Cell Biology Quiz: Organelles and Injuries

Pathogen 3.1: Cells and Inflammation

• This unit examines cells and the inflammatory process.

Objectives

• Analyze the components of a typical cell and their function.
• Analyze how cells coordinate and integrate their functions.
• Interpret the role of growth factors in cellular activity.
• Understand stem cells, and their roles in regenerative medicine.
• Illustrate how cells are injured (reversible and irreversible), including changes in cytoplasm and nucleus.
• Analyze common causes of cell injury.
• Contrast four types of cellular adaptations.
• Differentiate between metaplasia and dysplasia.
• Discuss cellular aging.
• Compare necrosis and apoptosis as cell death forms.
• Compare different forms of necrosis and provide examples.
• Analyze cellular and events of inflammation.
• Define vascular changes in acute inflammation.
• Debate the role of leukocytes in an inflammatory response, including margination, diapedesis, emigration, exudation, chemotaxis, phagocytosis, and microbicidal substances.
• Analyze the complement system, cytokines, and clotting system in inflammation.
• Compare and contrast acute and chronic inflammation.
• Describe the formation of granulomas and analyze pathologic terms related to inflammation (serous, fibrinous, purulent, abscess, ulcer, wound, scar, keloid).
• Investigate the typical local and systemic symptoms of inflammation.
• Analyze the pathogenesis of fever.

The Cell as a Unit of Health and Disease

• Cells are the basic units of health and disease.

Essential Components of Animal Cells

• Nucleus: DNA storage, transcription, mRNA processing
• Ribosomes: Translation
• Mitochondria: Energy production, apoptosis
• Endoplasmic Reticulum (ER): Rough - protein synthesis, Smooth - lipid synthesis, calcium storage
• Golgi Apparatus: Modifies proteins for transport
• Lysosomes: Digestive enzymes for macromolecules
• Proteasomes: Degrade proteins
• Cytoskeleton: Cell shape, polarity, organization
• Plasma membrane: Regulated movement of solutes, cell-to-cell interaction

Lysosomes/Proteasomes

• Lysosomes contain hydrolases to break down substances.
• Proteasomes dismantle denatured or misfolded proteins.
• Lysosomes form in three ways - pinocytosis, receptor-mediated endocytosis, and autophagy.

Plasma Membrane

• Permeable: Very small particles, non-polar particles (water, O2, CO2, ethanol, steroids, vit D)
• Impermeable: Polar particles, large particles (proteins, glucose, ions)
• Ways to get through:
• Passive transport (channels, carriers)
• Receptor-mediated
• Active transport (pumps - ATPase)
• Endocytosis (caveolae, receptor-mediated, phagocytosis)
• Exocytosis

ER/Golgi

• Rough ER synthesizes transmembrane proteins and lipids; chaperones ensure proper folding.
• Smooth ER synthesizes steroids, catabolizes lipid-soluble molecules, and stores calcium.
• Golgi apparatus packages proteins for organelles or plasma membrane; modifies N-linked oligosaccharides.

Mitochondria

• Oxidative phosphorylation
• Cell death (apoptosis)

Receptors

• Extracellular and intracellular receptors
• Ligands bind to receptors, initiating intracellular function or DNA interaction
• Effects: transcription

Kinase Activity

• Kinase is a molecule that phosphorylates other molecules, initiating cellular activity
• Receptor tyrosine kinases (RTKs)
• G-protein coupled receptors
• Steroids

Transcription Factors

• DNA-binding domains permit specific binding to short DNA sequences (promotor region or enhancers).
• Some elements interact with genes.

Growth Factors

• Promote cell entry into the cell cycle and replication.
• Enhance cellular component synthesis (nucleic acids, proteins, lipids, carbohydrates).
• Prevent apoptosis.
• Involved in regeneration and repair.

Stem Cells

• Totipotent stem cells give rise to all differentiated tissues.
• Adult stem cells replace damaged cells of the same type.
• Regenerative medicine uses stem cells to heal patients.

Cell Injury

• Underlying causes: Hypoxia/ischemia, infection, autoimmune diseases, toxins, immunologic reactions, physical agents, genetic abnormality, nutritional imbalance, aging
• Reversible injury: Intracellular swelling, mitochondrial/ER disturbance, plasma membrane blebbing, chromatin clumping
• Irreversible injury: mitochondrial failure, loss of membrane structure and function, DNA damage

Toxic Cell Injury

• Direct-acting toxins combine with cellular components, disrupting their function (mercury).
• Latent toxins are converted into reactive metabolites that damage target cells.
• Reactive Oxygen Species (ROS) are highly reactive and damage cellular components.

Reversible Injury Signs

• Intracellular swelling
• Mitochondrial and ER disturbance
• Plasma membrane blebbing
• Clumping of chromatin in nucleus
• Myelin figures (phospholipids of damaged membrane)

Cell Injury: When Badness Happens

• Normal cell (homeostasis) → Injurious stimulus → Reversible injury (if mild or transient) → Irreversible injury (severe, progressive) → Necrosis (or apoptosis)
• Irreversible signs: Inability to restore mitochondrial function, Loss of plasma membrane structure or function, Loss of DNA structural integrity

Apoptosis vs. Necrosis

• Apoptosis: Controlled programmed cell death. Organized disassembly, membrane bound, no inflammation.
• Necrosis: Unprogrammed violent, eventual lysis, swelling, inflammation, usually widespread.
• Apoptosis vs. necrosis overview.

Adapting to Cellular Injury

• Types of Adaptation: Hypertrophy, hyperplasia, atrophy, metaplasia.

Hypertrophy

• Size of cells increases. (due to increased demands, in relation to muscle for example)
• Pathological when concerning heart muscle

Hyperplasia

• Increased cell numbers. (physiological - puberty, pregnancy; pathological - if growth control is lost)
• Hyperplasia alone does not cause cancer

Atrophy

• Decrease in cell size (due to loss of workload, loss of innervation, diminished blood supply, nutritional difficulties etc).
• Aging is a factor.

Metaplasia

• Change in cell type. (smokers' bronchi, Barrett's esophagus)
• Distinguish between metaplasia and dysplasia

Metaplasia vs Dysplasia

• Dysplasia is disorderly proliferation of cells
• Polarity and uniformity are lost
• Dysplasia does not indicate cancer, though it is on the pathway to becoming cancerous

Types of Necrosis

• Coagulative
• Liquefactive
• Caseous
• Fat necrosi
• Fibrinoid
• Key features included: Increased eosinophilia.Nuclear changes (pyknosis, karyorrhexis, karyolysis)Fate of cells in types of necrosis: Coagulative, Liquefactive, Caseous, Fat, Fibrinoid.Biomarkers in necrosis: Identification of affected organs using biomarkers like creatine kinase, contractile protein troponin, alkaline phosphatase.

Apoptosis

• Controlled dismantling of the cell. "Edible" fragments break off.
• This process occurs without inflammation because it's done in a controlled manner.
• Types: Physiologic (embryonic development, immune system) and Pathologic (severe or irreversible damage, cancer emergence)
• Pathways: Intrinsic (Mitochondrial) and Extrinsic (Death Receptor)

Intrinsic Pathway

• The intrinsic pathway is the most common cause of physiological and pathological apoptosis.
• If the intrinsic pathway is not stopped, mitochondria release cytochrome C.
• This initiates the formation of caspase cascades.
• Key features like the role of BCL-2, BAD protein, and P53 are mentioned.

Extrinsic Pathway

• For apoptosis, the presence of antigens recognizes if a cell needs to be destroyed.
• Two main types - TNF-alpha and Fas ligand.
• These receptors initiate a caspase cascade.
• This is mainly for self-reactive T cells (in the thymus)
• Intrinsic/Extrinsic pathway

Pathways leading to cell demise

• Hypoxia, ischemia - Cellular injury -> Necrosis
• Multiple injurious stimuli - cellular Damage to proteins, lipids, nucleic acids -> Apoptosis
• Mutations, cell stress, infections - Accumulation of misfolded proteins - -> Apoptosis
• Radiation, other insults - DNA damage -> Apoptosis
• Infections, immunologic disorders, inflammation - Toxic molecules -> Necrosis/Apoptosis

Causes of Inflammation

• Infections, Bacteria, Viruses, Fungal, Parasitic, Microbial toxins, Tissue Necrosis, Foreign bodies, Immune reactions (hypersensitivity).

Two Big Things Happen in inflammation

• More fluid is sent to the area.
• Cells in the body actively "go to war".

External Manifestations of Inflammation

• Rubor - redness, Calor - heat, Tumor - swelling, Dolor - Pain, loss of function

Inflammation: Recognition

• Microbes and necrotic cells are recognized by foreign invaders from outside of the cell
• Internal stimuli within the cell, as cellular distress
• Circulating proteins that indicate damage has occurred

Inflammation: Stages

• Recognition of threat
• Vascular tissue response to insult
• Leukocytes and plasma proteins recruitment
• Destruction of offending substance
• Termination of sequence.
• Repair of injured tissue.

Recognition: Foreign Invaders

• Phagocytes (capture foreign invaders) & dendritic cells
• Detection of infectious invaders, which then trigger secretion of specific proteins.
• Cytokines for inflammation, anti-viral cytokines (interferons), cytokines & membrane proteins for lymphocyte activation.

Recognition of Internal Cellular Damage

• Signals inside the cytoplasm indicate issues like uric acid build-up, reduced ATP, reduced intracellular potassium and DNA in the cytoplasm.
• DAMPs (Damage-associated molecular patterns) are activated.
• Multiprotein cytosolic complex (inflammasome) recruits leukocytes, inducing inflammation

Recognition of Circulating Proteins

• Complement system reacts against microbes, produces inflammation mediators, destroys infectious organisms, activates further inflammatory cells, and opsonizes targeted agents.

Inflammation: Vascular Changes

• Two big steps: increased blood flow (vasodilation) and increased vessel permeability. Exudate (high protein, cellular debris) by contrast transudate (low content, less cells).

Changes in Vessels: Vasodilation

• Histamine is released from mast cells causing vasodilation and increased blood flow, one of the first signs of acute inflammation
• Vasodilation leads to increased permeability and exudative fluid build-up.
• Blood flow slows, and vessels become engorged.

Changes in Vessels: Permeability

• Histamine, Bradykinin, Leukotrienes cause endothelial cells to retract and open inter-endothelial spaces creating leakage.
• endothelial injury occurs due to tissue damage - microbes, burns.
• Continues until vessels are thrombosed or repaired.

Lymph Involvement

• Lymphatic vessels become involved, draining away extravascular fluid and its contents.
• Lymphangitis and secondary inflammation can occur, which sometimes lead to lymph node enlargement (lymphadenopathy).

Acute vs Chronic Inflammation

• Acute: Minutes to days, exudation of fluid, plasma proteins, edema, neutrophils, and macrophages
• Chronic: Longer duration, more tissue destruction, macrophages, blood vessel proliferation, fibrosis.

Three outcomes of acute inflammation

1. Complete resolution
2. Healing by connective tissue replacement or scarring/fibrosis
3. Chronic inflammation

Chronic Inflammation

• Prolonged, lasting weeks to months.
• Inflammation, tissue injury and repair occur simultaneously and in varying combinations.

Inflammation: Destruction, Termination and Repair

• The body's inflammatory response may destroy the source of inflammation.
• If the offending agent isn't destroyed, the inflammation becomes chronic.
• Mechanisms for repair and tissue healing may then occur.

Inflammation Recap

• Inflammation is a favorable host response to foreign invaders.
• Vascular reactions and cellular responses are key parts of this process.
• The major steps include recognition, recruitment of leukocytes, and removal of the offending agent.
• The outcome can be acute or chronic inflammation, depending on the body's ability to destroy the source of damage.

Mediators of Inflammation

• Multifunctional mediators.
  • Effects: Vasodilation, vasoconstriction, altered permeability, activation of inflammatory cells, chemotaxis, cytotoxicity, tissue degradation, pain, and fever.
• Two types: Cellular and plasma-derived.
• Major cells are macrophages, dendritic cells, and mast cells.
• Plasma-derived mediators are compliment proteins

Mediators: (Cell-derived)

• Histamine and serotonin
• Prostaglandins and leukotrienes
• Cytokines (TNF, IL-1, IL-6)
• Chemokines
• Platelet-activating factor

Mediators: (Plasma-derived)

• Complement system
• Kinins

Mediators: Suppression

• Lipoxins (suppress inflammation, and inhibit leukocyte recruitment)
• Pharmacologic interventions
  • Cyclooxygenase inhibitors (COX inhibitors) NSAIDS (COX-2 of particular interest)
  • Lipoxygenase Inhibitors
  • Corticosteroids (reduce transcription of genes)
  • Leukotriene receptor antagonists

Morphological Patterns of Acute Inflammation

• Serous inflammation (cell-poor fluid)
• Fibrinous inflammation (fibrinogen passes through vessels)
• Purulent inflammation (exudate, pus)
• Ulcers (defect in an organ or tissue surface)
• Granulomatous inflammation (collections of activated macrophages (epithelioid cells & giant cells))

Effects of Inflammation

• Systemic effects like fever (high temperature (>38°C), sometimes <36°C), Elevated temperature, pyrogens (chemicals that trigger fever), leukocytosis, left shift (immature neutrophils).
• Additional effects: chills, anorexia, somnolence, malaise, septic shock.

Fever Pathogenesis

• Treatment with NSAIDs (turn down prostaglandins), Tylenol (unknown mechanism but possibly targets prostaglandin production).

Tissue Repair Mechanisms

• Tissue repair involves either regeneration or scarring.
• Different tissue exhibit different capacities to regenerate or heal.

Tissue Repair Factors that Inhibit Repair

• Infection,
• diabetes
• Nutritional status
• Glucocorticoids
• Mechanical factors
• Poor perfusion
• Foreign bodies
• Type and extent of injury
• Site of injury; different tissues/organs heal differently

Cutaneous Wound Healing

• Main phases: inflammation, granulation tissue formation, and ECM remodeling.
• Primary union (first intention): more rapid healing.
• Secondary union (secondary intention): more extensive scarring.

Cellular Aging Processes

• Accumulations of errors in DNA (ROS, mutations)
• Decreased cellular replication
• Cells have a limited capacity for replication.
• Build up of various substances
  • Steatosis (triglycerides)
  • Cholesterol
  • Proteins
  • Glycogen Pigments (exogenous & endogenous)

Fatty Liver Changes

• Related to alcohol abuse, diabetes with obesity NASH (non-alcoholic steatohepatitis)

Atherosclerosis/Cholesterol

• Accumulation of cholesterol in vessels impacting blood flow

Exogenous Carbon

• Anthracosis (coal miner's lung): accumulation of carbon.

Lipofuscin

• Yellow-brown pigment (wear and tear pigment)
• Free-radical peroxidation of membrane lipids

Calcification

• Aortic valve.

Summary of Presented Information

• This detailed unit covers essential biological processes, including cells, inflammation, apoptosis, necrosis, and tissue repair.