Pathology 2

Cell Injury, Cell Death, and Adaptations

Presenter: Dr. M. Rahimi, MD PathologistFocus: Types of cell injury, death, and cellular adaptations.Study AidSource: Robbins Basic Pathology, Tenth Edition, Elsevier.Additional resources available in Enhanced Digital Version.

Key Concepts of Cell Injury

• Healthy Cell

  • Homeostasis: The stable equilibrium state of a healthy cell, maintained through various physiological processes that regulate internal conditions despite changes in the external environment.

  • Injurious Stimulus: Any external or internal factor (e.g., toxins, pathogens, hypoxia, or mechanical injury) that disrupts homeostasis, leading to cellular stress and injury.

Types of Cell Injury

• Reversible Injury:

  • This occurs when injury is mild and cells can recover their normal structure and function if the injurious stimuli are removed. Common indicators include cellular swelling and fatty changes.

• Irreversible Injury:

  • Severe, progressive damage that is beyond the repair capabilities of the cell, ultimately leading to cell death. Key distinctions in outcomes include different forms such as necrosis and apoptosis.

Outcomes of Irreversible Injury

• Necrosis:

  • An uncontrolled and chaotic process of cell death associated with inflammation. Cells lose their structural integrity, leading to leakage of cellular contents into the extracellular space. This process often results in a significant inflammatory response from surrounding tissues.

• Apoptosis:

  • A programmed form of cell death that is regulated and beneficial to the organism, allowing for the removal of unwanted or damaged cells without eliciting an inflammatory response. Apoptosis is critical during development, homeostasis, and in the response to cellular damage.

Irreversible Cell Injury

Morphological Changes

• Plasma Membrane Blebs:

  • Characterized by the formation of bubble-like protrusions in the cell membrane, indicating membrane damage.

• Increased Intracellular Volume:

  • This occurs primarily due to the influx of water, leading to cellular swelling (hydropic degeneration).

• Mitochondrial Changes:

  • Visible swelling, and eventual calcification signify severe metabolic alterations and impending cellular failure.

• Disaggregated Ribosomes:

  • These float free in the cytoplasm as ribosomes detach from the rough endoplasmic reticulum (ER), compromising protein synthesis.

• Dilated Endoplasmic Reticulum:

  • Characterized by the swelling and vesicular transformations of the ER during severe cellular stress.

Nuclear Changes:

• Condensed Chromatin:

  • Indicates nuclear and cellular deterioration; chromatin compacts due to heavy cellular damage.

• Shriveled Membrane:

  • A sign of significant membrane damage, indicating that the cell is unable to maintain its structural integrity.

Characteristics of Irreversibility

• Mitochondrial Dysfunction:

  • A critical indicator; lack of ATP production following injury signifies that the cell can no longer maintain essential metabolic processes.

• Structural DNA Integrity Loss:

  • Means that damage to the DNA structure is irreparable, compromising cell viability.

• Membrane Function Disturbances:

  • Profound disruptions in membrane function that hinder transport and signaling processes within the cell.

Reversible Injury Indicators

Early Signs of Recovery

• Increased Cell Size:

  • Cellular hypertrophy occurs as the cell works to restore homeostasis.

• Clumping of Chromatin:

  • An irregular arrangement of chromatin that can indicate recovery.

• Swelling:

  • Particularly observed in the endoplasmic reticulum and mitochondria, indicative of early reversible injury.

• Membrane Blebs:

  • These small blisters on the cell membrane may also form as signs of cellular distress.

• Myelin Figures:

  • Lipid deposits seen within cells due to membrane injury, often appearing as concentric whorls.

Additional Signs

• Vacuolation:

  • The formation of vacuoles, signifying loss of organized cytoplasmic structures and potential recovery indicators.

• Inflammatory Response:

  • Necrosis will typically trigger an inflammatory response, leading to agile movement of immune cells into the area for repair and cleanup.

Necrosis Overview

Definition:

• Accidental cell death characterized by a loss of membrane integrity and overall cellular function.

Features of Necrosis

• Cellular Content Leakage:

  • Consequence of membrane disruption allowing the contents to spill into the surrounding interstitial space.

• Inflammatory Response:

  • Localized response from surrounding tissues reacting to the dead cells, which can lead to further tissue damage if excessive inflammation occurs.

Necrosis Morphology

Light Microscopy Findings

• Increased Eosinophilia:

  • Due to loss of RNA and alterations in protein binding that result in more pronounced staining of the tissue.

• Glassy Appearance:

  • Changes seen under the microscope indicating loss of normal structure in the cytoplasm.

• Vacuolation:

  • Appearance of bubbles indicative of the digestion of organelles and necrotic processes.

Nuclear Changes in Necrosis

• Pyknosis:

  • Nuclear shrinkage and increased basophilia, signaling destructive processes at the nuclear level.

• Karyorrhexis:

  • Fragmentation of the nucleus; a final sign of nuclear failure.

• Karyolysis:

  • Fading of the chromatin's characteristic basophilia due to DNase action, leading to additional nuclear dismantling.

Tissue Necrosis Patterns

Types of Necrosis

• Coagulative Necrosis:

  • Characterized by the preservation of tissue architecture despite cell death; commonly seen following ischemic events. Eosinophilic anucleate cells remain that signal past cellular fingerprints.

• Liquefactive Necrosis:

  • Results in a pus-like liquid formation due to enzymatic digestion of tissues, particularly common in brain injuries due to ischemic insult.

• Gangrenous Necrosis:

  • Occurs due to a complete loss of blood supply to a region, commonly seen in limbs, leading to death of tissue.

• Caseous Necrosis:

  • Associated with tuberculous infections; this type leads to a granular necrotic mass that appears cheese-like due to the necrosis surrounded by a chronic inflammatory cell infiltrate.

• Fat Necrosis:

  • Results from trauma or inflammation of adipose tissue, presenting with white chalky appearances due to saponification.

• Fibrinoid Necrosis:

  • Occurs secondary to immune complex deposition in arteries, appearing bright pink and amorphous under H&E staining, indicative of vascular damage.

Coagulative Necrosis

• Description:

  • Maintains structural integrity despite cell death, where eosinophilic anucleate cells can survive, leading sometimes to scar formation or regeneration following an inflammatory response.

Liquefactive Necrosis

• Characteristics:

  • Formation of a pus-filled lesion; particularly common in infections where localized tissue accrues pus from inflammatory cells and dead tissue.

• Examples:

  • Commonly seen post-ischemic necrosis in the brain related to vascular occlusions.

Caseous Necrosis

• Description:

  • Characteristic finding in tuberculosis, results in a granulomatous formation filled with necrotic debris surrounded by lymphocytic infiltrate.

Fat Necrosis

• Causes:

  • Trauma or damage to adipose tissue or enzymatic effects during acute pancreatitis, which results in necrotic fat characterized by soap formation (saponification) leading to a chalky white appearance upon pathological examination.

Fibrinoid Necrosis

• Context:

  • Predominantly associated with immune-mediated vascular damage.

• Visual Presentation:

  • Bright pink amorphous appearance evident under H&E stain results from complex formation within the vessel walls.

Apoptosis Overview

Definition:

• Caspase-mediated programmed cell death which is a regulated physiological process orchestrated to eliminate cells in a controlled manner.

Physiologic Instances:

• Necessary during normal developmental processes and in pathological cases for the removal of defective or harmful cells to maintain homeostasis and tissue health.

Pathologic Instances:

• Occur in circumstances such as DNA damage (due to radiation or chemotherapy), infections, or during the elimination of aged cells, where apoptosis effectively prevents detrimental consequences of uncontrolled cellular proliferation.

Mechanisms of Apoptosis

• Signal Loss:

  • Results from the reduction of growth factor signaling that normally sustains cell survival in favorable conditions.

• Activation:

  • Through various extrinsic or intrinsic pathways involves the activation of specific receptors triggering the apoptotic machinery leading to cell dismantlement.

• Caspase Pathway:

  • A pivotal regulatory mechanism that involves nuclear fragmentation, chromatin condensation, and orchestrated signaling to recruit phagocytes for the effective removal of