Module 1 Altered Cellular/Tissue Biology Difference Between Prokaryotes and Eukaryotes Prokaryotes ➢ ➢ ➢ Eukaryotes ➢ ➢ ➢ ➢ No distinct nucleus (single, circular chromosome) Lack histones, organelles Cyanobacteria, bacteria, chlamydia and rickettsia Complex cellular organization Membrane-bound organelles Well-defined nucleus with several chromosomes Higher animals, plants, fungi, protozoa, and algae Differences in biochemical activity: ➢ ➢ ➢ Protein synthesis Transport across the outer cell membrane Enzyme content Cellular Functions Specialized through differentiation or maturation Movement ➢ Conductivity ➢ Metabolic absorption ➢ Secretion ➢ Excretion ➢ Respiration ➢ Reproduction ➢ Communication ➢ Eukaryotic Cell: Nucleus Consists of the plasma membrane, cytoplasm, and intracellular organelles ➢ Nucleus • Largest membrane-bound organelle Cell division Genetic information Eukaryotic Cell: Cytoplasm Cytoplasmic matrix ➢ Fills space between the nucleus and plasma membrane Cytosol Function Cytoplasmic organelles 7 Eukaryotic Organelles Ribosomes RNA protein complexes ➢ Synthesized in nucleolus ➢ Sites for cellular protein synthesis Saclike structures ➢ Contain enzymes for digestion ➢ Cellular injury causes enzyme release that leads to cellular self-destruction ➢ Cisternae ➢ Synthesis, folding, and transport of proteins and lipids Network of smooth membranes ➢ Processing and packaging of proteins ➢ Secretory vesicles Cytoskeleton “Bones and muscles” of cell ➢ Network of protein filaments ➢ Forms cell extensions ➢ Peroxisomes Contain oxidative enzymes ➢ Break substances down into harmless products ➢ Golgi complex ➢ ➢ Endoplasmic reticulum ➢ Lysosomes Mitochondria Cellular energy metabolism ➢ ATP generation ➢ Has role in: • Osmotic regulation • pH control • Calcium homeostasis • Cell signaling ➢ Plasma Membrane Controls the composition of a space or compartment it encloses Function ➢ Cell-to-cell recognition ➢ Cellular mobility ➢ Cellular shape ➢ Movement of molecules Composition ➢ Lipid bilayer • Solid-gel phase • Fluid-liquid crystalline phase • Liquid-ordered phase Lipids ➢ Amphipathic (hydrophobic and hydrophilic) • O2 and CO2 diffusion • Barrier to the diffusion of water ➢ Molecular glue Proteins ➢ Perform most of the plasma membrane tasks ➢ Functions • Receptors • Transport channels/carriers • Enzymes • Surface markers • Cell adhesion molecules (CAMs) • Catalysts Carbohydrates ➢ Protection ➢ Lubrication ➢ Recognition ➢ Adhesion Plasma membrane protein functions Plasma Membrane: Protein regulation (proteostasis) Main role is to minimize protein misfolding and protein aggregation Regulated by: ➢ Ribosomes (makers) ➢ Chaperones (helpers) ➢ Proteolytic systems • Lysosomes • Ubiquitin-proteasome system (UPS) Malfunction associated with human disease Cellular Receptors Ligands ➢ Bind with cellular receptors to activate or inhibit the receptor’s associated signaling or biochemical pathway Plasma membrane receptors ➢ Determine response to binding Cell-to-Cell Adhesions Basement membrane ➢ Specialized type of extracellular matrix ➢ Sheet of matrix: thin, tough, flexible ➢ Located: • Beneath epithelial cells • Between two cell sheets • Around individual muscle, fat, Schwann cells Cell junctions ➢ Symmetrical • Tight junctions—barriers • Desmosomes and belt desmosomes—unite cells • Gap junctions—communication ➢ Asymmetrical • Hemidesmosomes Gating: Enables uninjured cells to protect themselves from injured neighbors Cell-to-Cell Adhesions Formed on plasma membranes Held together by: ➢ Extracellular membrane ➢ Cell adhesion molecules ➢ Specialized cell junctions Extracellular matrix—secreted by cell ➢ Fibrous proteins in gel substance ➢ Produced by fibroblasts ➢ Diffusion of water, nutrients ➢ Composed of: Collagen, Elastin, Fibronectin ➢ Regulates cell growth, movement, and differentiation Cell-to-Cell Adhesions: Extracellular Matrix Cellular Communication Plasma membrane-bound receptors Intracellular receptors Gap junctions (contact signaling) Chemical signaling ➢ Paracrine ➢ Autocrine ➢ Hormonal ➢ Neurohormonal Neurotransmitters Signal Transduction Cells communicate via receptor protein ➢ Signals molecules to activate protein kinases • Instructs cells to grow and reproduce, die, or differentiate Cellular Metabolism Metabolism ➢ Chemical tasks of maintaining essential cellular functions ➢ Anabolism • Energy using ➢ Catabolism • Energy releasing Adenosine Triphosphate (ATP) Fuel for cell survival Created from the chemical energy contained within organic molecules Used in the synthesis of organic molecules, muscle contraction, and active transport Stores and transfers energy Cellular Energy Digestion ➢ Extracellular breakdown of proteins, fats, and polysaccharides to subunits Glycolysis ➢ Intracellular breakdown of subunits to pyruvate, then to acetyl CoA ➢ Limited ATP produced Citric acid cycle ➢ Also called Krebs cycle or the tricarboxylic acid cycle (TCA) ➢ Much ATP is produced via oxidative phosphorylation if oxygen present ➢ Waste products excreted Oxidative phosphorylation Cellular Energy ➢ ➢ ➢ ➢ ➢ Oxidative phosphorylation Occurs in the mitochondria Mechanism producing energy from fats, carbohydrates, proteins Involves the removal of electrons from various intermediates via a coenzyme such as nicotinamide adenine dinucleotide (NAD) to transfer electrons Anaerobic glycolysis: if oxygen is not available, carbohydrates (like glucose) are converted to pyruvic acid (pyruvate) in the cytoplasm with the production of two ATP molecules, which is insufficient for energy needs; pyruvate then converted to lactic acid Process reverses when oxygen becomes available and lactic acid is converted back to either pyruvic acid or glucose, which moves into the mitochondria and enters the citric acid cycle Membrane Transport: Introduction Cellular intake and output ➢ Cells continually take in nutrients, fluids, and chemical messengers from the extracellular environment and expel metabolites, or the products of metabolism, and end products of lysosomal digestion ➢ Transporters ➢ Channels Membrane Transport: Transporters ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ Passive transport Molecules move easily from a region of high concentration to a region of low concentration Requires no energy Osmosis, hydrostatic pressure, and diffusion Active transport Flows “uphill” Requires energy Pumps, endocytosis, and exocytosis Mediated transport Moves solute particles singly or two at a time Symport: two molecules moved simultaneously in one direction Antiport: two molecules moved simultaneously in opposite directions Uniport: single molecule moved in one direction Membrane Transport: Electrolytes Electrolytes ➢ Account for ~95% of solutes in body fluids ➢ Electrically charged • Cations (positive charge) • Anions (negative charge) ➢ Measured in milliequivalents per liter (mEq/L) or milligrams per deciliter (mg/dl) • Milliequivalent indicates the chemical-combining activity of an ion, which depends on the electrical charge, or valence (number of plus or minus signs) • Monovalent—one charge (+) • Divalent—2 charges (++) Passive Transport Diffusion ➢ Movement of solutes from area of greater concentration to area of lesser concentration ➢ Rate of diffusion influenced by difference of electrical potential across the membrane • Also influenced by size of molecules and lipid solubility Filtration ➢ Movement of water and solutes through a membrane because of greater force on one side than on the other • Hydrostatic pressure • Blood pressure Osmosis ➢ Movement of water down a concentration gradient • Membrane must be more permeable to water than solutes • Concentration of solutes on one side greater than the other ➢ Controls the distribution of water between body compartments ➢ Osmotic pressure ➢ Related to hydrostatic pressure and solute concentration ➢ Oncotic pressure or colloid osmotic pressure ➢ Tonicity Osmolality: Concentration of molecules per weight (kg) of water Osmolarity: Concentration of molecules per volume (mL) of solution Active Transport Transport system for Na+ and K+ Uses direct energy of ATP ➢ ATPase ➢ Process leads to electrical potential Transport of macromolecules ➢ Endocytosis • Vesicle formed and moves into the cell • Pinocytosis—ingestion of fluids • Phagocytosis—ingestion of large particles ➢ Exocytosis • Replaces plasma membrane removed by endocytosis • Releases synthesized molecules into the extracellular matrix Electrical Impulses Resting membrane potential Action potential ➢ Depolarization ➢ Threshold potential • Hyperpolarized vs. hypopolarized ➢ Repolarization ➢ Refractory period • Absolute and relative Propagation of an Action Potential The Cell Cycle Mitosis vs. cytokinesis Four phases ➢ G1 phase • Period between M phase and the start of DNA synthesis ➢ S phase • DNA synthesized ➢ G2 phase • RNA and protein synthesis ➢ M phase (M=mitosis) • Nuclear and cytoplasmic division The Cell Cycle: Mitosis M Phase ➢ Prophase ➢ Metaphase ➢ Anaphase ➢ Telophase Control of Cell Division and Growth Organ and body size depends on: ➢ Cell growth ➢ Cell division ➢ Cell survival Regulated by extracellular signal molecules ➢ Mitogens ➢ Growth factors ➢ Survival factors Tissue Formation Intercellular recognition and communication, adhesion, and memory Specialized patterns of gene expression Terminally differentiated cells Stem cells Types of Tissue Nerve ➢ Highly specialized cells (neurons) Epithelial ➢ Covers most internal and external body surfaces Connective ➢ Binds tissues and organs together Muscle ➢ Composed of myocytes, enables movement Altered Cellular and Tissue Biology Cellular Adaptation Reversible response to physiologic (normal) and pathologic (adverse) changes ➢ Adaptations to pathological conditions are usually only temporarily successful Adaptive changes ➢ Atrophy ➢ Hypertrophy ➢ Hyperplasia ➢ Dysplasia ➢ Metaplasia Cellular Adaptation: Atrophy Decrease in cell size Decreases organ size if enough cells shrink Physiologic ➢ Normal in early development Pathologic ➢ Results from decreases in workload, pressure, use, blood supply, nutrition, hormonal/neural stimulation Cellular Adaptation: Hypertrophy Increase in cell size Increases organ size Physiologic ➢ Results from increased demand, stimulation by hormones, growth factors Pathologic ➢ Results from chronic hemodynamic overload Cellular Adaptation: Hyperplasia Increase in number of cells Increased rate of cellular division Physiologic ➢ Compensatory—enables organs to regenerate ➢ Hormonal—in organs that respond to endocrine hormonal control Pathologic ➢ Hormonal—abnormal proliferation of normal cells Cellular Adaptation: Dysplasia Abnormal changes in size, shape, and organization of mature cells May be reversible if triggering stimulus is removed Tissue appears disorderly, but is not cancer ➢ If changes penetrate the basement membrane: invasive neoplasm Cellular Adaptation: Metaplasia Reversible replacement of one mature cell type by another Associated with tissue damage, repair, regeneration Reprogramming of stem cells or undifferentiated mesenchymal cells Cellular Adaptation: Metaplasia & Dysplasia in Bronchial Cells Cellular Injury Occurs if cell unable to maintain homeostasis ➢ Reversible • Cells recover ➢ Irreversible • Cells die Cellular Injury Mechanisms: Hypoxic Injury Single most common cause of cellular injury Results from: ➢ Ischemia: reduced supply of blood ➢ Reduced oxygen content in ambient air ➢ Loss of hemoglobin ➢ Decreased production of red blood cells ➢ Diseases of the respiratory and cardiovascular systems ➢ Poisoning of the oxidative enzymes (cytochromes) within the cells Anoxia: total lack of oxygen caused by obstruction Cellular Injury Mechanisms: Ischemia-Reperfusion Injury Cell injury and death caused by restoration of blood flow and oxygen Mechanisms: ➢ Oxidative stress ➢ Increased intracellular calcium concentration ➢ Inflammation ➢ Complement activation Cellular Injury Mechanisms: Free Radicals & Reactive Oxygen Species Free radicals and reactive oxygen species ➢ Cause oxidative stress ➢ Free radical is electrically uncharged atom or group of atoms with an unpaired electron that damage: • Lipid peroxidation • Protein alteration • DNA damage • Mitochondrial effects Cellular Injury Mechanisms Chemical or toxic injury ➢ Xenobiotics—toxic, mutagenic, carcinogenic • Carbon tetrachloride • Lead • Carbon monoxide • Ethanol • Mercury • Social or street drugs Chemical agents including drugs ➢ Over-the-counter and prescribed drugs ➢ Opioid abuse ➢ Leading cause of child poisoning is medications Environmental toxins ➢ Air pollution (indoor and outdoor) Heavy metals ➢ Lead ➢ Cadmium and arsenic ➢ Mercury Ethanol ➢ Fetal alcohol syndrome ➢ Fetal alcohol spectrum disorders Unintentional & Intentional Injuries More common among men and higher rates among blacks Blunt force injuries ➢ Result of application of mechanical force to body • Results in tearing, shearing, or crushing of tissues • Motor vehicle accidents and falls ➢ Contusions ➢ Lacerations ➢ Fractures Sharp force injuries ➢ Incised wound ➢ Stab wound ➢ Puncture wound ➢ Chopping wound Gunshot wounds Asphyxial injuries ➢ Caused by a failure of cells to receive or use oxygen • Suffocation Choking asphyxiation • Strangulation Hanging, ligature, and manual strangulation • Chemical asphyxiants Carbon monoxide, cyanide, and hydrogen sulfide • Drowning Infectious Injury Pathogenicity of a microorganism Disease-producing potential ➢ Invasion and destruction ➢ Toxin production ➢ Production of hypersensitivity reactions Immunologic and Inflammatory Injury Injury from substances generated during inflammatory response ➢ Phagocytes ➢ Biochemical substances • Histamine, antibodies, lymphokines, complement system products, and proteases Membrane alterations Manifestations of Cellular Injury: Cellular Accumulations (Infiltrations) Normal cellular substances ➢ Water ➢ Proteins ➢ Lipids ➢ Carbohydrates Abnormal substances ➢ Endogenous substances ➢ Exogenous substances Manifestations of Cellular Injury Accumulations result from four mechanisms 1. 2. 3. 4. Insufficient removal of normal substance because of altered transport Accumulation of abnormal substance because of defects Inadequate metabolism of endogenous substance because of lack of lysosomal enzyme Harmful exogenous materials Cellular Death Attributed to necrosis or apoptosis Necrosis ➢ Rapid loss of plasma membrane structure, organelle swelling, mitochondrial dysfunction, lacks typical features of apoptosis ➢ May be regulated or programmed ➢ Autolysis (autodigestion) Necrosis: Coagulative necrosis Protein denaturation Albumin is transformed from a gelatinous, transparent state to a firm opaque substance Infarction: obstruction of the blood supply to an organ or region of tissue, typically by a thrombus or embolus, causing local death of the tissue. Necrosis: Liquefactive necrosis Neurons and glial cells of the brain Cells digested by own hydrolases Tissues become soft and liquefied Triggered by bacterial infection ➢ Staphylococci, Streptococci, and Escherichia coli Necrosis: Caseous necrosis Results from pulmonary tuberculosis infection Combination of coagulative and liquefactive necrosis Necrosis: Fatty necrosis Breast and other abdominal organs Action of lipases Fatty acids combine with elements to create soaps Tissue appears opaque and chalky white Necrosis: Gangrenous necrosis Death of tissue from severe hypoxic injury Dry: Skin becomes dry and shriveled, brown or black Wet ➢ Area becomes cold, swollen and black ➢ Gas gangrene, caused by Clostridium Apoptosis Programmed cellular death Active process Physiologic vs. pathologic Normal part of aging Autophagy Self-destructive and a survival mechanism Cytoplasmic contents delivered to lysosomes for degradation Contributes to the aging process Aging and Altered Cellular and Tissue Biology Aging vs. disease vs. life span Normal life span and life expectancy Frailty ➢ Weakness, decreased stamina, and functional decline in older adults ➢ Increases vulnerability to falls, disability, disease, death Somatic Death Postmortem changes are diffuse ➢ Pallor mortis ➢ Algor mortis ➢ Rigor mortis ➢ Livor mortis ➢ Putrefaction ➢ Decomposition ➢ Skeletonization
