Cells, Tissues & Disease 2023 Dr Gupta PDF

Cells, Tissues & Disease Sanjeev Gupta Associate Professor in Pathology 19/01/2023 [email protected] By the end of this double lecture you should be able to: • Describe Cellular Adaptations • Describe Hyperplasia/Metaplasia/Dysplasia • Describe the causes and mechanism...

Cells, Tissues & Disease Sanjeev Gupta Associate Professor in Pathology 19/01/2023 [email protected] By the end of this double lecture you should be able to: • Describe Cellular Adaptations • Describe Hyperplasia/Metaplasia/Dysplasia • Describe the causes and mechanisms of cell injury • Explain difference between apoptosis and necrosis • Describe physiological and pathological apoptosis The Structure of a Healthy Cell Cells • A basic cell is bounded by a cell membrane. • Nucleus contains the majority of the cell's genetic material – material is organized as DNA molecules, along with a variety of proteins, to form chromosomes Cells • Cytoplasm contains the cytosol and organelles, • mitochondria that power the cell • endoplasmic reticulum and ribosomes that synthesize new materials and process old proteins for recycling • Golgi apparatus – packages proteins e.g. for secretion • Lysosomes - the cells waste disposal system Examples of Tissue Types • A tissue is a cellular organisational level between cells and a complete organ – its an collection of a combination of specific cell types that make up a structure that usually has a specific function • Epithelial tissue : surface epithelium , may contain glands Squamous , Columnar e.g. skin, lining of the digestive tract • Fatty tissue • Muscular tissue ( voluntary and involuntary) • Nervous tissue • Bony tissue Examples of Types of Tissues Connective Tissue e.g. dermis of the skin Muscle Tissue e.g. striated muscle Epithelial Tissue e.g. Transitional epithelium of the bladder Nervous Tissue e.g. grey matter of spinal cord (mN – motor neuron) Stages of cellular response to stress Types & causes : 1) Physiological -Atrophy of thymus gland after puberty & thyroglossal duct after birth (involution) -Decreased workload “ disuse ”: immobilized limb to permit healing of fracture -Loss of hormone stimulation : atrophy of ovaries & uterus after menopause Normal Brain (A) vs Alzheimers Brain: Atrophy (B) Fig 1 -5 Robbins Differs From Neoplasia By The Following : • It occurs in tissue made up of labile or stable cells that have the power of regeneration under normal or pathologic conditions. • Occurs in response to a stimulus , disappears when the stimulus when it is removed. • Usually performs a function . • It is a reversible non -neoplastic process. Metaplasia • A SUBSTITUTION of one NORMAL CELL or TISSUE type, for ANOTHER – COLUMNAR  SQUAMOUS (Respiratory tract) – SQUAMOUS  COLUMNAR (Barrets esophagus) – FIBROUS  BONE Metaplasia • Metaplasia is a reversible change in which one differentiated cell type (epithelial or mesenchymal) is replaced by another cell type. • Adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment. • The most common epithelial metaplasia is COLUMNAR  SQUAMOUS : respiratory tract in response to chronic irritation. • although the epithelial lining of respiratory tract becomes tough, important mechanisms of protection against infection are lost — mucus secretion and the ciliary action of the columnar epithelium • Moreover, the influences that predispose to metaplasia, if persistent, may initiate malignant transformation in metaplastic epithelium. Squamous metaplasia - In the respiratory epithelium of habitual cigarette smokers Barrett ’ s Oesphagus Squamous epithelium  intestinal -like columnar cells Esophageal squamous epithelium is replaced by intestinal -like columnar cells under the influence of refluxed gastric acid. SUMMARY - cellular adaptations Dysplasia • Literally means disordered growth - denotes a loss of architectural organization and a loss of cell uniformity in epithelium Dysplasia • Ranges from mild dysplasia to severe (carcinoma in situ) • Partial loss of differentiation. • Disordered maturation with impaired function. • No invasion of basement membrane. • It represents reaction to underlying inflammation or to chronic irritation. Dysplasia • Pleomorphism of cells (variation in size and shape). • Hyperchromatic nuclei with increased nucleo - cytoplasmic ratio and increased mitotic activity. • Loss of polarity (orientation) of cells. • Mild and moderate degrees of dysplasia are reversible when the evoking stimulus is removed. However, severe degree is considered pre -invasive malignancy. Hallmarks Cell Growth and adaptation Neoplasia Pre -cancerous stage (carcinoma in situ) Stages of cellular response to stress – oxygen deprivation (anoxia) – physical agents – chemical agents – infections agents – immunologic reactions – genetic defects – nutritional imbalances – aging Causes of Cell Injury Oxygen Deprivation • Hypoxia – deficiency of oxygen Causes: Ischemia, cardiorespiratory failure, decreased oxygen - carrying capacity of the blood ( anemia /CO poisoning), cyanide. Causes of Cell Injury Physical Agents • Mechanical trauma • Extremes of temperature – burns , extreme cold • Radiation • Electric shock Causes of Cell Injury Chemical Agents and Drugs • Hypertonic concentration of salt – deranging electrolyte homeostasis • Poisons – arsenic, cyanide, or mercuric salts • Insecticides and Herbicides • Air pollutant – SD, CO,Ozone,ND,Lead • Occupational hazard – asbestos • Alcohol and Narcotic drugs Causes of Cell Injury Infectious Agents • Parasites • Fungi • Bacteria • Rickettsiae • Viruses Causes of Cell Injury Immunologic Dysfunction • Immunodeficiency • Anaphylactic reaction to foreign protein or drug • Reactions to endogenous self - antigens – autoimmune diseases Causes of Cell Injury Genetic Derangements • Congenital malformations – Down syndrome • Decreased life of red blood cell – Sickle cell anemia (HgS) • Inborn errors of metabolism/dna damage/misfolded protein response Causes of Cell Injury https://evolution.berkeley.edu/evolibrary/article/mutations_06 Nutritional Imbalances • Protein -calorie deficiencies • Vitamin/Nutrient deficiencies • Anorexia nervosa • Excesses of lipids – Obesity , Atherosclerosis Causes of Cell Injury NUIG/UHG Teaching slides PathXL/Philips Aging • Accumulation of damage • ROS, DNA mutation, cell senescence, telomere shortening • Predisposition to neoplastic transformation - telomerase activation. Causes of Cell Injury Key targets of cell injury • ATP depletion or decreased synthesis. • Permeabilisation of Cell membranes. • Disruption of biochemical pathways ( esp Protein synthesis). • DNA damage. Mechanisms of Cell Injury Functional and morphologic effects of ATP depletion Role of rising intracellular Ca 2 + • Influx of Ca 2+ from extracellular fluid, mitochondria and ER. • Ca 2+ activates phospholipases (damages cell membranes), proteases (damages cell membranes and cytoskeleton) and endonucleases (damages DNA). Mechanisms of Cell Injury Role of ROS in cell injury Mechanisms of Cell Injury Mitochondrial Damage 1) Formation of high -conductance channel in mitochondrial membrane ATP production Mitochondrial Oxidative Phosphorylation Mechanisms of Cell Injury 2) Leakage of Cytochrome c into cytosol Defects in Membrane Permeability Mitochondria – • mitochondrial permeability transition; • this non -selective pore may be reversible or become permanent leading to cell death. • Leakage of cytochrome c can trigger apoptosis. Plasma membrane – • mechanisms include those occuring with hypoxia/ ischaemia and free radicals • immune mechanisms as with complement activation and • perforin from lymphocyte attack on cells infected with a virus. Lysosomal membranes - • Damage to can lead to cell death by necrosis. All membranes - • May be damaged and ruptured by mechanical force as in trauma, or by ice crystals as in extreme cold. Mechanisms of Cell Injury Mechanisms of Membrane damage in Cell Injury Damage to DNA and proteins • Cell cycle checkpoints and DNA damage repair mechanisms protect the cell • Damage too extensive - suicide program triggered. Mechanisms of Cell Injury • Accumulation of misfolded proteins - ER stress - - programmed cell death Morphology of injury Necrosis vs Apoptosis Necrosis : always pathologic, the most common type of cell death involving: 1. Severe cellular swelling 2. Denaturation & coagulation of proteins 3. Breakdown of organelles 4. Cell rupture 5. Usually involves a large number of cells possibly involving adjoining tissue and evokes an immune response. Apoptosis : may be normal developmental process or pathologic, occurs when a cell initiates a “ suicide ” program. 1. An orchestrated demolition of the cell particularly the DNA 2. Cell components are recycled. 3. Minimal involvement of neighboring cells/tissues 4. No activation of the immune system. Example of INJURY – CELIAC DISEASE Autoimmune Reaction to Gluten Leads to Damage of the Intestinal Villi Example of INJURY – CELIAC DISEASE Example of INJURY – Alzheimer’s Disease Alzheimer’s Disease is Currently Irreversible • Get accumulated damage over time • Starts with the accumulation of beta -amyloid around neurons, which develop into plaques • Then get hyperphosphorylation of tau, leading to tau tangles in the neurons • Accumulate damage, impacts cognition, and then leads to neuron death and dementia Example of INJURY – Alzheimer’s Disease Cellular Damage can h ave Pathological Consequences Summary Summary • Pathological changes occur in response to damage at both the cellular and tissue level • Injury can occur by multiple mechanisms, e.g. Ischaemia, Infection, Immune system, Inherited Genetic Mutations • Damage may be resolvable or permanent • Cell death may occur by - apoptosis or necrosis Summary • Adaption may also take place – Hypertrophy (increased size) – Atrophy (decreased size) – Hyperplasia (increased proliferation) – Metaplasia (cells change from one type into another – often a defensive mechanism) – Dysplasia (precursor to cancer) Reading for this course: