Cellular Injury

Normal Cellular Physiology and Homeostasis

  • Homeostasis: Cells must maintain a stable internal environment despite varying external conditions. This is regulated by structures and processes within the cell.

  • Cell Membrane:

    • Structure: A semi-permeable phospholipid bilayer.

    • Functions:

      • Regulates the intake of nutrients and the removal of waste.

      • Communicates information regarding the external environment.

      • Provides protection against pathogens and harmful substances.

  • Nucleus:

    • Acts as the cell control centre.

    • Contains the genetic material (DNA).

    • Regulates gene expression.

    • Executes the first stage of protein production.

  • Mitochondria:

    • Referred to as the power house of the cell.

    • Responsible for energy production via adenosine triphosphate (ATPATP) synthesis.

    • Contains its own unique DNA (mtDNAmtDNA).

    • Additional functions: Involved in calcium storage, apoptosis, and various metabolic pathways.

  • Lysosomes:

    • Organelles specialized for cellular digestion and waste management.

    • Contain hydrolytic enzymes.

    • Purpose: Digestion of macromolecules, cellular debris, and foreign substances.

    • Processes: Autophagy, defense against pathogens, and involvement in apoptosis.

Disruption to Normal Cellular Physiology

  • Plasma Membrane Disruption:

    • Causes uncontrolled movement of molecules across the membrane.

    • Leads to cell swelling or shrinkage and leakage of contents.

    • Increases susceptibility to pathogens.

    • Results in impaired communication and loss of structural integrity.

    • Can trigger the pathways for apoptosis or necrosis.

  • Nuclear Disruption:

    • Leads to impaired gene expression and damage to DNA.

    • Causes errors in cell division and problems with protein synthesis.

    • Results in an uncontrolled cell cycle and abnormal cellular differentiation.

  • Mitochondrial Disruption:

    • Results in reduced ATPATP production, leading to energy deficits.

    • Overproduction of Reactive Oxygen Species (ROSROS), which causes cell damage.

    • Leads to calcium dysregulation, metabolic imbalance, and apoptosis.

    • Associated with various degenerative diseases.

    • Lysosomal Disruption:

    • Impaired cellular digestion leads to waste accumulation and subsequent inflammation.

    • Increases susceptibility to pathogens.

    • Triggers apoptosis and necrosis.

    • Associated with lysosomal storage diseases.

Types of Cell Injury

  • Hypoxia:

    • Defined as cellular oxygen deprivation.

    • Causes: Ischaemia, anaemia, or respiratory failure.

    • Mechanism: The cell cannot produce sufficient ATPATP, resulting in energy depletion.

    • Consequences: Cell swelling, general dysfunction, and cell death.

  • Chemical Injury:

    • Result of exposure to toxic substances (e.g., drugs, environmental toxins, industrial chemicals).

    • Potential for damage to the cell membrane, which increases permeability.

    • Can induce oxidative stress via the generation of ROSROS.

  • Infectious Injury:

    • Caused by pathogens such as bacteria, viruses, parasites, and fungi invading the cell.

    • Involves various mechanisms of injury and triggers an immune response.

    • Inflammation from the immune response can cause further injury to the cell.

  • Physical Injury:

    • Mechanical Stress: Damages the membrane and compromises structural integrity.

    • Temperature Extremes: Burns (excessive heat) or frostbite (excessive cold) can denature proteins.

    • Radiation Exposure: Leads to DNA damage and the production of ROSROS.

Categorization and Reversibility of Cell Damage

  • Degeneration (Deterioration): A reduction in cellular functionality caused by the accumulation of metabolites or other substances.

  • Infiltration: The overloading of a cell by materials that are abnormal in either quantity or type.

  • Sub-lethal Effects:

    • Reduced viability and oxidative damage.

    • Mitochondrial dysfunction.

    • Altered gene expression and membrane permeability.

    • Sub-lethal changes are often reversible if the stressor is removed; however, damage can be cumulative over time.

Sub-Lethal Reversible Changes and Distubances

  • Water Disturbances (Hydropic Swelling):

    • Also known as cloudy swelling.

    • Normal Mechanism: Osmotic pressure between intracellular and extracellular fluid is equal, maintained by the sodium (Na+Na^+) pump.

    • Injury Mechanism: Cellular injury (e.g., ↓O2↓ O_2) $→$ damage to the cell membrane and mitochondria $→$ ↓ATP↓ ATP $→$ failure of the sodium pump $→$ ↑Na+↑ Na^+ enters the cell $→$ water influx.

    • Progression:

      1. Cloudy swelling (intracellular oedema) occurs as watery fluid accumulates in dilated endoplasmic reticulum (ER) and mitochondria.

      2. Progressive dilatation of the ER leads to hydropic vacuolation (the appearance of clear vacuoles).

      3. Mitochondria break down, becoming beaded and causing a granular appearance in the cytoplasm.

    • Causes: Infection, toxins, nutritional factors, and water/electrolyte imbalances.

  • Fat Disturbances (Fatty Change):

    • The accumulation of abundant triglycerides (fat globules) in the cytoplasm of high-metabolic organs like the liver, skeletal muscle, and heart muscle.

    • Primary problem: The inability of non-fatty tissues to metabolize the volume of lipids presented to them.

    • Causes: Anoxia (from severe anaemia), cardiac failure, respiratory disease, diabetes mellitus, chronic malnutrition, chemical poisons, chronic alcoholism, and infections (septicaemia).

    • Note on Obesity: Pathological adiposity (obesity) is distinct from intracellular fatty change. In obesity, fat is deposited between the cells of the liver and heart. Fatty change is reversible but indicates severe cell injury.

  • Protein Disturbances:

    • Misfolding: Failure of proteolysis leads to the accumulation and aggregation of proteins.

    • Impaired Synthesis: Problems in the production cycle of proteins.

    • Amyloid Degeneration (Amyloidosis): Deposition of a waxy substance in and around supporting tissue fibers, vessels, and basement membranes. Congo red stain reveals orange-red deposits.

      • Primary: Abnormal light chain proteins (part of antibodies); affects heart, kidneys, liver, GI tract, nervous system, and skin.

      • Secondary: Occurs after chronic inflammatory conditions (e.g., rheumatoid arthritis); affects kidneys, liver, spleen, GI tract, heart.

      • ATTR: Abnormal transthyretin (transport protein); affects heart, nervous system, and kidneys.

    • Hyaline Degeneration: A descriptive term for a glassy, refractive appearance. It is not a specific substance. Found in dense collagen, particularly in fibromyomata where collagen replaces muscle fibers.

    • Mallory Bodies: Red globular material composed of cytoskeletal intermediate filaments (sized between actin and myosin) in liver cells. Found in chronic damage from alcoholism; damage is often cumulative over years.

    • Mucoid Degeneration: Infiltration of tissue by mucin, causing pain and swelling. Often affects tendons and ligaments due to aging, chronic stress, or repeated trauma.

  • Carbohydrate Disturbances:

    • Disruption of metabolic processes and storage.

    • Includes glycogen accumulation, altered glucose metabolism, and abnormal glycosylation.

Cellular Accumulations: Calcification and Pigmentation

  • Calcifications: Abnormal deposits of calcium salts.

    • Dystrophic Calcification: Local deposits in necrotic tissue that is not absorbed (e.g., old tuberculosis lesions, old infarcts, or the stomach wall/arteries where bluish-purple deposits appear).

    • Metastatic Calcification: Caused by an increase in blood calcium levels.

      • Mechanism: Parathyroid adenoma/hyperplasia $→$ Mobilisation of Ca++Ca^{++} from bone $→$ ↑↑ Blood Ca++Ca^{++} $→$ Deposition of Ca++Ca^{++} in kidneys, arteries, and lungs.

  • Endogenous Pigmentation:

    • Melanin: Increased due to melanocyte tumors, suntan, Addison’s disease, or pregnancy.

    • Bilirubin: Accumulation leads to Jaundice.

    • Haemosiderin: Caused by local breakdown of red blood cells in tissue (severe contusions) or hemolytic anemia (visceral siderosis).

      • Hepatocytes and Kupffer cells may show large amounts of haemosiderin via Prussian blue reaction (iron stain).

    • Lipofuscin: Pigment observed during atrophy.

  • Exogenous Pigmentation:

    • Inhalation: Coal dust (carbon).

    • Ingestion: Metals such as silver or lead.

    • Injection: Tattooing.

Lethal Irreversible Changes and Necrosis

  • Cell Death Pathways: Apoptosis, Necrosis, and Autophagy.

  • Forms of Necrosis:

    • Coagulative Necrosis: Tissue architecture is preserved. Typical of ischemia and infarction (loss of blood supply). Example: A wedge-shaped pale renal infarction in the kidney cortex.

    • Colliquative (Liquefactive) Necrosis: Solid material is converted to liquid, destroying tissue architecture. Example: Cerebral infarction; removal of dead tissue eventually leaves a cavity.

    • Fat Necrosis: Necrosis of adipose tissue, usually caused by trauma, surgery, or inflammation.

      • Example (Pancreas): Injury to pancreatic acini releases enzymes that damage fat to produce soaps, appearing as soft, chalky white areas.

    • Caseous Necrosis: Dead cells disintegrate but are not fully digested, resulting in a characteristic cheese-like appearance. Microscopically seen as acellular pink areas surrounded by granulomatous inflammation. Commonly associated with Tuberculosis (TB).

Complications of Necrosis

  • Acute inflammation.

  • Chronic inflammation.

  • Immunological reactions.

  • Calcification (e.g., old caseous foci of TB).

  • Gangrene.