosis

• Cells shrink
• Cytoplasm and nucleus condense
• Apoptotic bodies form then phagocytize by macrophages and neutrophils
• There is no inflammation or scarring
• Intact cell membranes preserve organelles leading to cell shrinkage

Necrosis

• Cell/tissue death results from severe injury
• Ischaemia, chemical, and thermal factors can cause cell/tissue death

More on Necrosis

• An unregulated cell death process
• Process is regarded as passive
• Damage to cell membranes occurs
• Contents leak, causing neighbouring cells to undergo necrosis
• Lysosomal enzymes digest the cell (lysis)
• Acute inflammation occurs

Overview of Necrosis

• There is tissue involvement

Key Features of Necrosis in Tissues

• Architecture of Tissue: Coagulative
• Dead tissue must be preserved for a span of at least some days
• Texture: Firm
• Has pale areas because cells are not lysed for days
• Occurs in almost all tissues (except brain)
• Common result of hypoxia and ischaemia (localised area: infarct)
• Can become gangrenous due to bacterial infection

Liquefactive Necrosis

• Dead cells digest into liquid viscous mass
• Creamy, yellow pus forms, indicating leukocytes
• Ischaemic injury in the brain or localised microbial infections cause the process

Caseous Necrosis

• TB lesions form in lungs
• Fragmented/lysed cells and amorphous granular debris are enclosed within a distinctive inflammatory border (granuloma)
• Dead cells digest forming soft, 'cheesy' material

Session Checklist

• What are the differences between labile, stable, and permanent tissues?
• What are the three possible outcomes of cell stress/injury?
• Describe the four types of cell/tissue adaptations. Identify some causes of these adaptations. What factors determine whether cellular adaptations are possible? Are adaptations passive or active, reversible or not?
• Describe the differences between apoptosis and necrosis.
• Understand these terms: atrophy, hypertrophy, hyperplasia, hypertrophy, metaplasia, autophagy, apoptosis, necrosis.