Principles of Medical Biology - Cellular Responses to Diseases

Cellular Response to Disease

• Homeostasis: Normal cells maintain a steady internal state within physiological parameters.
• Cellular responses to changes in the internal or external environment form the pathophysiological basis of clinical symptoms.

Inflammation and Healing of Tissues

• Cells react to injury through adaptation.
• If the cell's capacity to adapt is exceeded, cell injury occurs.
• The severity of the injury determines whether the cell recovers or progresses to cell death.

Causes of Cell Injury and Examples

• Hypoxia: Vascular insufficiency
• Physical Injury: Burns
• Chemical Injury: Drug overdose
• Infectious Agents: Viral agents
• Immunological Reactions: Graft versus host disease
• Genetic Derangements: Cystic fibrosis
• Nutritional Imbalances: Scurvy

Interrelated Causes of Cell Injury

• Physical injury can cause hypoxic damage due to blood loss.
• Biochemical Changes:
  • Release of oxygen-derived free radicals
  • Increase in cytoplasmic calcium
  • Depletion of adenosine triphosphate (ATP)
  • Defects in cell membrane permeability

Patterns of Cell Death

• Apoptosis:
  • Regulated cell death in embryogenesis and physiological events (e.g., ovarian follicular atresia in menopause).
  • Also known as programmed cell death.
  • Chromatin condensation followed by nuclear fragmentation.
  • No release of proinflammatory mediators; therefore, no inflammation.
• Necrosis:
  • Cell death in living tissue.
  • Characterized by cell swelling, organelle death, and release of inflammatory mediators.
  • Accompanied by inflammation.
  • Cytoplasm appears more eosinophilic.
  • Nuclear changes: karyolysis (dissolution), pyknosis (shrinkage), and karyorrhexis (fragmentation).
  • Results in morphological changes in the tissue.

Types of Necrosis and Examples

• Coagulative Necrosis:
  • Example: Myocardial infarction
  • Outline of tissue preserved
• Colliquative Necrosis:
  • Example: Cerebral infarction
  • Liquefaction, tissue morphology lost
• Caseous Necrosis:
  • Example: Tuberculous lymphadenitis
  • Cheesy material, tissue morphology preserved
• Gangrene:
  • Example: Clostridial infection
  • Gaseous/frothy, tissue morphology lost
• Fat Necrosis:
  • Example: Acute pancreatitis
  • Outline of tissue preserved

Additional Patterns of Cell Death

• Autolysis: Death of cells post-mortem or after removal from the body at surgery.
• Inflammation: Response of vascularized tissue to injury
  • Series of events from tissue injury to vascular, chemical, and systemic responses.
  • Aimed at restoring tissue to normalcy.
  • Early Response: Vascular constriction followed by dilatation and slowing of blood flow.
  • Red blood cells aggregate, white cells adhere to endothelial cells (margination), and gaps between endothelial cells increase.
  • White cells emigrate (transmigration) through the vessel wall via diapedesis (neutrophils exit first, followed by mononuclear cells).
  • Chemical mediators released from plasma or cells.

Chemical Mediators of Inflammation

• Originate from plasma or cells.
• Production triggered by microbial products or products of the complement, kinin, and coagulation systems.
• Generally short-lived and removed by phagocytes.
• Balances and checks prevent excessive damage.

Chronic Inflammation

• Acute inflammation may resolve, heal by fibrosis, result in abscess, or progress to chronic inflammation.
• Chronic inflammation is prolonged inflammation.
• Can be a continuation of acute inflammation or start de novo.
• Characterized by concurrent tissue destruction and inflammation.
• Tissue changes include:
  • Mononuclear cell infiltration
  • Small vessel proliferation
  • Fibrosis

Granulomatous Inflammation

• Specific type of chronic inflammation with granulomas in the diseased tissue.
• Granulomas are collections of macrophages (epithelioid cells).
• Caseating Granulomas: Loss of cellular detail with cheese-like material centrally (e.g., tuberculosis).
• Giant cells (multinucleate cells) are seen.
  • Langhans Giant Cells: Nuclei arranged peripherally in a horseshoe shape.

Mechanisms of Increased Vascular Permeability

• Endothelial Contraction: Short-lived initial response
• Direct Injury (e.g., burns): May be long-lived
• Damage by Leucocytes: Long-lived later response
• New Blood Vessel Formation: Long-lived response seen in early repair

Main Chemical Mediators of Inflammation

Outcomes of Acute Inflammation

• Resolution: Cessation of inflammation without scarring
• Chronic Inflammation: Persistence of inflammation
• Abscess Formation: Pus formation
• Healing: Fibrosis and scarring

Effects of Inflammation (Cardinal Signs)

• Redness
• Heat
• Pain
• Swelling
• Loss of function
• Nonspecific Systemic Effects:
  • Raised erythrocyte sedimentation rate (ESR)
  • Raised C-reactive protein (CRP)
  • Leucocytosis
  • Fever

Wound Healing

• Replacement of dead tissue by living cells or fibrous tissue.
• Labile Cells: Great capacity for renewal (e.g., surface epithelial cells).
• Stable Cells: Slow regeneration but can renew nearly completely (e.g., liver and renal tubular cells).
• Permanent Cells: Lack regenerative capacity (e.g., cells of the central nervous system).
• Factors Adversely Affecting Wound Healing:
  • Extremes of temperature
  • Persistence of foreign material
  • Infection
  • Early movement or trauma
  • Poor glycaemic control
  • Lack of minerals (e.g., zinc)

Sequence of Events in Wound Healing

• Formation of granulation tissue.
• Growth of new vessels and myofibroblasts into injured tissue.
• Collagen accumulation to form a scar.
• Excessive fibroblast proliferation can result in a hypertrophic scar or a keloid.
• Healing by First Intention: Clean surgical incisions with approximated wound margins.
• Healing by Second Intention: Larger tissue loss with wound contraction.

Adaptive Responses

• Hypertrophy: Increase in cell size without cell replication
  • Physiological: Muscle hypertrophy in athletes
  • Pathological: Cardiac muscle hypertrophy in hypertension
• Hyperplasia: Increase in cell numbers by cell division
  • Physiological: Uterine muscle in pregnancy
  • Pathological: Bone hyperplasia in Paget’s disease of bone
• Atrophy: Decrease in the size of cells or organs
  • Physiological: Involution of the thymus with age
  • Pathological: Muscle atrophy in paralysis secondary to loss of innervation
• Metaplasia: Reversible replacement of one differentiated cell type with another
  • Physiological: Squamous metaplasia in the uterine cervix in response to change in pH of the vagina
  • Pathological: Squamous metaplasia in the bronchus secondary to cigarette smoke

Disturbance in Blood Flow, Shock, Infarction

• Oedema: Abnormal accumulation of fluid in tissues
  • Caused by alteration of haemodynamic forces (e.g., cardiac failure) or changes in plasma osmotic pressure (e.g., nephrotic syndrome).
  • Inflammation causes oedema due to increased vascular permeability.
• Thrombosis: Pathological process by which a blood clot forms within the uninterrupted vascular system.
  • Involves the endothelium, platelets, and coagulation cascade.
  • Three Factors:
    • Endothelial injury
    • Stasis or turbulence of blood flow
    • Hypercoagulability

Embolus

• Detached fragment of material (solid, liquid, or gas) seen in a blood vessel distant from its site of origin.
• Examples:
  • Pulmonary embolus: Usually from deep venous thrombosis of the limbs
  • Amniotic fluid embolus: Amniotic fluid in maternal vessels following a tear in placental membranes
  • Air embolism: In deep-sea divers from sudden decompression
  • Fat embolism: From fatty marrow of long bones following fractures

Infarction and Shock

• Infarction: Necrosis following ischaemia secondary to occlusion of arterial supply or venous drainage.
• Shock: Condition of circulatory failure resulting in hypoperfusion of vital organs
  • Can result in irreversible neuronal injury, acute renal tubular necrosis, cerebral damage, and death.
  • Types of Shock:
    • Cardiogenic shock: Secondary to myocardial infarction
    • Hypovolaemic shock: Secondary to traumatic haemorrhage
    • Toxic shock: Secondary to Gram-negative septicaemia.