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PHYSL 210 Entire Term Notes.docx

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Saswati Das

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Cell Physiology Dylan Feist Two Classes of Cells  Prokaryotic – do not have nuclear membrane or compartmentalization of organelles.  Eukaryotic – have a true, membrane bound nucleus and organelles. These include plants, animals, unicellular and multicellular fungi, and unicellular protozoans. Cell Structure and Function  Plasma Membrane – surrounds the cell surface and separates the intracellular fluid from the extracellular fluid.  Cell organelles – performs specific functions.  Cell interior – consists of the nucleus and the cytoplasm o Nucleus – contains the genetic material o Cytoplasm – everything outside the nucleus. Includes the cytosol (gel-like fluid) and the organelles. Biological Membranes  Functions o Physical barrier – maintains difference in fluid composition between ICF and ECF. o Cell-to-cell communication – receptors bind signaling molecules arriving at the cell surface. o Structural support – specialized connections exist between the plasma membranes and the extracellular materials. o Transport – the movement of ions, waste, and secretory products.  Composition o Double layer of lipid molecules o Embedded proteins o Different ratios of lipids and proteins in each membrane  Lipids o Carbon and hydrogen o Nonpolar  Fatty Acids o Carboxylic acid groups with a long chain of hydrogen and carbons. o Saturated = no double bonds o Unsaturated = one or more double bonds o Nonpolar  Phospholipids o Amphipathic – have a polar head group and a nonpolar fatty acid chain. o They spontaneously form a bilayer o They are distributed unequally between both halves of the bilayer.  Steroids o Amphipathic o Cholesterol o Maintains proper membrane fluidity o Fits between phospholipids o At low temperatures, it prevents crystallization  Glycolipids o Lipids with a short CHO chain o Found in outer leaflet of plasma membrane and form glycocalyx  Membrane Proteins o There are two classes of membrane proteins  Integral  Amphipathic  Partially span the membrane  Peripheral  Not amphipathic  On either the inner or outer surface of the membrane o Glycoproteins are proteins with an attached carbohydrate. They are found on the extracellular surface of the plasma membrane and form glycocalyx. They have selective properties (what gets into the cell).  Fluid Mosaic Model o Plasma membrane is a dynamic structure o Rapid lateral transfer of proteins and lipids o Transverse diffusion is rare o Fluidity is influences by temperature, cholesterol, and unsaturated tails o Double bonds cause more fluidity. o There are many types of macromolecules (mosaic) o The membrane is not symmetrical on both sides  Cell Adhesions o The adhesion of simmilar cells produces tissue o Three main components  Cell Adhesion Molecules (CAMs)  Extracellular matrix  Cell junctions o Cell Adhesion Molecules are specific integral membrane proteins.  Cell-cell adhesions are done by Cadherins  Cell-matric adhesions are done by Integrins o Extracellular Matrix  Surrounds the cell  Consists of fibrous proteins embedded in the gel-like substance made up of CHO’s.  Responsible for stable positioning of cells in tissues  Collagen – tensile strength  Elastin –tissue elasticity  Fibronectin – organizing matrix which links components of the matrix to proteins (such as Integrins) in the plasma membrane. o Cell Junctions  Specialized junctions between cells  Three main types i. Desmosomes ii. Tight Junctions iii. Gap Junctions  Desmosomes  Anchor the cells together  Structural integrity  Plaques – anchoring points for Cadherins  Cadherins – extend into extracellular space  Keratin intermediate filaments – anchor the cytoplasmic surface (strong connection).  Tight Junctions  Found in epithelial tissue.  Form impermeable junctions.  No space between cells.  Nutrients move from luminal side to blood side.  Essential for polarized cells.  Occludin = nearly impermeable junction.  Gap Junctions  Transmembrane channels linking cytoplasm of adjacent cells (connexons).  Movement of small ions and molecules.  Used for communication. Cell Contents  Cytosol o Water o High [K] o High [proteins] o Signal transduction  Organelles o Membranous  Nucleus, endoplasmic reticulum, Golgi apparatus, lysosomes, mitochondria. o Non-membranous  Ribosomes and cytoskeleton.  Nucleus o Control center of the cell – contains the genetic material (DNA). o Nuclear envelope – double porous membrane. o Nuclear pores – allow selective movement of molecules. o Nucleolus – synthesizes ribosomal RNA. o RBCs have no nucleus, skeletal muscle cells have many.  Ribosomes o Responsible for protein synthesis. o Translates DNA information into an amino acid based on mRNA instructions. o Two subunits – a small and large subunit. o Two main types:  Free ribosomes.  Ribosomes bound to the rough endoplasmic reticulum.  Endoplasmic Reticulum o Large organelle. o Extensively membrane bound. o Two components:  Rough ER – synthesizes protein with bound functional ribosomes. Produces soluble proteins to be secreted from the cell, or used in the lumen of lysosomes, or sent to the Golgi.  Smooth ER – synthesizes lipids, stores calcium, and helps in detoxification in liver cells. Sarcoplasmic reticulum functions solely in regulating calcium levels.  Golgi Apparatus o Made of flattened sacs, stacked in layers. o Functions:  Protein modification.  Sort and pack proteins, especially for secretion.  Renews and modifies the plasma protein by adding new lipids and proteins.  Lysosome o Produced at the Golgi. o Contains digestive enzymes that degrade extracellular and intracellular debris. o Also plays a role in cellular defense. o Primary lysosome – only digestive enzymes. o Secondary lysosome - digestive enzymes and particles to be broken down.  Peroxisomes o Use oxygen to remove hydrogen from molecules. o Produces toxic H2O2. o Catalase breaks down H2O2 into water and oxygen. o Lots of peroxisomes in the liver.  Mitochondria o Powerhouse of the cell. o Double membrane. o Inside is called the matrix, middle is intermembrane space, and the outside is the cytosol. o The matrix and cristae (sheets or tubules in inner membrane) produce ATP via cellular respiration. o The amount of mitochondria depends on need for a cell. For example, muscles, heart, and liver cells have lots of mitochondria. o Mitochondria has its own DNA which codes for proteins.  Cytoskeleton o Maintains cell shape. o Maintaines organelle positions. o Mediates cell and organelle motility. o Consists of three filaments: i. Microfilament – smallest filament. It is composed of actin and is continuously assembled and disassembled. It functions to provide mechanical strength to the cell, to assist in cell movements (microvilli, pseudopodia, organelle movement) and it interacts with myosin in muscle fibers to produce muscle contraction. ii. Intermediate filaments – intermediate size. They are responsible primarily for the formation and maintenance of the cell shape. They stabilize the position of the organelles. They play a structural role only and do not participate in cell movements. iii. Mictotubules – large hollow tubes composed of tubulin that are strong and are continuously assembled and disassembled. They function to strengthen the cytoplasm, the change cell shape, and to assist in cell movement (cilia and flagella) and to move organelles and chromosomes.  The intracellular transport of membrane bound vesicles and organelles is called axonal transport and it is propelled by motor proteins called kinesins and dyneins. Genes, DNA & Proteins  DNA – encodes the information for the synthesis of the structural and enzymatic proteins of the cell.  Gene – stretch of DNA that codes for the synthesis of a particular polypeptide.  DNA – (transcription) – mRNA – (translation) – Proteins o Transcription – a process by which RNA is synthesized using information contained in DNA. It occurs in the nucleus where mRNA is processed and then exported. o The mRNA binds to a free ribosome. o Translation – the process by which polypeptides are synthesized using mRNA as a template.  Protein Destination o The signal sequence on the initial amino acids direct protein to its destination. o ER Signal Sequence – sends protein the ER to finish translation. This includes secretory proteins, enzymes for the ER, Golgi, and lysosomes, and integral plasma membrane proteins. o Without a sequence, translation continues in the cytoplasm. This includes protein for nucleus, peroxisomes, mitochondria, or proteins that remain in the cytosol. Membrane Transport  Vesicular transport: o Endocytosis – the uptake of material into the cell via vesicles that pinch off from the cell membrane.  Phagocytosis – uptake of material into a cell via vesicles that pinch from the cell membrane. Extensions of the plasma membrane engulf the phagosome which the fuse with a lysosome.  Pinocytosis – cell drinking; an invagination forms, allowing the absorption of extracellular fluid.  Receptor-mediated endocytosis – receptors bind to specific particles. It works in low concentrations and requires a receptor.  Exocytosis – the release of material from the cell via vesicles that fuse with the cell membrane. Vesicles fuse with the cell membrane and release contents into the extracellular fluid. It functions to add components to the plasma membrane, and to secrete specific substances out of the cell into the ECF.  Transcytosis – the movement of large macromolecules. It can be either endocytosis or exocytosis. Eg. Glucose movement across epithelial cell.  Driving Forces for Non-Vesicular Transport o Chemical  Uses concentration gradients.  Molecules move passively from areas of high concentration to areas of low concentration. Rate is dependent on the concentration.  Analogous to pressure gradient. o Electrical  Membrane potential – the difference between cell membrane.  Exists because ions experience attractive and repulsive forces.  It depends both of the direction (the sign of the ion) as well as the magnitude (the sign of the membrane potential). o Electrochemical Driving Force  The sum of the electrical and chemical driving forces acting on an ion. The direction depends on the net direction of electrical and chemical driving forces.  Simple Diffusion o The passive movement of molecules through a biological membrane’s lipid bilayer. o Depends on lipid solubility and the size of the molecule.  Gases and small uncharged polar molecules can pass through.  Large uncharged molecules, ions, and charged polar molecules cannot pass. o Does not require energy. o Moves from high to low concentrations. o Net Flux – net exchange of molecules across a membrane. o Factors affecting simple diffusion:  Magnitude of driving force.  Membrane surface area.  Membrane permeability (temperature, thickness, size, shape, and lipid solubility). o Rate is not the same for all cases.  Membrane Transport Proteins o Mediated transport o Can either be facilitated transport (no energy, passive transport) or active transport (requires energy). o Carrier-Mediated Facilitated Diffusion:  Net Flux from high to low.  Does not require energy. o Channel-Mediated Facilitated Diffusion  Depends on electrochemical gradient.  High selectivity.  Voltage gated – changes in voltage.  Ligand gated – binding of signaling molecules.  Mechanically gated – mechanical stimuli, such as cell swelling. o Transport rates plateau because there are only a limited number of binding sites available. o Active Transport:  Pumps uphill, against the electrochemical gradient.  It uses energy.  Primary Active Transport  Uses ATP as the source of energy.  Example is the Sodium/Potassium Ion Pump  Antiporter enzyme  3 Na+ out  2 K+ in  Creates the concentration gradients  Protein constantly pumps sodium out of the cell.  Electrogenic – net movement of charge.  Secondary Active Transport  Uses electrochemical gradient.  Couples the movement.  Symport – two substances transported in the same direction.  Antiport – two substances transported in opposite directions.  Can be electroneutral or electrogenic. o Water Transport  Osmosis – passive movement of water across a membrane. It goes from low solute concentration to high solute concentration. o Epithelial Transport  Functional grouping of cells connected by tight junctions. They transport materials across the cell.  Paracellular (between cell) movement is limited.  Transcellular (through cell) movement is used.  Intestinal epithelium absorbs nutrients.  Uses the cell polarity to move glucose to the blood.  Uses many types of transporters. Chemical Messengers  Direct – gap junctions.  Indirect – chemical messengers.  Receptor-Mediated Signaling o Chemical messengers bind reversibly to receptors. o The receptors are highly specific, they can reach saturation, and they are regulated. o Signal transduction – sequence of events between binding and the cellular response.  Intracellular Receptors o Lipid soluble messengers that include steroid and thyroid hormones. o Bind in cytosol or nucleus. o Transcription factors alter the transcription of mRNA.  Membrane-Bound Receptors o Water-soluble messengers that include hormones, neurotransmitters, paracrine/autocrine compounds. o First messenger – binds to extracellular receptor. o Second messenger – intracellular messenger that is produced as a response to the first messenger. o Protein-kinase phosphorylates another protein.  Channel-Linked Receptors o Receptor is also a ligand gated ion channel. o First messenger causes ion to cross membrane. o Fast. o Ionotropic o Eg. Calcium channel.  Calcium as a Second Messenger o Calcium induces calcium release. o Binds to calmodulin to form complex, which alters the activity of enzymes and proteins.  Enzyme-Linked Receptors o Interact with enzymes to function as a unit. o Can also function as enzymes.  G Protein Coupled Reaction o Bind guanosine nucleotides. o Transmembrane receptors that sense molecules outside the cell and activate transduction pathways. o Conformational change.  cAMP Second Messenger System o Example of simulatory G-protein. o Phosphorylation by protein kinase either activates or inhibits a protein. o Alpha subunit activates adenylate cyclase, which promotes the formation of cAMP, which activates protein kinase A to signal a response in the cell.  Signal amplification – small changes in concentration can result in a marked response. This allows hormones and messengers to be effective at very low concentrations. Nerve and Muscle Dylan Feist Notes  Afferent – the information is transferred from the periphery toward a central nervous structure.  Interneuron – all of the structures are located within the central nervous system.  Efferent – the information flow is from the CNS toward the periphery. o Eg. May cause skeletal muscle fibers to contract in response to action potential.  Spinal Cord o Protected by bony structures called vertebra. o Ventral horn – location of motorneurons. o Dorsal horn – location of sensory integration. o Grey Matter – consists of neurons, dendrites, synapses, and nerve terminals. Neurons in the grey matter are neighbored by astro-glial cells. o White Matter – consists of axons and oligodendrocyte-glia, which electrically insulate and also functionally support the axons. o A typical mixed peripheral nerve contains both sensory afferent fibers and efferent motor axons.  Morphological Structure of a Motorneuron: o Dendrites originate from the cell body. o The axon wires neurons to communicate with each other via electrical action potentials. o Axon terminal is the presynaptic part of a synapse. o Axons can have a length of several meters.  Schwann cells enfold axons of both sensory and mororneuron. o The intracellular fluid contains the lipid myelin, which electrically insulates the cell. o Typical Schwann cell is 0.1 to 1 mm long.  Saltatory conduction is the most effective action potential propagation.  Oligodendrites cover axons in the CNS.  Bipolar neurons have two elongated processes.  Dorsal root ganglion cells are somatic sensors, sensitive to mechanical stimuli, temperature, or pain. o The dendritic branch is functionally an axon. o The real axon extends from the dorsal root ganglion into the spinal cord. o First node of Ranvier is closes to the receptor. o Pacinian corpuscles respond to vibration and pressure.  Electrical processes in neurons and muscle fibers are mediated by highly specialized proteins. o Found in plasma membrane o CNS neuron soma has diameter of 5-50 micrometers. o Diameter of transport proteins is 0.01 micrometers. o Mitochondria are ~1 micrometer in size. o Cell nucleus is several micrometers in diameter.  Diffusion – passive flux of solute towards a compartment of lower concentration.  Intracellular concentration of a cell have high potassium, low sodium, and low calcium.  The Na/K pump is the most important because it transports sodium out of the cells in exchange of K. o ATP hydrolysis powers this through a conformational change. o Secondary active pumps use this electrochemical gradient to move ions.  Voltage gated Na+ channels are important for sodium action potentials.  Osmolarity – a means to measure the extent to which water is attracted by the content of solutes.  Intracellular membrane surface is negatively charged.  Extracellular membrane surface is positively charged.  Electrochemical equilibrium – when the chemical driving force driving K+ out of the cell will be compensated by an electrical potential to do the separation of the negative charge of the impermeable anion and the positive charge of K+.  The Nerst equation allows us to calculate the equilibrium potential. However, determining the equilibrium potential is only valid if the membrane is exclusively permeable to that ion.  Conductance and permeability are often used to express the capability of flux ions through channels. The terms are proportional rather than equal.  Glial cells have the fewest Na(leak) cells.  Typical neuron has a membrane potential of approximately -70 Mv. o It is notable less negative than glial cells because there are more (leak) Na+ channels, as well as (leak) K+ channels. o Overshoot – the reversal of a negative value to a positive value during depolarization.  An action potential is approximately one millisecond. At the beginning of the action potential, depolarization occurs and causes an overshoot. Repolarization occurs immediately after. o Afterhyperpolarization – undershoot below resting baseline. o gNa is only greater than gK during depolarization and repolarization.  At rest, both Na+ and K+ channels are closed, while many leak K channels are open.  The threshold must be achieved before an action potential is solicited.  All or none response, meaning that the shape and size of an action potential is the same regardless of the stimulus.  The length constant is measured in mm. o Determined at the point on the abscissa where voltage has dropped by 63%.  Capacitance is the current flow delay. o Time constant has a greater value in neurons that have a high resistance and/or neurons with a high capacitance.  Continuous conduction is unmyelinated axons have a characteristic electronic voltage drop due to the intra-axonal leak currents. o Intra-axonal leak currents.  Saltatory conduction in myelinated axons is much faster, particularily in thicker axons. This is because myelin insulation prevents current flow through leak channels. The action potential typically jumps across several nodes of Ranvier. o Faster because leak channels are only present at the nodes of Ranvier o Up to 100x faster. o Factors that limit action potential speeds: charge of membrane capacitance, and conformational change of Na+ channels.  Saltatory action potential is up to 100 times faster than continuous conduction because the electronic potential drop is less pronounced.  Increasing the current also increases the frequency of the action potentials. o The magnitude of a receptor potential is encoded into a specific frequency of action potentials. o Action potential firing rate increases as depolarizing current increases.  The maximum spike frequency is approximately 600 spikes per second.  Adaptation – the return to a resting potential, despite the stimulus amplitude remaining constant.  Dorsal root ganglion cells are somatic sensors.  Mechano sensitive ion channels respond when the skin is touched because the membrane can stretch.  Glutamate interacts with postsynaptic ion channels to generate an excitatory postsynaptic potential.  Glutamate is the major excitatory neurotransmitter in the CNS. o Generates excitatory EPSP o Stored in synaptic vesicles o Activates ionotropic glutamate receptor. o Promotes influx of Na+ into the neuron. o Depolarization occurs  Acetylcholine (Ach) is the neurotransmitter of the motorneurons. The following occur at the Motor Endplate: o Vesicles release Ach in response to increased Ca+ o Diffused to postsynaptic Nicotinic receptors. o Mediates flux of Na+, Ca2+, and K+ o Endplate potential EPP solicited with amplitude 40-60 mV  Sensory information from a peripheral skin receptor propagates via afferent axons from dorsal root gangions neurons into the spinal cord, where the incoming action potentials elicit an EPSP (excitatory post synaptic potential) in an interneuron. This interneuron excites, also via EPSP, a motorneuron in the ventral horn. The action potentials propagate along the axon of the motorneuron to the periphery, specifically to activate a skeletal muscle fiber.  Acetylcholine is a neurotransmitter stored in synaptic vesicles. An influx of calcium ions causes a release of Ach, which induces the activation of a larger cation pore. There is a flux of Na, Ca, and K along their gradients. This results in an Endplate Potential, which has an amplitude of 40-60 mV. It does not overshoot because of the efflux of K+ which antagonizes the depolarization caused by Na and Ca.  A skeletal muscle consists of muscle fibres that are formed by a fused individual muscle cell.  Tendons – connective tissue.  Muscles contract and need energy such as glucose and oxygen.  Each muscle fibre contains many myofibrils that have characteristic bands.  Muscle fiber contains many myofibrils. o I band contains actin o A band made of thick myosin filaments. o Sarcomere is the basic unit of myofibril and is composed of actin and myosin filaments.  When muscle contracts, the extend of overlap between filaments increases.  Cross bridges are the part of myosin that bind to actin.  Tropomyosin filaments block cross bridge binding sites on actin.  Binding of Ca2+ causes change in tropomyosin and binding site is revealed.  ATP necessary for cross bridge detachment from actin.  Rigor mortis causes by lack of ATP  Arrival of Na+ Action Potential: o Enters invagination o Activates voltage sensor in DHP receptor o Release of Ca2+ due to conformational change. Ryanodine receptor mediates the release of calcium ions from the sarcoplasmic reticulum.  Muscle contraction lags behind muscle action by several tens of ms.  Fused tetanus – repetitive stimulation. Muscles cannot relax. Blood Dylan Feist Introduction to Blood  Facts: o Blood is approximately 7-8% of our body weight. o It is mainly present in blood vessels, but some important components are found in tissues. o Blood is thicker than water.  Functions o Transport oxygen, carbon dioxide, nutrients, waste, ions, hormones, and heat. o Regulates ion and pH balance. o Provides immune protection. o Prevents blood loss in Hemostatis.  Hematocrit o The percentage of blood volume occupied by packed red blood cells. o For men, it is approximately 47% o For women, it is approximately 42% o The difference is because males have testosterone, which increased red blood cell production. o A high Hematocrit indicates heavier blood, which moves slower and may cause stress on the heart. o A low Hematocrit indicates reduced oxygen delivery.  Extracellular Fluid o Made up of two parts: i. Interstitial Fluid ii. Plasma – non cellular part of the blood.  Plasma o Mostly water. It also contains electrolytes, as well as substances being transported, such as CO2 and nutrients/waste. o Functions in distributing body water, buffering, transport, defense, and hemostasis.  Plasma Proteins and Functions o Albumins – osmotic pressure and carrier of substances. o Globulins – clotting factors, enzymes, antibodies, and carriers for substances. o Fibrinogens – forms fibrin threads essential for blood clotting. o Transferrin – iron transport.  Blood Cell Types o Red Blood Cell (RBC)  Also called erythrocytes. o White Blood Cells (WBC)  Much fewer WBC than RBC  Also called leukocytes.  Many types:  Neutrophils – phagocyte  Pinched off nucleus  Eosiniphils – defense against parasites  Chromatin is clumpy and smudgy  Basophils – inflammation  Big dark granules  Monocytes – phagocyte and immune defense  Big cells  Lymphocytes – two types. B-Cells are for antibody production and humoral immunity, while T-cells are for cellular immunity.  Fairly standard looking o Platelets or Thrombocytes – assist in hemostasis.  More platelets than WBC, but more RBC than platelets.  Hematopoeisis o The formation of blood cells. o Prenatal, it occurs in the yolk sac, liver, and the spleen. o After birth, it occurs in the bone marrow. o It is regulated by cytokines, called hematopoietin.  Erythropoietin for RBCs  Interleukins for WBCs  Thrombopoietin for platelets.  Red Blood Cell o Have a lifespan on 120 days. o Function in O2 transport. o Loses nucleus during maturation.  Hemoglobin o Principle carrier of oxygen. o It is responsible for approximately 99% of O2 transport. o Binds loose and reversibly. o Process is called oxygenation, not oxidation. o Has extremely high affinity for CO and it is essentially irreversible.  RBC Production Factors o Erythropoietin  Hormonal regulation stimulated by low oxygenation, such as low blood volume, anemia, low hemoglobin, poor blood flow, and pulmonary disease. o Iron  Major cause of anemia.  Body stores it in hemoglobin and the liver and recirculates it.  Some is bound with Ferritin. o Folic Acid (leafy vegetables, synthesis in thymine) o Vitamin B-12  Forms complex with Intrinsic Factor.  Insufficient B-12 is called pernicious anemia. o Intrinsic Factor – need to be able to absorb B-12.  Fate of RBCs o The cell is broken down. o The iron recirculates. o The globin is broken down into amino acids. o Continuously broken down in spleen, and then in liver and then expelled as waste.  Anemia o Decreased oxygen carrying capacity. o Can be caused from decreased RBC production, RBC destruction, loss of blood, and abnormal production. o Causes include lack of iron, lack of B-12 and IF, damage of bone marrow, chronic kidney disease, abnormal shape, chronic menstration. o Sickle cell anemia produces hard and non flexible sickle shaped RBC which causes health implications. The White Blood Cell Story  Production o Occurs in the bone marrow. o T-cells are produced in the Thymus. o Granulocytes and monocytes are found in blood vessels. o Lymphocytes recirculate in the blood stream. o Granulocytes and macrophages enter the tissues and stay there.  Body Protection o Innate Defense  Intact skin, enzymes in saliva, tear, mucus, etc.  Acidic gastric secretion.  WBC (granulocytes, monoctyes/macrophages).  Non-specific.  Fast. o Acquired Defence  Lymphocytes.  The body remembers what it encountered previously.  Specific.  Has memory.  Slow (days/weeks).  The Immune System o Good:  Defense against foreign invaders.  Removal of old, damaged cells. o Bad:  Allergies: exaggerated response.  Autoimmune reaction.  Innate Defense (Inflammation) o Phagocytes involved (Neutrophils and Macrophages) o Innate response to infection or injury. o Redness, swelling, heat, pain, loss of function. o Characterized by increased blood flow, increased permeability of small blood vessels, and the release of inflammatory mediators.  More blood rushes in; arteriole and venule dilation.  Increased blood causes heat and redness.  Edema expands the cellular matric.  Histamine is released – itchy/swelling symptoms.  Cellular events – macrophages trap and kill pathogens, movement of WBCs into the area, phagocytosis. o The most important feature is the accumulation of WBC in the affected tissue. i. Marginalization of WBCs ii. Tethering and rolling of WBCs in blood vessel iii. Activation of WBCs iv. Arrest/firm attachment of WBCs to endothelial cells. v. Emigration/diapedesis – neutrophil expresses the selecting protein and the endothelial cell expresses selecting binding site. Called rolling adhesion. vi. Chemotaxis of WBCs – the ability to move along a concentration gradient in response to a chemical. Chemotactic factors include complement products, bacterial products, and arachidonic acid metabolites. vii. Recognition of nonself by WBCs viii. Phagocytosis of invader WBCs  Phagocytes are any cell that can chew things in its surroundings. They engulf bacteria by first recognizing, then attaching to it, then internalizing and finally destroying it.  They recognize bacteria based on Pattern Recognition Receptors, which are proteins expressed by the cells of the innate immune system.  Opsonins are added to the surface of bacteria to speed up phagocytosis. They are binding enhancer for the process of phagocytosis. o Phagocytosis  Opsonization – deposition of opsonins enhances engulfment of infectious agent.  Phagocytosis – the infectious agent is surrounded by pseudopods and internalized in a membrane bound phagocytic vacuole.  Killing and Degradation – two main types: i. Oxygen dependent killing – production of oxygen free radicals. ii. Oxygen independent killing – uses bacterial proteins and enzymes. o Inflammation is beneficial for short term fix, but in the long term it causes damage. o Complement proteins – plasma proteins that are inactive. There are activated and form a signal. Think OIL  O = Opsonization of pathogens  I = Recruitment of inflammatory and immunocompetent cells  L = Lysis of pathogens.  Acquired Immunity o Lymphocytes  The primary lymphoid tissue is the bone marrow and thymus.  The secondary lymphoid tissue is the lymph nodes, spleen, and tonsils, where the lymphocytes encounter antigen and become activatied.  Must be able to recognize antigens, respond to antigens, and remember their encounter. o Antigen – molecule that can bind to an antibody, forming a complex. o Antibody – has two antigen binding sites and is highly specific. It is the recognition molecule for B-cells. o B Cells:  Become short-lived plasma cells that make lots of antibodies and are secreted into the bloodstream.  Become memory cells that have antibody molecules so that next time, the immune response is faster.  Humoral immunity is the major defense against bacteria and involves B-cells. It acts hand-in-hand with the innate system. o Cellular Immunity  Major defense against viruses, cancer, transplants.  Involved T-cells  T-cells require antigen presentation  The antigen must be presented on an antigen presenting cell with a major histocompatibility complex before the T-cell will accept it.  Three signals before an immune response is triggered: i. APC presents antigen on MHC ii. Expression of co-stimulatory molecules on APC iii. Cytokine secretion by APC.  MHC (major histocompatibility complex)  Two main types:  MHC I – present on all nucleated cells.  MHC II – present on specialized antigen-presenting cells, such as macrophages, dendritic cells, and B-cells. Especially macrophages. o The body can handle different antigens at the same time. o Passive Immunity – from mothers milk, eg. Only lasts a few weeks. Platelets & Hemostatsis  Hemostatis is a process that causes bleeding to stop.  Hemeostasis is the maintenance of a standard state within a system.  Key Features of Hemostasis o Vasoconstriction o Platelet Plug formation (white thrombus) o Blood clotting (red thrombus)  Fibrinogen, clotting factors, etc. all come together.  Platelets o Come from stem cells, but specifically from pieces of the cytoplasm of meagakaryocyte. o Do not have a nucleus. o Have alpha granules  Adhesion molecules such as von Willebrand factor.  Growth factors  Some clotting factors  Cytokines o Have dense granules  ADP and ATP  Serotonin  Ca++ o Platelet Plug Formation  Adhesion – sticking to damaged walls  Activation – changing shape, express receptors, and secrete various substances.  Aggregation of platelets – stick together and form a plug.  Mechanism  Von Willebrand factors cause platelets to accumulate. Then they bind to fibrinogen and form networks. Thus, the platelets get trapped.  Activated platelets have two roles: the first is in vasoconstriction and the second is in further platelet aggregation in case secondary thrombus formation is needed.  Expansion does not occur because neighboring cells secrete prostacyclin or nitric oxide, which prevents platelet aggregation at healthy endothelial cells. o Arachidonic Acid  Produces Leukotrienes and Prostaglandins. o Aspirin blocks COX, causing the inactivation of both Thromboxane (pro- hemostatic effect) and Prostacyclin (anti-hemostatic effect). Since Thromboxane is found in platelets, it isn’t replenished. Prostacyclin, by comparison, is replenished, so the net gain is a anti-hemostatic effect. o Blood Clotting  The key step is the activation of Thrombin so that it can catabolize the reaction of fibrinogen to fibrin (which is an insoluble plasma protein).  Calcium is an important plasma clotting factor.  Traditional view saw factor XII as essential for the cascade of activation that results in blood clotting.  Modern view is that Thrombin influences other pathways and a very
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