Understanding Pathology: Disease Study

• Pathology is the study of disease, bridging science and medicine. It uses laboratory tests to investigate disease causes.

Divisions of Pathology

• Anatomical pathology includes biopsies, surgical pathology, and autopsies.
• Clinical pathology involves lab analysis of body fluids and tissues for diagnosis.
• Molecular pathology focuses on diagnosing disease by examining molecules in organs, tissues, or bodily fluids.

Key Aspects of Pathology

• Etiology studies the causes of disease.
• Pathogenesis explains mechanisms of disease development.
• Morphological changes are structural alterations in cells/tissues, characteristic of a disease.
• Clinical significance refers to functional consequences of morphological changes.

Cellular Adaptations

• Cells adapt to changes in their environment to protect against injury.
• Adaptations can be physiological (normal response) or pathological (response to stress).

Types of Cellular Adaptation

• Hypertrophy involves an increase in cell size, leading to increased organ size, due to increased workload or hormonal stimulation. It can be physiological (muscle growth with exercise) or pathological (cardiac enlargement due to hypertension).
• Hyperplasia involves an increase in cell number when tissues are capable of cell division. It can be physiological (hormonal hyperplasia of breast during puberty) or pathological (endometrial hyperplasia due to hormonal imbalance).
• Atrophy involves a decrease in cell size and number, resulting in reduced tissue/organ size, caused by decreased workload, loss of innervation/blood supply, inadequate nutrition/endocrine stimulation, and aging.
• Metaplasia is a reversible change where one differentiated cell type is replaced by another, usually in response to chronic irritation. An example is Barrett's esophagus, where squamous epithelium is replaced by columnar epithelium, in response to chronic acid reflux,

Cell Injury

• Cell injury occurs when cells can't adapt to stress or are exposed to damaging agents.
• Injury can be reversible or irreversible; irreversible injury leads to cell death.

Causes of Cell Injury

• Hypoxia: Oxygen deficiency, due to ischemia, inadequate oxygenation, or reduced oxygen-carrying capacity of blood.
• Physical agents: Trauma, heat, cold, radiation, electric shock, pressure changes.
• Chemical agents and drugs: Toxins, pollutants, therapeutic drugs.
• Infectious agents: Viruses, bacteria, fungi, parasites.
• Immunologic reactions: Autoimmune diseases, allergic reactions.
• Genetic defects: Mutations, chromosomal abnormalities.
• Nutritional imbalances: Deficiencies or excesses of nutrients.

Mechanisms of Cell Injury

• ATP depletion: Reduced energy production, leading to failure of cellular functions.
• Mitochondrial damage: Impaired oxidative phosphorylation, leading to ATP depletion and increased production of reactive oxygen species (ROS).
• Influx of calcium: Increased cytosolic calcium levels, activating enzymes that damage cellular components.
• Accumulation of reactive oxygen species (ROS): Oxidative stress, damaging lipids, proteins, and DNA.
• Membrane damage: Damage to plasma membrane, mitochondrial membranes, and lysosomal membranes, leading to cell injury and death.
• Protein misfolding and DNA damage: Activation of pro-apoptotic proteins leading to cell death

Reversible Cell Injury

• Cellular swelling: Increased cell volume due to failure of ion pumps and influx of water.
• Fatty change (steatosis): Accumulation of lipid vacuoles within cells, common in liver, heart, and kidney, often caused by alcohol abuse, obesity, or toxins.

Irreversible Cell Injury and Cell Death

• Necrosis: Cell death due to external injury, involving cell swelling, membrane rupture, inflammation, and release of cellular contents.
• Apoptosis: Programmed cell death, involving controlled cell shrinkage, DNA fragmentation, and formation of apoptotic bodies, without causing inflammation.

Types of Necrosis

• Coagulative necrosis: Tissue architecture is preserved; affected tissues become firm. Typical of hypoxic injury (except in the brain).
• Liquefactive necrosis: Complete digestion of cells, resulting in a liquid mass, typical of bacterial/fungal infections and hypoxic injury in the brain.
• Caseous necrosis: "Cheese-like" appearance; typical of tuberculosis.
• Fat necrosis: Specific to adipose tissue, resulting from the action of lipases on fats.
• Fibrinoid necrosis: Immune-mediated vascular damage with fibrin-like protein deposition in arterial walls.

Inflammation

• Inflammation is a protective response to tissue injury, infection, or foreign bodies.
• Its purpose is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and to initiate tissue repair.

Components of Inflammation

• Vascular changes: Alterations in blood flow and vascular permeability.
• Cellular events: Migration and activation of leukocytes.

Types of Inflammation

• Acute inflammation: Rapid onset and short duration (minutes to days), characterized by fluid and plasma protein exudation and neutrophil emigration.
• Chronic inflammation: Longer duration (days to years), characterized by infiltration with mononuclear cells (lymphocytes, macrophages), tissue destruction, and attempts at repair (angiogenesis, fibrosis).

Cardinal Signs of Inflammation

• Heat (calor): Increased blood flow.
• Redness (rubor): Increased blood flow.
• Swelling (tumor): Fluid exudation.
• Pain (dolor): Stimulation of nerve endings by chemical mediators.
• Loss of function (functio laesa): Combination of pain and swelling.

Vascular Changes in Acute Inflammation

• Vasodilation: Increased blood flow to the injured area, causing heat and redness.
• Increased vascular permeability: Endothelial cell contraction leads to widening of interendothelial gaps, allowing plasma proteins and leukocytes to exit the circulation and enter the site of inflammation.

Cellular Events in Acute Inflammation

• Leukocyte recruitment: Leukocytes migrate from the blood into the tissues.
• Margination: Leukocytes adhere to the endothelial lining of blood vessels.
• Adhesion: Leukocytes firmly attach to the endothelium; mediated by adhesion molecules (e.g., selectins, integrins).
• Transmigration (diapedesis): Leukocytes squeeze through interendothelial gaps.
• Chemotaxis: Leukocytes migrate toward the site of injury, guided by chemical gradients (e.g., chemokines, complement factors).
• Phagocytosis: Leukocytes engulf and destroy pathogens and necrotic tissue.

Chemical Mediators of Inflammation

• Vasoactive amines: Histamine (released from mast cells, basophils, and platelets) causes vasodilation and increased vascular permeability; Serotonin (released from platelets) has similar effects.
• Arachidonic acid metabolites: Prostaglandins cause vasodilation, pain, and fever; Leukotrienes cause increased vascular permeability, chemotaxis, and bronchospasm.
• Cytokines: Proteins produced by immune cells that modulate inflammatory responses.
• Complement system: Plasma proteins that are activated in a cascade, contributing to inflammation, opsonization, and cell lysis.

Outcomes of Acute Inflammation

• Resolution: Complete restoration of normal tissue structure and function.
• Healing by fibrosis (scar formation): Occurs if substantial tissue destruction, inflammation affects tissues that do not regenerate, or abundant fibrin exudation.
• Progression to chronic inflammation.

Chronic Inflammation causes

• Persistent infections: Prolonged exposure to pathogens that are difficult to eradicate.
• Autoimmune diseases: Immune reactions against self-antigens.
• Prolonged exposure to toxic agents.

Cellular Characteristics of Chronic Inflammation

• Infiltration with mononuclear cells: Macrophages, lymphocytes, and plasma cells.
• Tissue destruction.
• Attempts at healing by connective tissue replacement of damaged tissue (angiogenesis and fibrosis).

Macrophages

• Dominant cell type in chronic inflammation.
• Derived from monocytes in the blood.
• Phagocytose pathogens and cellular debris.
• Secrete cytokines and growth factors.
• Present antigens to T lymphocytes.

Lymphocytes

• T lymphocytes: Activate macrophages and participate in cell-mediated immunity.
• B lymphocytes: Differentiate into plasma cells and produce antibodies.

Granulomatous Inflammation

• A distinctive form of chronic inflammation.
• Characterized by the formation of granulomas.
• Granuloma: A collection of macrophages, often with a rim of lymphocytes.

Causes of Granulomatous Inflammation

• Infections: Tuberculosis, fungal infections.
• Foreign bodies: Sutures, splinters.
• Autoimmune diseases: Sarcoidosis, Crohn's disease.

Tissue Repair

• Tissue repair refers to the restoration of tissue architecture and function after an injury. It occurs by two main mechanisms: regeneration and scar formation.

Regeneration

• Regeneration: Complete restoration of the original tissue structure and function.
• Occurs in tissues with a high capacity for cell proliferation (e.g., liver, epidermis).

Scar Formation

• Scar formation: Replacement of damaged tissue with connective tissue (fibrosis).
• Occurs when tissue damage is extensive or when tissues lack the capacity to regenerate.
• Results in a scar, which provides structural stability but lacks the specialized functions of the original tissue.

Steps in Scar Formation

• Angiogenesis: Formation of new blood vessels.
• Migration and proliferation of fibroblasts: Fibroblasts deposit collagen and other extracellular matrix components.
• Scar maturation and remodeling: Collagen is reorganized and strengthened.

Factors Influencing Tissue Repair

• Infection: Delays healing.
• Nutrition: Protein deficiency, vitamin deficiencies (especially vitamin C).
• Glucocorticoids: Inhibit collagen synthesis.
• Mechanical factors: Increased pressure or tension can disrupt healing.
• Poor perfusion: Inadequate blood supply impairs healing.
• Foreign bodies: Delay healing.
• Type and extent of tissue injury: Large wounds heal more slowly.
• Location of injury: Healing is better in richly vascularized tissues.