The Cell: cellular biology, altered cellular and tissue biology and the cellular environment
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THE CELL: CELLULAR BIOLOGY, ALTERED CELLULAR AND TISSUE BIOLOGY AND THE CELLULAR ENVIRONMENT DNP 604 Advanced Pathophysiology Prokaryotes and Eukaryotes Prokaryotes Blue-green algae, bacteria, rickettsiae Contain no organelles Lack distinct nucleus Single chromosome Eukaryotes Cells of higher animals, plants, fungi, protozoa, most algae Larger, more extensive intracellular anatomy and organization Contain organelles (membrane-bound intracellular compartments) Well defined nucleus Have several chromosomes Cellular Functions Differentiation (maturation) is the process by which the cells become specialized Eight chief cellular functions: Movement- muscle cells generate forces that produce motion Conductivity- chief function of nerve cells- a stimulus causes a wave of excitation (electrical potential) that passes along the cell surface to reach other parts Metabolic absorption- all cells take in and use nutrients and other substances from surroundings, cells of intestine and kidney are specialized to carry out absorption Cellular functions Contd Secretion- cells synthesize new substances from substances they absorb and secrete new substance to serve need elsewhere, such as mucous gland, adrenal gland, ovary, testis Excretion- cells rid themselves of waste products from metabolic breakdown, lysosomes within cells contain enzymes that break down or digest large molecules and turn into waste products that are released from the cell Respiration- cells absorb O² to transform nutrients into energy in the form of ATP Reproduction- tissue requires new cells from growth and maintenance Communication- critical for all of the above functions, enable the survival of the “society” of cells, constant communication allows for a steady state Cellular Component Structure and Function Typical eukaryotic cell consists of 3 components: Plasma membrane- outer membrane Cytoplasm- fluid filling Intracellular organelles- “organs” of the cell such as the nucleus Nucleus Largest membrane bound organelle Generally located in center surrounded by cytoplasm Nuclear envelope- 2 membranes Outer membrane continuous with membranes of endoplasmic reticulum Contains nucleolus- composed of RNA, most of cellular DNA, DNA binding proteins the histones Cellular Component Structure and Function Contd Nucleus contd. Primary function cell division and control of genetic info Replication and repair of DNA and transcription of info stored in DNA Genetic info is transcribed into RNA which can be processed into messenger, transport, and ribosomal RNA and introduced into the cytoplasm, where it directs cellular activities Cytoplasm (Cytoplasmic matrix) Organelles are suspended in cytoplasm Aqueous solution (cytosol) Function includes intermediary metabolism and ribosomal protein synthesis Cellular Component Structure and Function Contd Intermediary metabolism Intracellular reactions that include synthesis, degradation, and transformation of small organelles These reactions enable energy to be used for cellular activities and for providing substrates to maintain cellular integrity Ribosomal protein synthesis Takes place on free ribosomes in cytosol Storage of excess nutrients not needed for ATP production is converted in the cytosol into storage forms Cellular Component Structure and Function Contd Cytoskeleton Provides the “bones and muscles” of the cell Maintains cell’s shape and internal origination Permits movement of substances within the cell Composed of network of protein filaments, two of the most important Microtubules Actin filaments (microfilaments) Cellular Component Structure and Function contd. Organelles Ribosomes Suspended in cytoplasm and enclosed in biologic membranes Many of the functions are directed by coded messages from the nucleus and carried on RNA RNA protein complexes Chief function is to provide sites for cellular protein synthesis Endoplasmic reticulum (ER) Network of tubular channels that extend throughout the outer nuclear membrane. A membrane factory specializing in synthesis and transport of protein and lipid components of most of the cell’s organelles Responsible for protein folding and sensing cell stress. Cellular Component Structure and Function Contd Two types of endoplasmic reticulum (ER) contd. Rough (granular) endoplasmic reticulum Rough because ribosomes and ribonucleoprotein particles are attached Some proteins synthesized by these ribosomes remain in ER and others are used to construct membranes or other organelles Smooth Does (agranular) endoplasmic reticulum not have ribosomes or ribonucleoprotein Membrane surfaces contain enzymes involved in synthesis of steroid hormones and are responsible for variety of reactions required to remove toxic substances from the cell Cellular Component Structure and Function Contd Golgi complex Network of flattened, smooth membranes and vesicles located near nucleus Responsible for processing and packaging proteins into secretory vesicles that break away and migrate to variety of intracellular and extracellular destinations These vesicles fuse with the plasma membrane and their contents are released from the cell Cellular Component Structure and Function Contd Lysosomes Saclike structures that originate in golgi complex Contain 40 digestives enzymes called hydrolases Digest most cellular substances to their basic compounds These catalyze bonds in proteins, lipids, nucleic acids and carbohydrates Lysosomal membrane prevents these powerful enzymes from leaking into cytoplasm which would cause cellular self digestion Lysosomal storage diseases may be the result of genetic defect or lack of one or more lysosomal enzymes i.e. Pompe disease, Tay-Sachs disease Necessary for normal digestion of cellular nutrients, intracellular debris, potentially harmful substances that must be removed from the body Cellular Component Structure and Function Contd Lysosomes contd. As cells complete their life span and die lysosomes are needed to digest cellular debris (autodigestion) Cellular debris is encapsulated within vesicle that reacts with a lysosome to complete its degradation- a process called autophagy which plays a crucial role in health and disease Peroxisomes (similar to lysosomes) Contain enzymes that use O² to remove hydrogen atoms from specific substrates in an oxidative reaction that produces hydrogen peroxide (H²O²) Important role in synthesizing phospholipids necessary for nerve cell myelination Cellular Component Structure and Function Contd Mitochondria Responsible for cellular respiration and energy production Appear as rods, spheres, or filaments bound by a double membrane Outer membrane smooth and convoluted forming cristae Inner membrane contains the enzymes of the respiratory chain (electron transport chain), generate most of cell’s ATP Enzymes are essential to the process of oxidative phosphorylation that generates most of the cell’s ATP Cellular Component Structure and Function Contd Vaults Cytoplasmic organelles also called ribonucleoproteins, larger then ribosomes May be the cellular “trucks” Thought to dock at nuclear pores, pick up molecules synthesized in the nucleus, and deliver their load somewhere in the cell Thought that vaults may carry messenger RNA from nucleus to ribosomal sites of protein synthesis within cytoplasm Cellular Component Structure and Function Contd Cytoskeleton is the “bone and muscle” of cell Network of filaments including microtubles and actin filaments Plasma Membrane Encloses the cell and important because it controls the composition of the space or compartment it encloses Controls the movement of substances from one compartment to another therefore exerting a powerful influence on metabolic pathways Important in role of cell to cell recognition Cellular mobility and maintenance of cellular shape Cellular Membrane Membrane function is determined largely by proteins Recognition and binding units (receptors) for substances moving in and out of the cell Pores or transport channels Enzymes that drive active pumps Cell surface markers Cell adhesion molecules catalysts of chemical reactions Membrane composition Bilayer of lipids and proteins that can separate into units called microdomains Provide new route for transport into cell, repository for some receptors, and act as initiator for relaying signals from several extracellular chemical messengers into the cells interior Cellular Component Structure and Function Contd Major components of cell membrane Lipids Most abundant Basic component is bilayer of lipid molecules Responsible for structural integrity and membrane structure Each lipid molecule is polar or amphipathic The membrane spontaneously organizes itself into a bilayer because of these two incompatible solubilities Amphipathic molecules are: One part hydrophobic (uncharged or “water hating”) One part is hydrophilic (charged or “water loving”) The hydrophobic region of each lipid molecule is protected from water The hydrophilic region is immersed in it This bilayer accounts for one of the essential functions of the plasma membrane- it is impermeable to most water soluble molecules (molecules that dissolve in water) Cellular Component Structure and Function Contd Proteins Although lipid molecules are more abundant protein molecules are so large that in total mass the two constituents are roughly equal Two ways to classify membrane proteins Integral membrane proteins- those embedded in lipid bilayer Peripheral membrane proteins- are not embedded but reside at one surface or the other bound to integral protein Another way to think about it is- Proteins are associated with lipid bilayer in four ways Transmembrane proteins- exposed to aqueous environment on both sides Extend polypeptide chain partially through the bilayer Attached to bilayer by covalent linkage Bound to membrane by noncovalent linkages with other membrane proteins Cellular Component Structure and Function Contd Proteins contd. Proteins exist in densely folded configuration resulting in an excess of hydrophilic units at the surface of the molecule and an excess of hydrophobic units is inside Membrane functions determined by proteins Facilitate transport across membranes by serving as receptors, enzymes or transporters Carbohydrates Significant amount is contained in plasma membrane in form of glycoprotein Abnormal surface carbohydrate markers have been identified in certain tumor cells Proteolytic Cascades Proteases are enzymes that break down proteins and peptides Proteases are involved in the physiological regulation of essential processes by participating in a strictly orchestrated sequence of events- proteolytic cascade Four major proteolytic cascades Cell death or caspase-mediated apoptosis Blood coagulation Degrading membrane enzymes or matrix metalloproteinase cascade Complement cascade Proteases can act as initiators, act to amplify, propagate, and execute Dysregulation of proteases features predominantly in human diseases such as cancer, autoimmunity, and neurodegenerative disorders Cellular Receptors Are protein molecules on plasma membrane, in cytoplasm or in nucleus that are capable of recognizing and binding with specific smaller molecules called ligands Ligands are molecules that bind to another (usually larger) molecule Plasma membrane receptors are important for cellular uptake of ligands Ligands that bind with membrane receptors include hormones, neurotransmitters, antigens, complement components, lipoproteins, infectious agents, drugs and metabolites Receptors are classified based on location and function Cell-to-Cell Adhesions Plasma membranes are not only outer boundaries but also allow groups of cells to be held together in cell-tocell adhesions Once arranged cells are held together by 3 different means: Extracellular matrix-like glue and provides pathway for diffusion Interwoven in matrix 3 groups of macromolecules- fibrous structural proteins like collagen and elastin, adhesive glycoproteins and hyaluronic acid Cell adhesion molecules in plasma membrane Specialized cell junctions Cell-to-Cell Adhesions contd. Specialized cell junctions Specialized region in plasma membrane that hold together neighboring cells Hold cells together and allow small molecules to pass from cell to cell allowing coordination of activities of cells in tissues Three main types of cell junctions: Desmosomes- adhering junctions Tight junctions- impermeable junctions Gap junctions- communicating junctions Junctional complex is highly permeable part of plasma membrane- permeability controlled by gating (depends on calcium ions in cytoplasm) Cellular Communication and Signal Transduction Cells need to communicate to maintain homeostasis, regulate growth and division and coordinate their junctions Cells communicate in 3 ways: Form protein channels (gap junctions)- directly coordinate activities of adjacent cells Display plasma membrane-bound signaling molecules (receptors)- that affect cell itself and other cells in direct physical contact Secrete chemicals that signal to cells some distance away (most common) Signal Transduction Involves incoming signals or instructions from extracellular messengers (ligands) that are communicated to the cell’s interior for execution Important for homeostasis If deprived of appropriate signals cells exhibit a programmed death or apoptosis Signaling cascades have several important functions Physically transfer signal from place received to another Amplify the received signal, making it stronger Distribute signal so it influences several processes Signal can be modulated by interfering factors from inside or outside the cell Signal Transduction contd. Two responses from binding of the extracellular chemical messenger or first messenger Opening or closing specific channels (channeling) in membrane to regulate the movement of ions into or out of the cell Transferring the signal to an intracellular messenger, or second messenger which triggers a cascade of biochemical events in the cells Two major second messenger pathways are cyclic adenosine monophosphate (cyclic AMP, (cAMP) and Ca⁺⁺) Cellular Metabolism Chemical tasks of maintaining cellular function Anabolism- energy using Catabolism- energy releasing Dietary proteins, fats, starches hydrolyzed in intestine to amino acids, fatty acids, and glucose, then absorbed circulated, taken to cell to be used (including for production of ATP) ATP functions as an energy transferring molecule produced in series of reactions called metabolic pathway Oxidative phosphorylation occurs in mitochondria and is the mechanism by which the energy produced from CHO, fats and proteins are transferred to ATP. Role of Adenosine Triphosphate (ATP) Cell must be able to extract and use chemical energy contained within the structure of organic molecules ATP is created from chemical energy contained within organic molecules Energy stored in ATP used in many energy requiring reactions Cellular Energy Phase 1- digestion- proteins to amino acids, fats to fatty acids, starches to simple sugars Phase 2- small molecules taken into cell and broken down in cytoplasm Lysis of glucose called glycolosis Oxidative cellular metabolism involves 10 biochemical reactions and yields 6 ATP molecules for each molecule of glucose Phase 3- begins with citric acid cycle (Krebs cycle) and ends with oxidative phosphorylation Occurs in mitochondria Energy produced from CHO, fats, and proteins transferred to ATP Membrane Transport Cellular Intake and Output Passive transport- water and small electrically uncharged molecules move easily through pores in the plasma membrane’s lipid bilayer Occur naturally through any semi permeable barrier Driven by diffusion, filtration, osmosis Body fluids composed of two types of solutes Electrolytes (95% of solutes in body)- electrically charged and dissociate into constituent ions when placed in solution Exhibit polarity- orient toward negative or positive pole Positive ions- (cations) migrate toward negative pole and negative ions (anions) migrate toward positive pole Non-electrolytes- ex. Glucose, urea, creatinine which do not dissociate Passive Transport Diffusion Movement of a solute molecule from an area of greater solute concentration to an area of lesser solute concentration Difference is known as concentration gradient If the concentration of particles in one part of the solution is greater than in another part the particles distribute themselves evenly throughout the solution The diffusion rate is influenced by differences of electrical potential across the membrane The overall effect of diffusion is the passive movement of particles “down” a concentration gradient, from an area of high concentration to an area of low concentration Passive Transport Filtration- Hydrostatic pressure Movement of water and solutes through a membrane because of a greater pushing pressure (force) on one side of the membrane than on the other Hydrostatic pressure is the mechanical force of water pushing against cellular membranes Ex. in the vascular system hydrostatic pressure is the blood pressure generated in vessels by contraction of heart Partially balanced by osmotic pressure- water moving out of capillaries is partially balanced by osmotic forces that tend to pull water into the capillaries Passive Transport Osmosis Movement of water “down” a concentration gradienti.e. across a semi permeable membrane from a region of higher water concentration to a lower water concentration For osmosis to occur membrane must be more permeable to water than to solutes and the concentration of solutes must be greater so that water moves more easily Osmosis is directly related to both hydrostatic pressure and solute concentration Passive Transport Osmosis contd. Osmolality is the number of milliosmoles per kilogram of water, or the concentration of molecules per weight of water Normal osmolality of body- 285-294 milliosmoles per kilogram Osmolality is the number of milliosmoles per liter of solution, or the concentration of molecules per volume of solution The amount of hydrostatic pressure required to oppose the osmotic movement of water is called osmotic pressure of the solution The overall osmotic effect of colloids, such as plasma proteins is called oncotic pressure or colloid osmotic pressure Tonicity is the effective osmolality of a solution Isotonic solutions- has the same osmolality or concentration of particles as the intracellular fluid (ICF) or extracellular fluid (ECF) Hypotonic solution has lower concentration and is more dilute that body fluids Hypertonic solution has a concentration more than 285 to 294 mOsm/kg Mediated and Active Transport Mediated transport involves transmembrane proteins with receptors having a high degree of specificity for the substance being transported Inorganic anions and cations (Na⁺, K⁺, Ca⁺⁺, Cl⁻, HCO⁻₃) and charged and uncharged organic compounds (amino acids, sugars) require specific transport systems Mediated and active transport requires metabolic energy (ATP) to move molecules against the concentration gradient Cellular Reproduction: The Cell Cycle Cell reproduction in body tissues involves mitosis (nuclear division) and cytokinesis (cytoplasmic division) Maturation occurs during a stage of cellular life called interphase (growth phase) Four phases of cell cycle S phase- DNP synthesis takes place in cell nucleus G2 phase- period between completion of DNA synthesis and next phase (M) M phase- both nuclear (mitotic) and cytoplasmic (cytokinetic) division G1 phase- growth phase or interphase after which the cycle begins again. Tissues Cells of one or more types are organized into tissues Different types of tissues compose organs Organs are organized to function as tracts or systems Stem cells are cells with the potential to develop into many different cell types during early growth and development Four basic tissue types Epithelial- covers most internal and external surfaces of body Muscle- composed of long, thin and highly contractile cells or fibers called myocytes. Neural- highly specialized cells called neurons that transmit and receive electrical impulses across junctions called synapses Connective-binds various tissues and organs and provides support. Altered Cellular and Tissue Biology Altered cellular and tissue biology can be the result of adaptation, injury, neoplasia, aging, or death Adaptation occurs in response to both normal (physiologic) conditions or adverse (pathologic) conditions Injury to cells and surrounding environment (extracellular matrix) Cellular injury may be caused by factors that disrupt cellular structures or deprives the cell of oxygen and nutrients required for survival Cellular death results from structural changes- most importantly nuclear changes Cellular aging causes structural and functional changes that lead to cellular death or decreased capacity to recover from injury Cellular Adaption Cells adapt to their environment An adapted cell condition is somewhere between normal and injured Common and central part of many diseases Adaptive changes include atrophy, hypertrophy, hyperplasia, and metaplasia Dysplasia is not a true cellular adaption but an atypical hyperplasia Atrophy Decrease in cell size If atrophy occurs in enough of an organ’s cells the entire organ shrinks Physiologic atrophy- occurs with early development Ex- thymus gland involutes Pathologic atrophy results from decreases in workload, use, pressure, blood supply, nutrition, hormonal stimulation and nervous stimulation Aging causes brain cells and endocrine dependent organs (think gonads) to become atrophic Hypertrophy Increase in the size of cells and consequently in the size of the affected organ Increase in cellular size associated with increased accumulation of protein in the cellular components Can be physiologic or pathologic and is caused by specific hormone stimulation or by increased functional demand Physiologic hypertrophy during pregnancy is hormone induced and involves hypertrophy and hyperplasia Pathologic hypertrophy in the heart secondary to hypertension or valvular problem Hyperplasia Increase in the number of cells resulting from an increased rate of cellular division A response to injury Hyperplasia and hypertrophy often occur together Hyperplasia and hypertrophy both take place together if the cells are capable of synthesizing DNA, in non-dividing cells such as myocardial fibers only hypertrophy occurs Compensatory hyperplasia is an adaptive mechanism and enables certain organs to regenerate i.e. after removal of part of the liver hyperplasia of remaining liver cells enables remaining liver to compensate for the loss Hyperplasia Contd. Pathologic hyperplasia is an abnormal proliferation of normal cells and occurs in response to excessive hormonal stimulation or the effects of growth factors on target cells Hyperplastic cells identified by pronounced nuclear enlargement, clumping of chromatin and one or more enlarged nucleoli Common example hyperplasia of the endometrium Dysplasia May also be called abnormal hyperplasia Abnormal changes in the size, shape and organization of mature cells Not considered a true adaptive process but related to hyperplasia and often called atypical hyperplasia Term dysplasia does not indicate cancer and may not progress to cancer Metaplasia The reversible replacement of one mature cell by another sometimes less differentiated cell type An example is replacement of normal columnar ciliated epithelial cells of the bronchial lining by stratified squamous epithelial cells The newly formed squamous epithelial cells don’t secrete mucus or have cilia and therefore cause loss of protective mechanism Thought to develop from reprogramming of stem cells Cellular Injury Injury to cells and extracellular matrix (ECM) leads to injury to tissues and organs ultimately determining the structural patterns of disease. Cellular injury : Can be reversible or irreversible injury Cell injury can be acute or chronic Can involve necrosis, apoptosis, autophagy, accumulation, pathologic calcification Occurs if cell unable to maintain homeostasis- the normal or adaptive steady state- resulting from injurious stimuli Injurious stimuli include- chemical agents, hypoxia, free radicals, infectious agents, physical and mechanical factors, immunological reactions, genetic factors, and nutritional imbalances Cellular injury is caused by lack of oxygen (hypoxia), free radicals, caustic or toxic chemicals, infectious agents, unintentional and intentional injury, inflammatory and immune responses, genetic factors, insufficient nutrients, or physical trauma from many causes. Cellular Injury Contd. Four biochemical considerations are important to cell injury: Depletion of ATP Decreased levels of oxygen and increased levels of oxygenderived free radicals Increased concentration of intracellular calcium and loss of calcium steady state Defects in membrane permeability Sequence of events leading to cell death- decreased ATP production →failure of active transport mechanism →cellular swelling →detachment of ribosomes from ER →cessation of protein synthesis →mitochondrial swelling as a result of calcium accumulation →vacuolation →leakage of digestive enzymes from lysosomes → autodigestion of intracellular structure → lysis of plasma membrane → death Hypoxic Injury Initial insult in hypoxic injury is usually ischemia Hypoxia- lack of sufficient oxygen is the most common cause of cellular injury Progressive hypoxia caused by gradual arterial obstruction better tolerated then sudden anoxia Cellular responses Most common cause of hypoxia is ischemia or reduced blood flow Ischemic injury often caused by gradual narrowing of arteries (arteriosclerosis) and complete blockage by blood clots (thrombosis) Decrease in ATP causing failure of sodium-potassium pump and sodiumcalcium exchange resulting in cellular swelling Restoration of oxygen can cause additional injury called reperfusion (reoxygenation) injury Free Radicals and Reactive Oxygen Species (ROS) Another common mechanism of cellular death is membrane damage induced by free radicals, especially by excess reactive oxygen species (ROS)- called oxidative stress Free radical is an electrically uncharged atom or group of atoms having an unpaired electron It is now capable of injurious chemical bond formation with proteins, lipids, carbohydrates- key molecules in membranes and nucleic acids Oxidation- Losing an electron Reduction- Gaining an electron Free radical can cause the following: lipid peroxidation or destruction of unsaturated fatty acids, alterations of proteins and alterations of DNA Free radicals and ROS contd New data suggests ROS play a major role in initiation and progression of cardiovascular alterations associated with hyperlipidemia, diabetes, hypertension, ischemic heart disease, heart failure Free radicals may be initiated within cells byabsorption of ultraviolet light, oxidative reactions that occur during normal metabolic processes, enzymatic metabolism of exogenous chemicals or drugs Chemical Injury Biochemical interaction between toxic substance and cell membrane, causing damage and leading to increased permeability Most serious damage to plasma membrane is hypoxic injury to the mitochondria causing influx of calcium ions from extracellular compartment and ultimately DNA degradation Many chemicals cause cellular injury- lead, carbon monoxide, ethanol, mercury, social or street drugs Unintentional and Intentional Injury Blunt force injuries Application of mechanical energy to the body resulting in tearing, shearing, or crushing of tissues Contusion- bleeding into the skin or underlying tissue (bruise) Collection of blood in soft tissues or an enclosed space may be referred to as a hematoma Abrasion- removal of superficial layers of the skin caused by friction between skin and object (scrape) Laceration- tear or rip resulting when tensile strength of the skin or tissue is exceeded, often jagged and irregular with abraded edges Unintentional and Intentional Injury Sharp force injuries Gunshot wounds Incised wound- cut that is longer than it is deep Stab wound- penetrating sharp force injury that is deeper than it is long Puncture wound Chopping wound Entrance wound Exit wound Asphyxial injuries Caused by failure of cells to receive or use oxygen Suffocation, strangulation, chemical asphyxiates, drowning Injurious Nutritional Imbalances Proteins carbohydrates, lipids, vitamins and minerals are required for cells to function Proteins- consist of amino acids are major structural units of the cell and required for many enzymatic and hormonal functions Glucose- major carbohydrate obtained from breakdown of starch Lowered plasma proteins, particularly albumin cause fluid to move into the interstitium (edema) Hyperglycemia and deficiencies in glucose cause problems and in both conditions the body compensates by metabolizing fat (lipids) Lipid deficiency and excess have consequences Vitamins- are not sources of energy but necessary for maintaining normal cellular functions Most vitamins are not synthesized by the body 13 vitamins are essential for humans- 8 B vitamins (thiamine, niacin, riboflavin, folate, vitamin B6, vitamin B12, biotin, pantothenic acid) vitamin C and fat soluble vitamins A, D, E and K. Injurious Physical Agents Temperature extremesHypothermic injury- slows cellular metabolic processes and formation of ROS Hyperthermic injury Heat cramps- cramping of voluntary muscles as a result of salt and water loss due to sweating Heat exhaustion- salt and water loss results in hemoconcentration resulting in hypotension secondary to hypovolemia Heat stroke- life threatening rise in core body temperature as a result of thermoregulation At risk are older adults, athletes, military recruits, and people with cardiovascular disorders Other Causes of Injury Atmospheric pressure changes Ionizing radiation Illumination injury Mechanical stresses Noise Manifestations of Cellular Injury Manifestations of cellular injury include accumulations of water, lipids, carbohydrates, glycogen, proteins, pigments, hemosiderin, bilirubin, calcium and urate. Cellular accumulation (infiltration) Harm cells by “crowding” the organelles and causing excessive metabolites to be produced during catabolism Result from sub lethal injury sustained by cells but also normal but inefficient cell function Common accumulations consist of substances that are normally present- fluids, electrolytes, triglycerides, glycogen, calcium, uric acid, proteins, melanin, bilirubin Abnormal accumulations of these substances can occur in cytoplasm or in nucleus Normal endogenous substance is produced in excess or at an increased rate Endogenous substance (normal or abnormal) not effectively catabolized due to lack of lysosomal enzyme Harmful exogenous materials such as heavy metals, mineral dusts, or microorganisms accumulate because of inhalation, ingestion, or infection Manifestations of Cellular Injury Contd. Water- hypoxic injury causing shift of extracellular water into cells causing cellular swelling Cellular swelling is reversible and is early manifestation of most types of cellular injury Lipids and carbohydrates- caused by certain metabolic disorders May accumulate anywhere but primarily in cells of spleen, liver and CNS Lipids accumulate in Tay-Sachs, Niemann-Pick, Gaucher diseases Carbohydrates accumulate in diseases know as mucopolysaccharidosis Manifestations of Cellular Injury Contd. Glycogen- seen in genetic disorders called glycogen storage disorders, but most common is diabetes mellitus Proteins- protein accumulation damages cells in 2 ways Pigments- melanin, hemoproteins Calcium- salts accumulate in both injured and dead tissues Metabolites produced are enzymes that when released from lysosomes can damage cellular organelles Excessive amounts of protein in cytoplasm push against cellular organelles and disrupt function and intracellular communication Protein excess accumulates primarily in epithelial cells and renal convoluted tubule, and antibody forming plasma cells of immune systems Dystrophic calcification- calcification of dying and dead tissues Metastatic calcification- mineral deposits that occur in undamaged normal tissues as a result of hypercalcemia Urate- a product of purine catabolism, chronic hyperuricemia results in the deposition of urate in tissues, cell injury and inflammation Cellular Death Two types Necrosis or accidental cell death occurs after severe and sudden injury Cell death is not neat, the cells that die as a result of acute injury swell, burst and spill their contents all over their neighbors Apoptosis is programmed cell death Necrosis The sum of cell changes after local cell death and the process of cellular lysis causing an inflammatory reaction in the surrounding tissue Four types Coagulative- results from hypoxia usually in kidneys, heart and adrenals and caused by protein denaturation Liquefactive- ischemic injury to neurons and glial cells in brain and caused by hydrolytic enzymes Caseous- tuberculosis pulmonary infection is combination of coagulative and liquefactive Fatty- breast, pancreas and other abdominal organs and is result of action of lipases Gangrenous Necrosis Not a distinctive type of cell death Refers to larger areas of tissue death that results from severe hypoxic injury, commonly occurring because of arteriosclerosis, or blockage of major arteries and subsequent bacterial invasion Dry gangrene- usually result of coagulative necrosis Wet gangrene- results from invasion of neutrophils causing liquefactive necrosis Skin becomes very dry and shrinks, resulting in wrinkles, color changes to dark brown or black Occurs in internal organs causing the site to become cold swollen and black with a foul odor and pus Gas gangrene- infection of injured tissue by one of many species of Clostridium Gas bubbles form in muscles Apoptosis Active process of cellular self destruction- called programmed cell death in both normal and pathologic tissue changes Defects in apoptosis can cause cancer Required to maintain balance between cell proliferation and cell death Affects scattered, single cells Apoptosis is nuclear and cytoplasmic shrinkage of the cell (unlike necrosis in which cells swell and lyse) Depends on tightly regulated cellular program for initiation and execution Cells that die from apoptosis release chemical factors that recruit phagocytes that quickly engulf the remains of the dead cells thus reducing chances of inflammation Somatic Death Death of the entire organism Postmortem change is diffuse Manifestations of somatic death Cessation of respiration and circulation Gradual lowering of body temperature Dilation of pupils Loss of elasticity and transparency in the skin Stiffening of muscle (rigor mortis) Discoloration of skin (livor mortis) Signs of putrefaction are obvious about 24-48 hours after death Cellular Environment: Fluids and Electrolytes, Acids and Bases Cells of the body live in a fluid environment that is regulated in a very narrow range and requires Electrolyte concentration Changes effect electrical potentials and cause shifts of fluid from one compartment to another pH value (measure of acidity or alkalinity of a solution) Alterations of pH disrupt the cellular function of enzyme systems Distribution of Body Fluids Fluids of body are distributed among functional spaces and provide a transport medium for cellular and tissue function Total Body Water (TBW) Varies with age and amount of body fat 2/3rds of body’s water is intracellular (ICF) 1/3rd in the extracellular fluid (ECF) compartments Interstitial Intravascular Lymph, synovial intestinal, biliary, hepatic, pancreatic, cerebrovascular fluids, sweat, urine, pleural, peritoneal, pericardial and intraocular fluids Water moves between the ICF and ECF compartments by osmosis Water moves between plasma and interstitial fluid by osmosis and hydrostatic pressure, which occur across the capillary membrane Movement across the capillary wall is called net filtration and is described according the Starling law. Total Body Water (TBW) Sum of fluids within all compartments is the TBW Expressed as percentage of body weight (in kilograms) Amount of fluid within various compartments relatively constant The standard value of TBW is 60% of the weight of a 70 kg. adult male Exchange of solutes and water occurs between compartments and maintains their unique compositions The percentage of TBW varies with the amount of body fat and age Fat is water repelling (hydrophobic) little water is contained in adipose Aging and Body Fluid Distribution Distribution and amount of TBW change with age Newborns TBW is 75-80% (because infants have less fat) TBW decreases to about 67% during first year Infants are susceptible to significant changes in TBW due to high metabolic rate During childhood TBW decreases and approaches adult proportions during adolescence With increasing age TBW percentage declines further Due to increased fat and decreased amount of muscle and reduced ability to regulate sodium and water balance The normal reduction of TBW in older adults particularly important when body is under stress (fever, dehydration) Water Movement Between ICF and ECF Movement of water between ICF and ECF compartments primarily a function of osmotic forces Osmolality of TBW normally at equilibrium Sodium is most abundant ECF ion and is responsible for the osmotic balance of ECF space Potassium maintains the osmotic balance of the ICF space Osmotic Equilibrium Water Movement Between Plasma and Interstitial Fluid Distribution of water and movement of nutrients and waste products among capillary, plasma and interstitial spaces occur as a result of changes in hydrostatic pressure and osmotic forces at the arterial and venous ends of the capillary Because water, sodium and glucose easily move across the capillary membrane it is the plasma proteins that maintain effective osmolality Osmolality- concentration of solutes per kg. of solution Osmotic forces within the capillary are balanced by the hydrostatic pressure (arises from cardiac contraction) Water Movement Between Plasma and Interstitial Fluid The movement of fluid back and forth across the capillary wall is called net filtration and is best described by the Starling hypothesis Net filtration= (Forces favoring filtration)- (Forces opposing filtration) Forces favoring filtration (movement of water out of the capillary and into interstitial space) Capillary hydrostatic pressure (BP) and interstitial oncotic pressure (water pulling) Forces opposing filtration Plasma oncotic pressure (pressure of plasma proteins) and interstitial hydrostatic pressure Water Movement Contd. As plasma moves from arterial to venous end of the capillary the force of hydrostatic pressure facilitates movement of water across the capillary membrane Oncotic pressure remains fairly constant because plasma proteins don’t usually cross the capillary membrane At the arterial end of the capillary, hydrostatic pressure is greater than capillary oncotic pressure and water filters into the interstitial space At the venous end of the capillary, oncotic pressure exceeds hydrostatic pressure Fluids then are attracted back into the circulation The overall effect is filtration at the arterial end and reabsorption at the venous end Water Movement Between the ICF and ECF Alterations in Water Movement Edema- A problem of fluid distribution Excessive accumulation of fluid within the interstitial spaces Caused by venous or lymphatic obstruction, plasma protein losses, capillary permeability, and increased vascular tone. Pathophysiologic process related to an increase in forces favoring fluid filtration from the capillaries or lymphatic channels into the tissues 4 most common mechanisms Increased capillary hydrostatic pressure Decreased plasma oncotic pressure Increased capillary membrane permeability Lymphatic obstruction (lymphedema) Sodium and Chloride Balance Sodium and water balance are related and chloride levels are generally proportional to changes in sodium levels. Sodium Primary ECF cation Positively charged Important functions Neuromuscular irritability Acid-base balance Cellular chemical reactions Membrane transport Concentration maintained within a narrow range of 135-145 mEq/L Regulated by aldosterone which increases reabsorption of sodium by the distal tubule of the kidney Renin and angiotensin enzymes promote or inhibit secretion of aldosterone and thus regulate sodium and water balance. Atrial natriuretic hormone is also involved in decreasing tubular resorption and promoting urinary excretion of sodium Sodium and Chloride Contd. Chloride Major ECF anion (negatively charged) Provides electroneutrality Transport is generally passive and follows the active transport of sodium so that changes in chloride are proportional to changes in sodium Balance Kidney regulates sodium balance through renal tubular reabsorption Renin–angiotensin-aldosterone system Hormonal regulation of sodium balance mediated by aldosterone Natriuretic peptides Atrial natriuretic peptide, Brain natriuretic peptide Water Balance Maintained by balancing the amount of water excreted with water intake (ingestion and generated by metabolism) Secretion of anti-diuretic hormone (ADH) and thirst perception primary factors Thirst perception Volume depletion Increase in osmolality activates osmoreceptors Baroreceptors stimulated ADH secretion Stimulated by increase in plasma osmolality or decrease in circulating blood volume and a lowered blood pressure Alterations in Na⁺, Cl⁻ and Water Balance Alterations in sodium and water balance are closely related Water imbalances may develop because of changes in osmotic gradients caused by gain or loss of salt Sodium imbalances occur with alterations in body water volume Alterations classified as: Isotonic alterations- changes in TBW accompanied by proportional changes in concentrations in electrolytes Hypertonic alterations- osmolality of ECF is elevated above normal usually because of increased concentration of ECF sodium or deficit of ECF water Hypotonic alterations- osmolality of ECF is less then normal Isotonic Alterations Changes in TBW with proportional electrolyte change Isotonic volume depletion causes contraction of the ECF volume with resulting weight loss, dryness of skin and mucous membranes, decreased urine output and symptoms of hypovolemia Isotonic volume excess results from excess administration of IV fluid, hypersecretion of aldosterone, effects of drugs such as cortisone or renal failure The plasma volume expands with symptoms of hypervolemia Hypertonic Alterations Hypernatremia Serum sodium >147 mEq/L Related to sodium gain or water loss Water movement from the ICF to the ECF Intracellular dehydration Manifestations- intracellular dehydration, convulsions, pulmonary edema, hypotension, tachycardia Water deficit Dehydration Pure water deficits Renal free water clearance Manifestations- tachycardia, weak pulse, postural hypotension Elevated hematocrit and serum sodium levels Hypotonic Alterations Occur when osmolality of the ECF is less than normal Most common causes hyponatremia or free water excess Either of these leads to an intracellular overhydration (cellular edema) and cell swelling Hyponatremia Hyponatremia (Na⁺ <135 mEq/L) Sodium deficits cause plasma hypoosmolality and cellular swelling Pure sodium deficits- Usually caused by diuretics and extra renal losses such as vomiting, diarrhea, GI suctioning or burns Low intake- rare Dilutional hyponatremia Hypoosmolar hyponatremia- both TBW and Na⁺ are increased but TBW exceeds increase in Na⁺ Hypertonic hyponatremia – a shift of water from the ICF to the ECF- can occur with hyperglycemia, hyperlipidemia and hyperproteinemia Hypotonic Alterations Water Excess Compulsive water drinking Decreased urine formation Syndrome of inappropriate ADH (SIADH) ADH secretion in the absence of hypovolemia or hyperosmolality Hyponatremia with hypervolemia Manifestations- cerebral edema, muscle twitching, headache, and weight gain Hypochloremia Usually result of hyponatremia or elevated bicarbonate Develops due to vomiting and loss of HCl Occurs with cystic fibrosis Potassium Major intracellular cation Predominant ICF ion and functions to regulate ICF osmolality, maintain the resting membrane potential and deposit glycogen in liver and skeletal muscles The difference in intracellular and extracellular K⁺ is maintained by a sodium-potassium pump Changes in pH affect K⁺ balance The ratio of ICF to ECF K⁺ is the major determinant of the resting membrane potential which is necessary for the transmission and conduction of nerve impulses, maintenance of normal cardiac rhythms and skeletal and smooth muscle contraction Hydrogen ions accumulate in the ICF during states of acidosis K⁺ shifts out to maintain a balance of cations across the membrane Aldosterone, insulin and catecholamines influence serum K⁺ levels Hypokalemia Potassium level < 3.5 mEq/L Potassium balance described by changes in plasma potassium levels (intracellular and total body stores of K⁺ are difficult to measure) Causes- reduced intake, increased entry of K⁺ into cells, increased potassium loss Manifestations Membrane hyperpolarization causes a decrease in neuromuscular excitability, skeletal muscle weakness, smooth muscle atony, cardiac dysrhythmias Hyperkalemia Potassium level > 5.5 mEq/L Hyperkalemia is rare due to efficient renal excretion Caused by increased intake, shift of K⁺ from ICF, decreased renal excretion, insulin deficiency, or cell trauma Mild Hyperpolarized membrane, causing neuromuscular cramping and diarrhea Severe Cell is unable to repolarize resulting in muscle weakness, loss of muscle tone, flaccid paralysis, cardiac arrest Calcium and Phosphate Calcium Most calcium is located in the bone Necessary for structure of bones and teeth, blood clotting, hormone secretion, cell receptor function, and membrane stability Phosphate Most (85%) located in the bone Necessary for high energy bonds located in creatine phosphate and ATP and acts as an anion buffer Acts as a buffer in acid-base regulation Calcium and phosphate concentrations are rigidly controlled If concentration of one increases the concentration of the other decreases Calcium and Phosphate Regulated by 3 hormones Parathyroid Increases Vitamin hormone (PTH) plasma calcium levels via bone reabsorption D Fat soluble steroid, increases calcium absorption from the GI tract Calcitonin Decreases plasma calcium levels Hypocalcemia and Hypercalcemia Hypocalcemia (serum calcium concentration <8.5 mg/dL) Causes: Inadequate intestinal absorption, deposition of ionized Ca into bone and soft tissue, blood administration or decreased PTH and vitamin D levels Manifestations: Increased neuromuscular excitability (partial depolarization) Hypercalcemia (>12 mg/dL) Confusion, paresthesias around the mouth and in digits, hyperreflexia Two clinical signs- Chvostek sign and Trousseau sign Severe- tetany and convulsions Causes: Hyperparathyroidism, bone metastases, sarcoidosis and excess vitamin D Manifestations: Decreased neuromuscular excitability Muscle weakness Increased bone fractures Kidney stones Constipation Hypophosphatemia and Hyperphosphatemia Hypophosphatemia- usually caused by intestinal malabsorption and increases renal excretion of phosphate Osteomalacia (soft bones) Muscle weakness Bleeding disorders (platelet impairment) Anemia Leukocyte alterations Hyperphosphatemia- develops with acute or chronic renal failure with significant loss of glomerular filtration High phosphate levels are related to low calcium levels Magnesium Intracellular cation Plasma concentration 1.8-2.4 mEq/L Acts as a co-factor in protein and nucleic acid synthesis reactions Required for ATPase activity Decreases acetylcholine release at the neuromuscular junction Hypomagnesemia and Hypermagnesemia Hypomagnesemia (<1.5 mEq/L) caused by malabsorption syndromes Associated with hypocalcemia and hypokalemia Neuromuscular irritability Tetany Convulsions Hyperactive reflexes Hypermagnesemia (>2.5 mEq/L) rare- usually caused by renal failure Skeletal muscle depression Muscle weakness Hypotension Respiratory depression Lethargy, drowsiness Bradycardia Acid-Base Balance pH is the negative logarithm of the H⁺ concentration If a solution moves from a pH of 7 to a pH of 6 the H⁺ ions have increased 10 fold Neutral- pH of 7 H⁺ high in number, pH is low (acidic) H⁺ low in number, pH is high (alkaline) Ranges from 0-14 Each number represents a factor of 10 If a solution moves from a pH of 6 to a pH of 5, the H⁺ has increased 10 times pH Acids are formed as end products of protein, carbohydrate, and fat metabolism To maintain the body’s normal pH (7.35-7.45) the H⁺ must be neutralized or excreted Bones, lungs and kidneys are major organs involved in regulation of acid-base balance Body acids exist in two forms Volatile- H₂CO₃ (can be eliminated as CO₂ gas) Nonvolatile Sulfuric, phosphoric and other organic acids Eliminated by the renal tubules with the regulation of HCO₃⁻ Buffering Systems Buffer systems exist as buffer pairs Associate and dissociate very quickly Buffer changes occur in response to changes in acidbase status A buffer is a chemical that can bind excessive H⁺ or OH⁻ without significant change in pH A buffering pair consists of a weak acid and its conjugate base The most important plasma buffering systems are the carbonic acid-bicarbonate system and hemoglobin Carbonic Acid-Bicarbonate Pair Operates in the lung and the kidney The greater the partial pressure of carbon dioxide the more carbonic acid is formed If amount of bicarbonate decreases the pH decreases causing a state of acidosis The pH can be returned to normal if the amount of carbonic acid also decreases At a pH of 7.4 the ratio of bicarbonate to carbonic acid is 20:1 Bicarbonate and carbonic acid can increase or decrease but the ratio must be maintained This type of pH adjustment is- compensation The respiratory system compensates by increasing or decreasing ventilation The renal system compensates by producing acidic alkaline urine Other Buffering Systems Protein buffering Proteins have negative changes, so they can serve as buffers for H⁺ Renal buffering Secretion of H⁺ in the urine and reabsorption of HCO₃⁻ Cellular ion exchange Exchange of K⁺ for H⁺ in acidosis and alkalosis (alters serum potassium) Acid-Base Imbalances Normal arterial blood pH- 7.35-7.45 Acidosis Systemic increase in H⁺ Alkalosis Systemic decrease in H⁺ Acidosis and Alkalosis 4 Categories of acid-base imbalances Respiratory acidosis- elevation of pCO₂ due to ventilation depression Respiratory alkalosis- depression of pCO₂ due to alveolar hyperventilation Metabolic acidosis- depression of HCO₃⁻ or an increase in noncarbonic acids Metabolic alkalosis- elevation of HCO₃⁻ usually due to an excessive loss of metabolic acids Compensation Renal Alters bicarbonate and H⁺ levels in response to acidosis or alkalosis Respiratory Alters CO₂ retention or loss in response to alkalosis or acidosis Much slower response Excretion and/or reabsorption Rapid response Respiratory rate alterations When adjustments are made to bicarbonate and carbonic acid in order to maintain the 20:1 ratio and therefore maintain normal pH The actual values for bicarbonate to carbonic acid ratio are not normal but the normal ratio is achieved Correction Correction occurs when the values for both the components of the buffer pair (carbonic acid and bicarbonate) have also returned to normal levels Metabolic Acidosis Anion Gap Used cautiously to distinguish different types of metabolic acidosis The concentrations of anions (-) should equal the concentration of cations (+) Normal anion gap= Na⁺ + K⁺= Cl⁻ + HCO₃⁻ =10-12 mEq/L Abnormal anion gap occurs due to an increased level of abnormal unmeasured anion Examples- DKA- ketones, salicylate poisoning, lactic acidosisincreased lactic acid, renal failure etc. As the abnormal anions accumulate the measured anions have to decrease to maintain electroneutrality Metabolic Alkalosis Respiratory Acidosis Respiratory Alkalosis
