Herrara`s Biology- lecture
Some definitions of physiology:
1) It is the study of the normal functioning of a living organism and its component parts, including all its chemical and physical processes. Silverthorn, in Human Physiology 2) Physiology is not a science or profession, but more a point of view--Ralph Gerald
Internal Environment:
Different systems exist in the body: digestive (digests food to extract the nutrients from it and eliminates waste from the body), respiratory (supplies oxygen to the body and eliminates carbon dioxide as a waste product during exhalation), circulatory (central role because it transports the oxygenated blood all around the body), excretory system (filtering and processes the blood to maintain the composition of the body`s fluid and the skin (provides mechanical strength, barrier to infection, way of preventing water loss from the body and it separates the internal environment from the external. -In order for cells to maintain their integrity and to function properly, its essential that their immediate physical and chemical environment to be ideal for their life. -Homeostasis: Maintenance of the constancy of the internal environment. -Every physiological system mentioned above is homeostatic in some way. -Mechanism of homeostasis is negative feedback. Eg. Glucose homeostasis. Regulation of glucose concentration involves the pancreas, the liver and the cells of the body. After a meal, there is a rise in glucose concentrations, this provides a stimulus to beta cells in the pancreas, and this secretes the hormone insulin and causes the cells in the body to take up glucose. Liver cells synthesize glycogen which stores excess glucose. This then leads to a drop in blood glucose which returns the glucose concentration to the normal level. During fasting or not eating for a while, the blood glucose concentration decreases which provides a stimulus to the alpha cells in the pancreas which releases the hormone glucagons which releases glucose into the blood to bring the levels back up to normal.
The Circulatory System
-Central function of the circulatory system is to transport materials such as water, ions, nutrients, waste products and respiratory gases through an animal`s body. -Diffusion is adequate for the circulation only for very short distances. Protists or porous organisms can exist without a circulatory system. -2 general types of circulatory system: open and closed. These systems both have a heart that acts as a muscular pump, there is a fluid that circulates-blood, and there is a set of branching tubes called blood vessels through which the blood flows. The way this works
is that through muscular contraction raises the hydrostatic pressure of the blood which creates a pressure gradient-pushes blood through the system. -The distinction between an open and closed system is whether or not the blood is always contained in blood vessels. If the blood is not always contained in blood vessels, its known as an open system- most invertebrates have this. In an open system there is a heart and blood vessels, but at some point the blood leaves the vessels and as it does this, it enter sinuses which directly bathes the organs in the body. The blood in an open system is called hem lymph` (have functions of blood and extra cellular fluid.)
-The Vertebrate hearts
There is a single heart, the heart may have 1 or 2 atria that receive blood, and have 1 or 2 ventricles that pump blood out to the body. The large vessels that pump blood away from the heart are called arteries. These feed blood into arterioles which then feeds blood into the capillaries. Capillaries are the only vessels within which exchange of blood within the blood and surrounding tissues occur. These then drain into venules and then veins. -The vein and arteries have nothing to do with the oxygenation of the blood, just the direction the blood flows. The second common feature is that there is two major subdivisions of the circulatory system: 1) The respiratory circuit which delivers the blood to the gaseous exchange organ and 2) The systemic circuit that delivers the blood to the rest of the body. Fish: -In fish, the heart is a single pump consisting of 1 atrium and 1 ventricle. Blood pressure in highest in aortas and it falls continually down the pressure gradient as we go through the arterioles, capillaries and veins. -Fishes have a problem because when the blood leaves the heart, and goes through the gill capillaries, the pressure falls considerably. The pressure is very low in the veins, so it leaves little pressure to push the blood into the systemic system. This limits the maximum metabolic rate that fish can operate. Amphibians: -These have corrected this problem to some extent by having a heart that has evolved into a double pump. Blood from the respiratory system returns to the left atrium of the heart before going to the systemic capillaries, this allows the heart to pump the blood the second time to boost the pressure to create a strong enough gradient to deliver blood. This allows for high pressure in both respiratory (pulmocutaneous) and systemic circuit. -However, there is a problem with amphibian hearts, the right atrium which contains deoxygenated blood and the left atrium that contains oxygenated blood, empty into a single ventricle. This ventricle mixes oxy and deoxy blood so the blood going out to the body isn`t as high in oxygen content as it could be. There are ridges in the ventricle wall however to try and separate these two kinds of blood. Reptiles: -Reptiles have a partially divided ventricle (some even have a fully divided ventricle). By having this, it minimizes the mixing of oxygen rich and oxygen poor blood and it separates the pulmonary circulation from the systemic body circulation.
-They have a unique feature which is special to them; they have a right systemic aorta. This is a blood vessel that leads directly from the right ventricle to the systemic circulation. This allows reptiles to deliver right sided partially deoxygenated blood to the systemic circulation. Happens when the reptile is not breathing (eg. Aquatic reptiles) When they don`t breathe, their pressure in the lung builds up to the point where blood can no longer be forced into the lung and under those conditions blood flows to the right systemic aorta. Birds and Mammals: In birds and mammals, the right and left halves of the ventricles are fully divided-no mixing of oxygenated and deoxygenated blood. This allows for a very efficient high metabolic rate so birds and mammals have enough body heat to support an endothermic way of life. Human heart: -Systemic veins are the anterior and posterior vena cava`s collect deoxygenated blood (from the systemic circulation) and bring it into the right atrium. -From there, the blood passes through one of the four one way valves in the heart-right atrial ventricular valve (tricuspid valve). Blood can flow in one direction because of the valves; they don`t allow the backflow of blood. -From the right atrium to the right ventricle, blood then flows to the pulmonary artery to the lungs. This carries deoxygenated blood to the lungs. Blood returning from the lungs is now oxygenated and enters the pulmonary vein and returns the left side of the heart (left atrium). -Blood then flows through the left atrial ventricular valve known as the bicuspid valve to the left ventricle. Left ventricle pumps blood out into the systemic arteries (in this case the aorta). -Walls of the left ventricle are thicker than the walls of the right ventricle because there are more blood vessels in the systemic circulation than the pulmonary circulation- the systemic circulation has a higher resistance to blood flow and so the left side of the heart has to be more muscular to generate a higher pressure to drive the blood through this higher resistant blood flow. Cardiac Cycle: This is the mechanical and electrical events associated with the heart beat. The heart alternates between two states- 1) Diastole (relaxation) and 2) Systole (contraction). The heart goes through this cycle 75 beats per minute. Phase 1: -Atrium and Ventricle are in diastole. Both of the atrial ventricular valves are open. All 4 chambers of the heart are passively filling with blood because the pressure in the veins returning blood to the heart is higher than the pressure in the atria or ventricles, so blood flows forward. -Both semi lunar valves are closed because in the previous contraction of the ventricles, the pressure in the pulmonary artery and aorta were boosted up to a high level so this energy was stored in the expanded wall of the arteries. This is important because this
higher pressure is greater than pressure in ventricles which keeps the semi lunar valves closed so there is no backflow of deoxygenated blood. Phase 2: -Atrium is contracted (atria systole) and ventricles are relaxed (ventricular diastole). When this happens, a pressure gradient is created which drives more blood into the ventricles. -Semi lunar valves are still closed. Phase 3: -Ventricular systole and atria diastole. The pressure builds up rapidly, so the AV valves close preventing backflow. -Semi lunar valves are now open and blood will be ejected into the arteries. The opening and closing of the valves makes the heart beat noises. In this phase, the blood is emptied into the arteries. -Following phase 3, the ventricles relax and the atria are still in diastole, then we re enter phase 1, and the cycle begins again. -An important parameter describing the performance of the heart is the cardiac output. This is a measure of the amount of blood pumped per minute out of the left ventricle into the systemic circulation. It is equal to the heart rate times the stroke volume. -So: Cardiac Output = Heart Rate (BPM) * Stroke Volume. The range is ~530 L/min. -Typical heart rate for a resting adult is 75 beats per minutes and the stroke volume is 70 ml of blood per contraction. These multiplied together equals 5 L per minute as the resting cardiac output. -Total amount of blood in the human body averages 5 L, we can see that one side of the heart pumps this out in 1 minute-extraordinary amount of work that the heart is producing. Also, the capacity of the heart to increase cardiac output due to the demands of exercise is amazing. Electrical Activity in the Heart: -In order for the heart to pump efficiently, the contractions have to occur in a precisely timed sequence. -The events that trigger the contraction of the heart is called the action potential. For now, we can think of the action potential as an electrical signal that is generated by the heart, spreads through the heart muscle and as it spreads, triggers contractions. The action potential spreads from cell to cell via gap junctions which act as electrical connections between adjacent cells. -Excitation that occurs in the vertebrate hearts is myogenic- this means that the electrical activity originates within the heart muscle itself (beating is intrinsic in the heart). The opposite situation to a myogenic heart is a neurogenic heart which many invertebrates have. This is where the excitation (action potential) comes from nerve cells that impose their activity on the heart muscle. -The heart generates action potential at different rates. They are connected by gap junction to allow the action potential to spread from cell to cell, this was lead us to the conclusion that whichever part generates action potentials at the highest frequency is
going to entrain the rest of the heart- dictate the rhythm that the entire heart will beat. Such a region is known as the pacemaker`. -In the human heart, the pacemaker is an area of modified heart tissue called the SA node (Sino atria- This is because it is at the place where the large arteries come in and the atrium.) -The events of how electrical activity spreads through the heart are: Step 1: -Once the action potential starts at the SA node, it spreads across both atria (because the atria muscle cells are connected by gap junctions). This triggers contraction of the atriasystole. -The action potential doesn`t spread directly into the ventricular muscle because there is a layer of insulating tissue between the atria and ventricles which does not have gap junctions. Step 2: Instead the action potential from the SA node spreads from the right atrium and excites another patch of pacemaker tissue called the AV node (Atria ventricular node). Step 3: -Extending from the AV node are specialized modified muscle fibers that don`t contract but do conduct action potential called purkinje fibers in a structure known as the Bundle of His. -This carries the excitation down the septum (the partition between right and left ventricles) down to the bottom/ apex of the heart. Step 4: -From there the purkinje fibers distribute the action potential to the ventricles and ventricular systole occurs. -Something interesting is that the atria contracts from the top down, and the ventricle contract from the bottom to the top which is most efficient for the expulsion of blood because that is the direction that blood flows. -These ways of electrical activity passing through the heart muscle spread not just through the heart but also through the whole body. -One can record these ways of activity by putting electrodes on the body. Such recordings are known as ECG` or electro cardiogram. -The normal synchronized electrical activity of the heart is called a sinus rhythm` because it is rhythm set by the SA node. -Characteristic features of an ECG are the waves- p waves at the beginning of the cycle, the qrs complex and the t waves. These waves correspond with the events in the electrical activity of the heart. The p wave corresponds to the spread of the excitation across the atria. -Fibrillation is a pathological condition that is characterized by uncoordinated contraction of the heart. There are two types of fibrillation- atria and ventricular. Atria fibrillation is a chronic condition (can be lived with). There are no p waves and irregular R-R intervals because the pacemaker activity is disrupted. Ventricular fibrillation is a life threatening emergency. It appears on the ECG as random disorganized activity. No pumping of blood is occurring, and unless this correction happens in a few minutes death is likely to occur. The treatment for V-Fib is defibrillation which involves passing a large electrical shock
to the entire heart/chest-this depolarization will after a pause allow the SA node to reassert itself as the pacemaker restoring a normal sinus rhythm. -Although beating of the heart is intrinsic, there are extrinsic controls of the rate of heart beating. The most important control of the intrinsic beating of the heart is the nerves. There are 2 types of nerves in the autonomic nervous system- Sympathetic and Parasympathetic. They have antagonistic effects. -Sympathetic activity releases the neurotransmitter norepinerphrine` into the heart which increases the heart rate (tachycardia). Parasympathetic releases acetycholine which decreases the heart rate (bradycardia). -Hormones can also affect the heart beat- Epinephrine released from the medulla of the adrenal gland can lead to tachycardia. -There are other external factors that can increase the heart rate such as temperature and exercise.
Blood Vessels
The general field is that of hydraulics. Fluids flow down pressure gradients from an area of higher pressure to an area of lower pressure. As a consequence of this, pressure continually falls in the direction of flow. Blood pressure falls continually along the length of vessels. As one goes from arteries to arterioles to capillaries to venules to veins and then finally to the heart the pressure in the blood vessels is continually falling. The rate of flow is proportional to the pressure gradient. Pressure can change without a change in volume. (Imagine squeezing a water balloon-pressure increases, but volume stays the same.) The relation to the vascular system is the muscles in the smooth muscle cells in the walls of blood vessels act the same as the hand on the balloon. When they contract, they squeeze the blood increasing the pressure. Flow rate is inversely proportional to the total cross section area. Flow is faster in an area where the cross sectional area is the smallest and vice versa. This is because the volume of water/fluid moving through the pipe/vessel has to be a constant all along the length of the pipe. Conclusion is in places in the vascular system where total CSA is the largest; the flow of blood is the slowest (capillary beds). This is important; because all the exchanges occur in the capillaries- a slow blood flow facilitates this exchange of materials. Relationship between blood pressure, velocity of blood flow and CSA: -Study yourself. Structure and Function of blood vessels: Lumen: -Refers to the hollow interior of a tubular organ through which something flows. Many organs are hollow and something flows through it.
-All blood vessels have in common the fact that the Lumina are lined with a single layer of very thin endothelial cells. This applies to all the blood vessels and to all the chambers of the heart, so blood is always in contact with endothelial cells. For example, the wall of the capillary which is the smallest blood vessel contains of nothing but a layer of endothelial cells and a basement membrane. -Other 4 types of blood vessels have several layers to their structure outside the endothelial cells: The first layer outside the endothelial cell is the smooth muscle- this is important because by contracting and not contracting, it can regulate the flow and pressure of the blood. The outer most layer is a layer of connective tissue that provides which provides strength and various degrees of elasticity. Arteries: -Walls of arteries are highly elastic and thick, such that they are distended by the pressure created by ventricular systole. -One can easily feel this distention as the pulse (radial and carotid). The energy of ventricular systole is stretching the elastic wall of the artery. -Some of the pressure of ventricular contraction is stored in the distention of the arteries. This storage of this energy is important because it allows the energy to be released slowly during diastole- smoothing out the pressure pulses. Arterioles: -These can direct blood from one tissue to another. They play an important role in regulating blood pressure by the means of contraction of their smooth muscle. -Vasoconstriction is the term applied when the smooth muscle and blood vessels constrict. This narrows the diameter of the lumen, increases resistance to blood flow and increases the pressure. -Vasodilatation occurs when the smooth muscle relaxes and this allows the blood pressure to inflate the vessel which increases the diameter of the lumen and reduces the resistance to blood flow. -State of contraction of the smooth muscles of the arterioles is under a good deal of regulation, some of it is extrinsic due to activity in autonomic nerves, and some of it is intrinsic or local in that various chemicals (such as oxygen) can affect the state of arteriolar constriction or dilation. Capillaries: -These are the smallest and the most numerous blood vessels. All the exchange of materials occurs through the very thin wall of the capillary endothelium. -Capillaries are leaky- adjacent endothelial cells do not quite meet each other, so there are gaps between these cells. -They also may be perforated by pores that go from the lumen of the blood vessel to the outside. These pores are filled with an extra cellular matrix of proteins that act as filterholds back large molecules like proteins, but allow small molecules like water and ions pass through. -Fluid leaks through the capillaries through these gaps- fluid is driven by the pressure gradient. In addition to this passive transport by the leakage, endothelial cells can also
actively transport material from one side to the other. Endothelial cells are also known to secrete many locally acting hormones. -Precapillary sphincters: At the places where the arterioles feed into capillary beds, there are bands of muscles called precapillary sphincters. Blood can go one of two ways: 1) If the sphincter is relaxed, then the blood will flow into the capillaries and the blood will be profused through the channel or 2) If the sphincter is contracted, then the blood will not go through the capillary bed, but will instead be redirected through this bypass or thoroughfare channel that shunts blood directly from the arteriole to the venule. Eg. Constriction and dilation due to temperature. Blood flow can also be increased to an injured area. Venules/Veins: -The walls of the veins are much thinner and are much more flexible than arteries. Their purpose is not to store the energy of the pressure pulse. -This has several consequences: Allows blood to be stored in veins and it is difficult to return blood to the heart-takes considerable pressure to deliver blood from the body to the heart. The method used to fix this is auxiliary pumps. -Veins run in between skeletal muscles and contain 1 way valves. When the muscle contracts, they squeeze on the veins, this pushes the blood (in one direction) which assists in the flow of blood to the heart. -Another pump is the respiratory pump. The large veins (vena cava) run in the posterior wall of the abdomen and thoracic cavity. During inhalation, the diaphragm muscle contracts causing it to move downwards. This compresses the organs in the abdominal cavity resulting in a higher hydraulic pressure. And the expansion of thoracic cavity causes a lowering in the pressure in the organs in the thoracic cavity. The increase in pressure in the large veins in the posterior abdomen during inhalation and the decrease in pressure in the same veins in the atria of the heart when one inhales-this creates a pressure gradient which assists blood flow to the heart. Capillary Function: -Fluid movements across the walls of the capillaries. Blood flows from the arterioles on the left to the venules on the right- it`s surrounded by a sea of interstitial fluids. -Blood pressure falls continually as it moves through the vascular system. Capillaries have high blood pressure at the upstream end and low at the venule end. Capillaries are also leaky due to the falling blood pressure. -There are also changes in the osmotic pressure as it flows down the capillaries. This is because, the fluid leaking out of the capillariesf are filtered- proteins don`t leave but water and ions do. Capillaries are picking up material as it goes through the tissues (CO2, waste products, urea, lactic acid). These solutes increase the osmotic pressure of the blood. -Osmotic pressure at the end is higher than the left side as it picks up the materials as it moves from left to right. Osmosis is a force that drives fluid into the capillaries. So, the inward movement of fluid is greatest in the downstream end and less in the upstream end. -At any location during the capillary, the net movement of fluid is going to be the difference between the outwardly directed blood pressure and the movement due to the
inwardly directed osmotic pressure. At the upstream end, the net movement is outward and in the downstream end, the net movement is outward. Fluid leaks out through the upstream end and returns into the capillaries in the downstream end. -Although most of the fluid that is leaked out is reabsorbed, some of the fluid doesn`t get reabsorbed and is called lymph (this remains in the tissues). This is drained out of the fluid by lymph capillaries and the lymph veins which form the lymph system- eventually goes back to the vena cava. Lymph nodes filter the cells.
Blood
-Blood is a fluid connective tissue. It consists of 2 parts: plasma (which comprises of 55% of the volume) and various cells (comprised of 45% of volume). -Centrifuging the blood would show that the 45% volume of cells would be at the bottom of the test tube. Plasma: -Plasma consists of water mostly, has various ions (most abundant ions are Na and Cl, but K, Ca, Mg and bicarbonates are also present.) Also contains many protein molecules, nutrients, waste products, respiratory gases and many different hormones. -All of these materials in the plasma have the same concentration as the concentration in the surrounding fluid except for proteins (because capillary leakage filter proteins). This similarity reflects the fact that these 2 fluid compartments (the plasma and the extra cellular fluid) are in equilibrium with each other. Regulation of the composition of plasma is extremely important in regulating the composition of extra cellular fluid. -These solutes contained in plasma contribute to the osmolarity of the plasma, which in turns affects the osmolarity of the extra cellular fluid. -The concentration of H ions in blood is very important. The normal pH of the blood is about 7.4. Even slight deviations of this normal pH level of the plasma will cause seriously illness or even death. To guard against changes in the pH of the blood, there are several redundant systems that maintain homeostasis of the blood pH. The first defense is the sodium bicarbonate buffer. -There are many different proteins in the blood. The most abundant protein is albumin. This contributes to the osmolarity of the plasma, acts as a buffer and can transport lipids. There are also specific transport proteins for lipophillic molecules. -Serum is plasma from which the clotting proteins are removed. -Immunoglobulin are the antibodies of the body`s defense system. Cells: -The most abundant of the cells are the erythrocytes or the red blood cells. There are 5-6 million per microliter of blood. The erythrocytes function in the transport of respiratory gases (especially O2 and sometimes CO2). -Erythrocytes are packed with a large number of molecules of an iron containing protein called hemoglobin. This can reversibly bind oxygen (250 million of hemoglobin in each blood cell). Each hemoglobin can carry 4 oxygen molecules. -The other class of blood cells is the leukocytes or the white blood cells. There are 7 different types of leukocytes.
-They are the basophils, eosinophills, neutrophils, monocytes which mature into macrophages and 2 types of lymphocytes- T cells and B cells. These function and cooperate against infections. -Last cellular element in the blood is platelets. These aren`t cells, but are fragments of cells that break off of large cells called megakaryocytes (that live in the bone marrow). Platelets function in blood clotting. -There are stem cells that live in the bone marrow and give rise to the mature blood cells. This is necessary throughout life because these white and red blood cells need to be replaced continually. Red blood cells live three or 4 months before they are destroyed. -Mechanism for regulating the production of red blood cells is a hormone secreted by the kidney called EPO (erythropoietin). These hormones are secreted when a low concentration of oxygen is detected. When the kidney secretes EPO, EPO stimulates myeloid stem cells to produce more red blood cells which boost oxygen carrying capacity of the blood-negative feedback. Blood Clotting: -When blood vessels are damaged, hemorrhage (bleeding) occurs. This bleeding occurs for a limited period of time. If the damage is not too severe, then hemostasis occurs because the blood contains within itself a self-sealing mechanism that limits the amount of leakage. -Blood clotting is a very complex process. -The first step is the damage of blood vessels where the endothelium of the vessel is damaged exposing connective tissues. This makes platelets exposed to collagen fibers in the extra cellular matrix in the tissue outside the endothelium. When platelets contact collagen fibers, they adhere to them and become sticky. The platelets secrete clotting factors which cause nearby platelets to react and also become sticky. -Other clotting factors come from damaged cells and plasma (factors include calcium and vitamin K). What they do, is they stimulate the conversion of an inactive enzyme in the plasma called prothrombin to its active form thrombin. Thrombin is an enzyme and it catalyzes the conversion of another inactive plasma protein called fibrinogen to its active form- fibrin. -The platelet forms a temporary plug to seal the vessel. When fibrin is formed, it polymerizes into long sticky fibers that adhere to each other and the walls of the vessel. They form a mesh that traps blood cells and platelets and forms a solid plug. Fibrin also contract and shorten to tighten up the mesh work and to pull the ends of the damaged vessel together, further sealing the leak. -There are many defects that can affect these mechanisms which can cause diseases. Any type of mutation that affects clotting factors will cause the disease hemophilia that`s characterized by excessive bleeding. -Another pathological condition occurs when blood clots at the wrong time and place. If a blood clot forms spontaneously in the absence of a damaged blood vessel, this clot is called a thrombis. They are dangerous because they break loose from the point where they are formed, go through the circulation and get stuck in the narrowing arteries and arterioles cutting off blood flow in certain places in the body. In the case of the coronary
or cerebral artery, it damages the heart muscle or the brain causing a heart attack or a stroke.
RESPIRATORY SYSTEM
Introduction: -At the cellular level, gas molecules move by diffusion down concentration gradients. -Air is a mixture of gases- consists mainly of nitrogen (78%), oxygen (21%), CO2 (1-3%) and variable levels of water vapor. -Air has mass, and gravity acting on the air causes air to have weight and this weight, presses down on all surfaces with a force that generates a pressure. This pressure generated by air at sea level is a well defined quantity known as 760 mm Hg/ 1 atm. This is under standard conditions. -Physiologists express the concentration of gases in units of partial pressures. This is the total pressure of the air mixture multiplied by the total fraction of that gas. -All respiratory organs have several things in common: 1) Wet surfaces. This is because all living things need water to maintain the integrity of the membrane. If all living cells have to be kept wet, this means gas molecules either entering cells or leaving cells are going diffuse as single molecules in solution 2) Respiratory organs have a very large surface area and are covered by a thin layer of epithelial cells. This large surface area allows the organ to have a high rate of diffusion of respiratory gases and therefore support a high level of metabolism. Also, this distance that diffusion occurs has to be very short (thin epithelium). 3) Blood is brought very close to the respiratory surface to pick up oxygen or drop off CO2. This means the wall of capillaries have to be very thin. In the lung, capillary endothelium cells have a thickness of 1/10 of a microliter. 4) The ability of the blood to transport respiratory gases is often enhanced by having respiratory pigments-protein molecules that are colored that enhance the ability of the blood to carry respiratory gases (especially oxygen). Insect Trachea -Only insects have a tracheal system out of the invertebrates. -The tracheal system is a series of air filled tubes that branch throughout the insect`s body. -The holes through which these tubes open have valves on them which they can open or close-spiracles. The tracheal system has bellows like arrangement- this assists in pumping of air in and out of the trachea. -As you go further into the body, the trachea branches into tracheoles that are filled with fluid. Its in this fluid the oxygen and carbon dioxide are dissolved and exchanged with the cells of the body. -Every cell in the insects body are very close to a tracheole.
Gills of Fish -Fish are aquatic so the fluid the flows over their respiratory surface is not air, but water. -Gases that they need to exchange are dissolved in the water. Water is a much more viscous medium than air is and contains less oxygen. -The gill of the fish develops as an out pocketing of an embryo in the pharynx. -Fish actually pump water through the gills by opening and closing the mouth/operculum. Its pumped out through the gills. -The gill consists of many filaments. These are covered with many lamella (rib like protrusions), and its in this that blood flows. Within each lamella, there is a bed of capillaries that carry blood from the oxygen poor gill arteries to the left to pick up oxygen. This then leaves the venules to go back to the systemic circulation. -Exchange of gases occurs between these capillaries in the lamella and the surrounding water. -The direction of the flow of blood and water is opposite. This forms a counter current exchanger. This makes possible the very efficient extraction of oxygen from the water. Because the water and blood is flowing in opposite directions, at every point there is a concentration gradient. To get oxygen to move from the water to the blood there needs to be a concentration gradient. So, due to this system blood leaves the gill almost a 100% saturated with oxygen. Human Lung -In embryonic development, the lung also develops as an out pocketing of the pharynx, but the lung is an internal organ. The lung lies with the thoracic or plural cavity. -Terminal bronchiole is the smallest of the bronchi that branch through the lungs. Each terminal bronchiole ends in several grape like clusters of air sacs called alveoli (plural). -Each alveolus is surrounded by a dense mesh of capillaries. The epithelial cells that line the alveoli are very thin to make the exchange of gases efficient. -There is a problem caused by the fact that the alveoli are very thin and flimsy and they`re inner lining is wet. Water has surface tension so assumes the smallest volume possible. This effect creates a strong force making the lungs want to collapse. To counter this effect, the epithelial cells include in their secreted watery mucous a surfactant (a detergent like molecule that lowers the surface tension of water). This makes it possible for the alveoli to remain inflated with air and for gaseous exchange to occur. -The lungs thoracic cavity is separated from the abdominal cavity below by a dome shaped muscle called the diaphragm. When this muscle contracts, it`s shape gets more concave. Other muscles called intercostals muscle expands when it contracts pushing the ribcage up and out and this increases the volume of thoracic cavity. Inhalation -Is actively taking air into the lungs. -Occurs because of downward movement of the diaphragm and also by contraction of one of the sets of rib muscles to expand the ribs up and out. -The outside of the lung is not physically attached to the inner lining of the thoracic cavity, but its attached by the space between the outer lining of the lung and the inner
lining of the thoracic cavity having a slight negative pressure. Due to the negative pressure of this space, this keeps the outside of the lung closely applied to the inside of the chest wall. This allows the lung volume to follow changes in the thoracic cavity. -So during inhalation, when the diaphragm muscle moves down and the intercostals muscles move the rib up and out, the volume of the thoracic cavity expands and so does the volume of the lung. -This increase in the volume of the lung creates a slight negative pressure in side the lung which is less than the surrounding atmospheric pressure. So, this higher atmospheric pressure pushes air into the lung and you have inhalation. Exhalation -This is the opposite process of inhalation-it is passively expelling air out of the lungs. -The lung is elastic, which means it has a natural tendency to want to shrink. This is due to 2 factors: 1) Residual surface tension that is left in the alveolar mucus. 2) There are elastic fibers in the tissues between the alveoli that are stretched during inhalation, and want to coil during exhalation. -Exhalation is due to the relaxation of the inspiratory muscles (diaphragm and intercostals muscles) so there is a natural tendency of the lung to shrink takes over. The thoracic cavity also shrinks, the ribs move down and in, the diaphragm moves up. The compression of the lung creates a slight positive pressure which exceeds the ambient surrounding pressure, pushing air out of the lungs -During active breathing (exercise), there is another set of intercostals muscles that contract to pull the ribs down and in. -This fact that the lung`s natural elasticity is necessary for normal ventilation is important because of certain diseases in which this is disrupted. -These two are 1) Emphysema. This is a progressive lung disease caused by smoking. In this disease, the alveoli of the lungs are destroyed. Instead of the lungs consisting of pink and frothy bubbles of alveoli, it`s nothing but black empty spaces. These large spaces are ineffective in taking up oxygen or removing CO2 from the blood. Because of the destruction of alveoli, there is a loss of surface tension and a loss of elastic fibers. Exhalation can not be passive but only active, because there`s not enough force to allow this person to exhale normally. As a result, the lungs are chronically hyper inflated. The diaphragm is depressed (too low). There is also an air space behind the sternum. 2) Pneumothorax. This can happen in patients with emphysema or people that have had traumatic injuries to the chest. For example, if there`s a puncture wound air will be driven into the space, obliterating the negative pressure. Without this pressure, the lung will no longer adhere to the inside of the chest wall and lung will collapse. This disease, doesn`t allow the person to inspire. The treatment for this is to seal the holes in the chest wall, and to insert a tube to suck the air out of the space and to recreate the negative pressure making the lung reinflate.
Regulation of Breathing -The chemical cues that the respiratory system uses to regulate breathing are the levels of PCO2 and the levels of Hydrogen ions measured as pH. -Oxygen isn`t used as cue because there is a surplus of oxygen in the blood, so it isn`t a sensitive indicator of metabolism or the need for respiration. -On the other hand, CO2 is a direct product of metabolism, and so therefore the more CO2 there is, the higher the need for respiration to get rid of the CO2 and pick up oxygen. -The regulation of breathing are controlled by a group of neuro cells in the brain cells (medulla) called the respiratory center. This receives input from various sensors that measure the need for respiration. The outputs of respiratory center go to the muscles involved in respiration. -The main input the respiratory center is getting is the level of PCO2 and pH in the blood. Relationship between these two is in the reaction where: CO2 + H2O H2CO3 H + HCO3This combination is assisted by the enzyme called carbonic anhydrase. This causes the pH to fall. When stimulated by a rise in PCO2 or a drop in pH, the respiratory center responds by bringing about an increase in respiratory rate or the depth of breathing which causes a negative feedback to counteract the drop in CO2 and pH. It`s also going to counteract a drop in O2. -The neuro regulation of breathing are more complicated than this. There is a sensor for PO2 in arteries and send this information into the brain stem. However, during normal quiet breathing CO2 and pH is the main sensor. -The brain doesn`t respond passively to a change in O2 or CO2 or pH, but responds information from the other part of the brain that knows what the body is doing- like exercising for example. This information makes it possible for the respiratory center to begin deeper and more rapid breathing. Nervous system can anticipate changes and predict them before they occur. Transport of O2 and CO2 -Gases only move by diffusion into and out of cells via concentration gradients. -The inhaled air has a partial pressure of oxygen of 160mm Hg and the P CO2 is 0.2 mmHg. -Once the air is inhaled and gets into the alveoli, the concentrations are not the same. Concentrations of oxygen in the alveoli air is 104 mm Hg and the concentrations of CO2 is 40. This shows that when you inhale, the incoming fresh air is mixed with stale air that was in the airways from the previous breath and previous exhalation. Air in the alveolus has less oxygen and more CO2. -When we exhale air through our nostrils/mouth the concentration of O2 is back up to 120 because the stale air has mixed with fresh air. CO2 has decreased down to 27. The high concentration of oxygen in exhaled air is the reason why one can do mouth to mouth resuscitation. -Blood entering the alveoli capillaries has an oxygen concentration of 40 and CO2 concentration of O2. This blood has just come from the systemic veins and has been
depleted of oxygen and the blood has picked up CO2 from the systemic tissues. There are concentration gradients in the alveoli and the blood causing the oxygen to diffuse from the alveoli air into the blood surrounding capillaries. In the same way there is a gradient for CO2 to leave the blood and go to the alveoli to be exhaled. -Blood leaving the alveoli capillaries in the pulmonary vein. Gaseous exchange in the lungs is so efficient that blood leaving the capillaries has a PO2 of a 140 mm Hg which is the same with the alveoli air. -Blood enters the tissue capillaries and has the same O2 concentration as in the lung (1oo Hg mm). At the tissues, we have concentrations of O2 of less than 40 and CO2 of greater than 45. This is because of the respiration in mitochondria- this is the place in the body that has the lowest amount of oxygen and the highest amount of CO2. Again, there is a concentration gradient driving CO2 out of the tissue into the -Blood blood. leaving the tissues dropped it`s oxygen and picked up its CO2. The concentration gradients are appropriate for each step that needs gases dropped off or picked up. How does the blood transport oxygen? -Gases are not very soluble in water. There has to be another mechanism to transport oxygen rather than in the plasma. -Blood contains the respiratory pigment hemoglobin, which tremendously increases the carrying capacity of oxygen in the blood. -Each hemoglobin consists of 4 identical subunits that can each bind an oxygen molecule. It is an iron atom that is in the heme structure of hemoglobin. -Hemoglobin O2 dissociation curve: PO2 vs. percent saturation of Hb with O2. The curve is sigmoid (s shaped) so this shows cooperativity in the binding of oxygen with the subunits. At low oxygen levels, when the first subunit of hemoglobin binds an oxygen molecule, this increases the affinity of the second subunit to bind oxygen which then increases the affinity of the 3 subunit and so on. -A high respiratory pigment has to have a high affinity of oxygen in the lungs and a low affinity around tissues so these are two conflicting issues. -At a 100 mm Hg (concentration of oxygen in the alveolar air), hemoglobin is completely saturated with oxygen molecules. As oxygen concentration decreases, hemoglobin gives up its oxygen. At 40 mm Hg, in normal metabolizing tissues, blood only gives up a of the oxygen they are carrying and the rest is kept in storage. -This affinity of hemoglobin for oxygen can be affected by several different factors such as an increase of PCO2 and a decrease in pH. These decrease the affinity of hemoglobin for oxygen. This happens because structure of proteins is strongly affected by changes in pH. This is most likely to happen in actively metabolizing tissues- so as blood passes through the tissues where CO2 levels are higher and more acidic, affinity of oxygen for hemoglobin decreases and dumps its oxygen in the tissues. -Conversely in the lung, CO2 is removed. Removal of CO2 is going to cause a decrease in H ions and a rise in pH. So, blood coming out of the lungs is slightly alkaline. So, just a drop in pH causes less affinity for oxygen, a rise in pH causes increased affinity. -Temperature also affects the structure and function of hemoglobin. In this case, a drop in temperature increases the affinity, and a rise in temperature decreases the affinity. Metabolism produces heat as a waste product, so actively metabolizing tissues are
warmer than the rest of the body. So when blood flows through the blood tissues, since its warmer its affinity for oxygen decreases. There is a drop of temperature in the lung because of the wet surface of the alveoli which increases affinity of oxygen for hemoglobin. -Red blood cells manufacture chemicals that can adjust the affinity for oxygen such as DPG (2,3-diphosphoglycerate). This molecule lowers the affinity of oxygen for hemoglobin for the tissues. -Hemoglobin also transports CO2. 7% of the blood is dissolved in plasma, 23% is bound to amino groups (NH2) on hemoglobin and 70% exists as HCO3 -. Excess H- binds to hemoglobin so it doesn`t affect pH.
Lymphatic System and Innate Immunity
General Functions of Immunity -All organisms have some ability to defend their bodies. This is necessary because for every organism, there is a host of viruses, bacteria, fungi and parasites that are constantly attacking. The cells of our body need to be replaced, and could spontaneously mutate into cancer cells. - When the immune system works... 1) It defends against infection by pathogenic organisms such as viruses, bacteria, fungi 2) It destroys and recycles worn out cells. 3) Identifies and destroys cancer cells. -When it doesn`t work... 1) Allergies: exaggerated immune responses 2) Autoimmune diseases: Where immune system inappropriately attacks cells of your own body. Eg, Type 1 diabetes. 3) Immunodeficiency diseases: Where individuals have ineffective immune systems-become susceptible to wide range of infections. If this is inherited or caused by a developmental defect, it`s called primary. If it is caused by exposure to an infective agent it is called secondary. 4) Limits tissue organ transplants. -There are 2 types of immunity: Innate (non specific) and Acquired (specific). Innate defenses aren`t targeted at any specific agent but work against them all. It is effective before exposure pathogens. Acquired immunity only occurs after exposure to inducing agents called antigens. It is highly specific and involves recognition of antigens by lymphocytes. Lymphatic System -Lymph is the filtered plasma that leaked out of capillaries but is not reabsorbed. Blind ended lymph capillaries (walls made of epithelium), these capillaries convey the lymph to lymphatic veins which drain into lymph nodes. These lymph nodes are scattered across the body.
-The lymph after passing through the lymph nodes, empty into lymphatic ducts. -Functions of the lymphatic system: 1) Drains lymph from tissues. 2) Transports digested lipids from the small intestine into the blood stream. In the intestine, fats are broken down into fatty acids and glycerol. These diffuse into intenstinal epithelium cells and are reassembled into triglycerides and are coated with protein to form a structure called chylomicrons. These diffuse into lymphatic fluid and eventually drain into lacteals. 3) Plays a central role in the immune defense of the body: Primarily responsible for producing, housing and supporting the maturation of lymphocytes (B and T cells responsible for acquired immunity). -Lymphatic organs include adenoid, tonsils, lymphatic ducts, appendix, spleen, lymph nodes, thymus gland. -Red bone marrow across in the proximal ends in the femur and humurus. This houses the stem cells that produce all the red and white blood cells. -Thymus gland is located in the thoracic cavity. T (thymus) lymphocytes migrate in the immature state to the thymus where they mature and distinguish between self and non self. -Lymph Nodes collect lymphatic fluid and are full of B lymphocytes that secrete antibodies. They contain macrophages which attack and consume foreign matter by phagocytosis. -Spleen contains many blood vessels as well as lymphatic tissue, these structure filter the blood and remove foreign particles. This is where worn out red blood cells are recognized and destroyed so their materials can be recycled. -Adenoid defend against inhaled pathogens, tonsils protect pharynx and upper respiratory tract, and peyer`s patches defend through pathogens that enter from the lumen of the small intestine. Overview of Innate Immunity -Refers to those defenses that are inherited, rapid (allow organism to respond immediately), require no activation, no memory or primary exposure and are effective against a broad range of threats- non specific. -Barrier Defenses: The innate barrier defense comes into place where the body comes into contact with the external environment, such as skin, eyes, nasal pharynx, gastrinal intestinal tracts, respiratory tract, urinary and genital tract. Skin is known as a stratified squarrious epithelium. As the cell divides in the outer layer of the skin, they mature and flatten and fill their cytoplasm with a protein called keratin. Outer later called stratum corneum contains a dense layer of keratin filled cells. It is impervious to water loss and micro organisms. The skin also contains oil and sweat gland and these secretions are very acidic (pH 3-5) to kill micro-organisms. Other epithelia covered with mucus. This forms a sticky physical barrier between underlying cells and environment. The mucus traps microorganisms, dust, debris and other foreign particles. In the nasal passages,
trachea and airways of the lung there are ciliated mucous cells which continually move the mucous with the trapped foreign matter toward the mouth so it can be spit out or swallowed. Normal Flora are symbiotic bacteria compete with pathogens to defend our bodies. -Innate cellular defenses: Mainly carried by 6 types of leukocytes. 3 found in the blood- neutrophils, monocytesmacrophages and eosinophils. The 3 that reside in tissue are called dendritic cells, natural killer (NK) cells and mast cells. All of these cells are able to recognize bacteria because they have plasma membrane receptors called pattern recognition receptors`. These bind to proteins on the surface of bacteria and not on the surface of our body cells. The 3 in blood and dendritic cells are macrophages. Macrophage`s digest the bacteria by releasing lysosome`s which contain enzymes also NO, free radicals, ROI`s- These are toxic chemicals to digest bacteria Phagocytic leukocytes in the blood can leave blood vessels and enter blood tissue by squeezing through blood cells. Can ingest 5-20 bacteria in its short life span. Monocytes ingest up to a 100 bacteria Eosinophils attack muticellular parasites by attaching to the side of the parasite and releasing toxic molecules. Dendritic cells also have low phagocytic activity. But, play an important role in presenting antigens to lymphocytes to trigger specific immune responses. NK cells patrol the body and attack virus infected cells and cancer cells. NK cells release chemicals called perforins and granzymes. Perforins assemble into large channels that perforate membrane of the targeted cell and the granzyme is injected through the pores and trigger a poptocis resulting in a death of the cell. Mast cells are involved in inflammation and allergic responses. Chemical Defenses: Many type of chemical defenses in nasal and vaginal secrete mucous and in sweat, saliva and tears all contain an enzyme called lysozyme. Lysozyme attacks the walls of bacteria. Gastrointestianl tract is protected by infection by firstly the very low pH of the stomach. Also, there are strong proteases in the stomach which kill bacteria. Bile salts produced in the liver and secreted into small intestine can kill bacteria. Also, symbiotic bacteria in large intestine are present. Urinary tract protected by acidic urine. Several groups of proteins involved in innate immunity: 1) Cytokines comprise a group of cell signaling molecule. Promote the production and release of neutrophils and macrophages. Attract leukocytes to sites of infection and promotes fever. Fever regulates body temperature and are promoted by pyrogens- so brain recognizes body temperature is too low
and responds by stimulating metabolism and eliminating heat loss. Fever interferes with metabolism and replication of bacteria. Complement is a set of interacting proteins in the plasma-these proteins can bind to antibodies or bind to molecules of foreign cells. When it is bound, a series of reactions is triggered and results in the assembly of a membrane attack complex`-large water filled pore and the targeted cell burst. Interferons are chemical messenger released by virus infected cells. Stimulate near by cells to produce anti viral proteins that inhibit viral replication-limits the spread of virus. Can be mass produced by DNA technology to treat hepatitis and cancer Inflammation -This has been recognized as a medical condition for a long time. Redness and swelling with heat and pain`. -Penetrating injury of the skin introduces pathogenic micro-organisms. One of the first responses is blood clotting. In addition, the damage releases chemical signals such as histamines (from mass cells) and prostaglandins (from activated macrophages). These two cause vasodilation in the affected cells. More blood then flows in the area, facilitates migration of phagocytic cells into the tissue. Phagocytic cells are attracted to the damage by signals called chemokines. All these phagocytes destroy bacteria.
Acquired Immunity
-Although the mechanism of innate immunity can protect against many threats, pathogenic organisms have involved counter measure (bacteria have changed their cell walls to make them lysozyme resistant). -All viruses and some bacteria penetrated inside of cells, they are then protected from organism`s innate defenses -Job of acquired immunity that provide the main defense against these types of threats. Terminology -The word acquired means that these mechanisms appear only after exposure to antingens. -Acquired immunity is highly specific using lymphocytes: B and T. -Antibodies, BCR (B cell receptors) and TCR bind to epitopes on antigens (a foreign molecule recognized and provokes a response from a lymphocyte). - B cells secrete antibodies which bind to the epitopes (small accessible chemical groups) on the specific antigens. Overview of Acquired Immunity -The process has to be so complicated because it helps ensure effective and safe control.
-To begin with: Antigens engulfed by macrophages and displayed by dendritic cells. Within the dendritic cell, there is a set of proteins continually made and transported to the plasma membrane, they pick up fragments including digested bacteria. So, when these proteins get inserted into the dendritic cell membrane, they are carrying these antigens- process called antigen presentation`. Dendritic cell inform the immune system of antigen invasion. The message goes to a Helper T cell`. These T cells whose receptors are able to bind the antigen become activated, which can then activate the B cells. Antigens can also bind directly to B cell receptors if the B cell binds the antigen directly to its receptor. B Cell Receptor: Pair of heavy chains (anchors protein plasma membrane) and a pair of light chains. There is a constant region (amino acid sequence is quite consistent) and a variable region (a.a sequence very variable). Antigen binding sites is at the two V` sites of the chains. All the B cell receptor has the same structure-produces one type of receptor. The antigen binding specificity of a B cell and the binding specificity of the antibodies is the same. An activated B cells will peliforate to forms 2 types of clones: Plasma cells-secrete antibodies (humural immunity). The secreted antibodies attack the same antigen that activated the B cell in the first place. Some of the daughter cells have become long lived inactive memory cells. They make the system capable of more rapid secondary response. Cytotocic T cells specialize in attacking cells that are infected by viruses, cancer cells and other foreign cells. Almost every cell has proteins transported to the plasma membrane that pick up peptide fragments. So in effect, every cell in the body display these proteins. If the cell is infected by a virus or cancer, the peptide fragments displayed will be abnormal. They call out T cell receptor. These consists of 2 polypeptide chains-alpha and beta linked by a disulfide chain. There is a C region and V region. There is 1 antigen binding site at the tip of the T cell. Unlike B cell, T cell can not directly bind antigens. Activated cytotoxic T cells that are activated by antigens displayed by infected cells give rise 2 clones of cells known as memory cytotoxic T cells (long term immunity) and the active cytotoxic T cells (directly attack infected cells). Memory cells together, protect the individual against secondary response to the same antigen-underlying understanding of vaccinations -Practise of exposing patients to disease was being practiced in the middle ages. -The disease trying to protect against is Smallpox (caused by variola virus). -Exposure to vaccinia triggers an immune response to protect against the virus. Effector Mechanisms -An effector is an agent that brings an effect. -Antibodies can inactivate antigens by several different mechanisms:
-Neutralization and Opsonization. Neutralization refers to the coding of virus particles with antibodies which interferes with their need to bind to and penetrate host cells. Opsonization refers to the coding of bacteria with antibodies. Phagocytes have receptors for the tails of antibodies, so this stimulates phagocytosis. IgG -Agglutination reactions: Due to antibodies have several binding sites, they can clump bacteria/viruses together- which also stimulates phagocytosis. IgM -Precipitation reactions- this is what happens against soluble antigens (dissolved in body fluids). These remove the soluble antigens from solution to prevent interaction with cells. This can then facilitate phagocytosis. -Complement activation: Bound antibodies activate the complement response. Complement refers to a series of more than 30 plasma proteins that can bind to antibodies that have stuck to a foreign cell or bind to a unique molecules on the surface of foreign cells. When complement protein bind to antibodies that are in turn bound to the surface of a foreign cell this triggers a series of protolytic reactions occur. This results in an assembly of a membrane attack complex (MAC). This is a large water filled pore that develops in the membrane of a targeted cell causing the cell to burst. -Cell mediated immunity: This is how cytotoxic lymphocytes kill targeted cells. Mechanism is the same as the NKC- CTL when activated secretes perforins and granzymes (enter perforated cells and activate apoptosis).
Immunoglobulins
Structure and Function: -Antibody molecules: 1) IgG is a monomer and has same form as B cell receptor, except no transmembrane region. There are two identical heavy and light chains, held together by disulfide bridges. Constant and variable regions. Two antigen binding sites. Hinge region: place of angle between two arms/binding sites is flexible and can change. It is the most abundant. 2) IgM is a pentamer of five identical subunits, each similar to an IgG. IgM has ten identical binding sites. Together, IgG and IgM are responsible for humoral immunity. Early in response, cell will secrete IgM (confined to blood plasma, too large). Later they switch to IgG which are small enough to diffuse out of capillaries into tissues. Secreted through breast milk with IgA. 3) IgA is a dimmer, 4 identical binding sites. Most abundant antibody found in epithelial secretions (musuc, saliva, etc). Functions to keep bacteria, etc from attaching to underlying epithelial cells. 4) IgD is a monomer and has a transmembrane region (n ot secreted) but is a receptor on nave B cells (not yet activated but mature). 5) IgE is a monomer with two binding sites, found on surfaces of basophils and mast cells. Role of IgE on basophils is vague but with mast cells, they are involved in allergic reponses. Allergies: -Allergy (hypersensitivity) = exaggerated immune response to usually harmless stimulus. Allergen= antigen that triggers allergic response.
-Two types of allergies: Immediate (within seconds or minutes, due to abnormal B-cell activity) and Delayed (within hours, due to abnormal T-cell activity). -Immediate: B-cell exposed to allergen and activated, differentiate into plasma cells but secrete IgE (not IgG, like normally). Those without allergies only secrete IgE with parasitic worms. IgE don`t circulate in blood but bind to surface of cells. -Mast cells have proteins that can bind IgE`s. IgEs act as receptors that sensitive mast cells to allergen. Antigen binds to IgE receptors and triggers degranulation or the release of pre-formed granules from mast cells which contain histamine and other signaling molecules (cause allergy symptoms). -Anti-histamine drugs block histamine receptors. Histmine can cause bronco-constriction which leads to difficult breathing. Inhalers include albuterol which causes relaxation of smooth muscle in bronchi and dilates airways. Anaphylaxis: -Problems: increased secretion from mucous membranes, bronchoconstriction, vasodilation, increased capillary permeability. Vasodilation leads to drop in blood pressure and increased capillary permeability leads to increased fluid in blood and lower blood pressure. -These can all be fatal due to damage to heart and brain. Most common treatment is epinephrine injection (dilate airways and triggers vasoconstriction and stimulates rapid heart beating), raises blood pressure. Origin of Antibody and Receptor Diversity: -Key to specific immunity is that for any one antigen, there are specific receptors on T and B-cells that can be made to counter effects. -Because immune system cannot anticipate different antigens, they must have varied responses. -Artificial substances also provoke strong immune reactions. 1976--Genes for Ig`s occur in pieces. For each piece, there are several versions. During development of lymphocytes, pieces put together in random compositions to yield complete Ig gene. -Different pieces of DNA code for variable, constant, and joining regions. During DNA recombinases select one V region and one C region and combine them. This kind of DNA recomb. leads to diversity. -Light Chain (LC) has 40 V x 5J x 1C = 200 different LCs -Heavy Chain (HC) has 200 V x 12 D (diversity) x 4J x 1V = 9600 different HCs -Randomly combining 200 LCs x 9600 HCs = 1.9 X10^6 immunoglobulins -Other sourves of variability: Inaccurate recombination of V and J regions code for different peptides. Mutations (somatic) of various sorts also vary. Mutations in these genes are allowed to occur and persist. Each individual acquires capability of making billions of different antibody molecules and lymphocyte receptors.
Cellular Interactions in Acquired Immunity
-Although B-cells can respond to antigens directly, they are not activated unless Helper T cells bind to same antigens, which don`t bind antigens unless they are presented by phagocytic cells.
Clonal Selection: Each T or B cell can make one type of receptor and B cell can only secrete one kind of antibody. 100s of millions of cell types though. During embryonic development, genes for immunoglobulins are permanently rearranged and mutations occur. Clonal Selection Model: Three inactive, nave B-cells each have diff type of B-cell receptor. When a particular antigen is presented, it activates only B-cells with matching B-cell receptor binders. The nave B-cell respond by clonal expansion. It proliferates by mitosis to form large numbers of genetically identical cells (memory and plasma). Antigen Presentation and Lymphocyte Activation: MHC (major histocompatibility complex) genes that code for cell surface glycoproteins. In humans, products are Human Leukocyte Antigens, or in mice, they`re called H-2 proteins. Functions: 1) Enable immune system to recognize self cells because there are several different MHC genes and for each one, the gene is very polymorphic (100 diff alleles for each) and most individuals are heterozygous for the MHC gene. The function protein consists of alpha and beta subunits, combined at random. Final set of MHC proteins is unique. Though to have evolved from immunoglobulin family. 2) They present antigens to lymphocytes. There is a groove in all MHC proteins so pepties can bind. They pick up peptide fragments from cytoplasm and transport so they`re expressed on outside of plasma membrane, and are presented on outer surface of cell. Tells world I`m a self cell and these are my peptide fragments. Tells the immune system that this is a self cell that should be tolerated. By presentin g peptide fragments, tell of its internal state (viral, bacterial, cancerous peptides??). Indicates infection, etc. Classes of MHC proteins Class I: all cells with nuclei: T-cell receptor of cytotoxic T cell binds to molecules presented by Class I. They express CD8 which is necessary for binding. This is used to detect virus infected or cancerous cells. Class II: dendritic cells, macrophages, B-cells: presents fragments of ingested bacterial proteins and only Helper T cells can bind molecules presented by class II. They present CD4, needed for binding. Activation of Humoral Immunity: CD 4 stabilizes T-Cell receptor and antigen. When activated, all binding events are stabilized by CD4, and Helper T cell goes on to activate B cell. B cell clones itself to memory and plasma cells. Plasma cells secrete antibody molecules. B cell must be binding same molecule and Helper T cell. Activation process includes release of cytokines. Activation of Cytotoxic T Cells Target cells presents antigen held by Class I MHC to Cytotoxic T cells. TCR binding to MHC and antigen by CD8 responds by killing targeted cell. Release of perforin and granzymes allows for killing. Two events must occur for CTT to be activated. Second event is simultaneous activation of a helper T cell. Dendritic cell presents antigens to
helper T cell w/ appropriate TCR. Cytokine signals released by activated helper T activate B cells and cytotoxic T cells. Cytotoxic t cells humoral immunity cell-mediated immunity (attack on infected cells). B cells (secretion of antibodies by plasma cells). Prevention of Autoimmunity: Some Autoimmune Diseases Systemic lupus erythematosus : widespread, skin rash, fever, arthritic, lung and kidney disfunction, heart inflammation. Immune system produces antibodies against self proteins. Treatable, no cure. Rheumatoid arthritis: inflammation and damage to joints, cause unknown but infection may lead to mistaken identity, non-specific antibodies are not specific enough. Diabetes mellitus type I: widespread, due to poor regulation of plasma glucose, lack of insulin-secreting pancreatic beta cells. Multiple sclerosis: destruction of myelin sheaths in central nervous system. Numerous neurological problems. Abnormal conduction of nerve impulses, ultimate destruction of axons. Mechanisms of Self-Tolerance: MHC molecules present self-peptides to immature T and B cells: Immature cells tested. In bone marrow, presented with antigens. Vigorous response (would cause autoimmune disease) apoptosis (clonal deletion; negative selection) Weak response apoptosis survival, release from thymus or bone marrow Moderate response- responses suppressed by clonal energy (positive selection) This used to be the only credible mechanism for self-tolerance, but later experiments showed that situation is more complicated. Some cells found that reacted to self-cells, but they were repressed. What about proteins not in thymus or bone marrow? During lymphocyte development, non-thymic tissue specific antigens are expressed in thymus. Current view is that mechanism of self-tolerance don`t stop when embryonic development ends because new lymphocytes are produced throughout life and selfreactive ones must be screened out, new proteins are expressed at different points in life. Process of testing lymphocytes is something that continues throughout life. What is mechanism of clonal anergy (self-reactivity)? Existence of 3rd type of T lymphocyte (suppressor T cell). They leave thymus shortly after birth and help prevent self-reactive t cells. Another mechanism is co-stimulation: CD-28 also expressed on surface of dendritic cells and macrophages. T cells must bind to it to be strongly activated. Activation of T cell: TCR receptor must bind to antigen and MHC, and CD-28 molecule. Most body cells don`t express CD-28 molecule.
Osmoregulation and Excretion
-One of the most important aspects of homeostasis is the regulation of the water content and solute composition in our fluids. Without water in the tissues cells would either swell or shrink due to ions. The cells depend on ion gradients such as Na for the transport of materials across membranes and for the generation of electrical signals in nerves and muscles. -Osmoregulation is the term that describes the regulation of water and solute concentration in body fluids. Metabolism produces toxic waste products that must be removed such as CO2, waste products and acid. Excretion is the term used for the processes animals rid themselves of nitrogen containing wastes and other toxic chemicals. -Fresh water has very low osmolarity while sea water has high osmolarity. Most body fluids contain 240-450 mosm/L. Humans have an osmolarity of around 300. The osmolarity of every animal must be maintained within certain limit, but this does not mean that every animal must osmoregulate. Osmoconformers are some marine animals have their body fluids to be isosmotic with the environment. -However, many marine invertebrates and all vertebrates are osmoregulators that needs to regulate their body fluid osmolarity because its not the same as the surrounding environment. -All fresh water and terrestrial animals must be osmoregulators because the surrounding water/air is so hypo-osmotic to their body fluids. -If an animal has a net loss of water it will shrink, and a net gain of water results in the cell swelling. If the ions are not balanced then over time, the animal will surface lethal changes in its internal ion environment. Problem in fresh water is that it contains too much water and too less ions. Fish adapted to this problem by 1) Drinking very little water to counteract loss of ions from the gills, 2) Spend a lot of energy actively transporting salts into blood via gills, 3) Kidney is very active by actively reabsorbing most of the salt and kidney excretes a large amount of water. -Marine bony fish have the opposite problem; sea water is hyper-osmotic to the body fluids and contains too many ions and too little water. In the gills, there is an unavoidable loss of water by osmosis and a gain of salts across the gills by diffusion. In addition, they ingest water and in it is a heavy dose of salts. They cope with this problem by: 1) Drink a large volume of water to compensate for the loss of water, 2) Gill epithelium engaged in active transport to transport blood out of the gills, 3) Kidney`s secrete salts instead of reabsorbing it, 4) Produce small volume of concentrated urine. -Some fish known as Anadromous fish` live in fresh and marine water. The young is hatched in fresh water, then as they mature they live their life in the ocean. These fish have 2 different ion transport mechanisms: When in fresh water, cells in the gill epithelium Cl are being actively transported and Na is passively transported from the cells to the extra cellular fluid. When in marine water, different genes are turned on and the whole mechanism reverses itself. Cl and Na is pumped out of the extra cellular fluid into the sea water. -Cartilagionous fish (sharks and rays): Body fluids of these fish are isoosmotic with sea water. Na, K and Cl ions in ECF are similar to other vertebrates. They use urea as the form to excrete nitrogenous waste and trimethylamine oxide adds to the osmoregularity
of the body fluids. They have to regulate their internal ion composition by excreting salt via kidneys, feces and rectal gland. Nitrogenous Wastes -When proteins and nucleic acids are metabolized for energy, one of the early steps is removal of nitrogen-which creates nitrogen baring toxic molecules which must be removed. The form in which this waste is removed has big effects on osmoregulation which has an impact on their habitats it can occupy. -Three forms of nitrogenous wastes excreted by animals: 1) Ammonia: When the amino groups are stripped off amino acids they are immediately converted to ammonia. To excrete nitrogen as ammonia carries low energy cost. It is highly soluble in water and is a strong base which makes it toxic to cells and can tolerated in low concentrations. It can substitute for K atoms in transport which can mess up pumps. It can only be tolerated in low concentrations and needs to be diluted with water. The only animals that can tolera 2) Urea 3) Uric Acid
The Kidney
-The excretory system plays a primary role during homeostasis. It has different functions: 1) Regulates amount of water/ionic composition in the body, 2) Maintains osmolarity in the body. 3) Maintains volume of the plasma and since the plasma is in direct equilibrium with the blood, the kidney also maintains volume of the blood and blood pressure. 4) Eliminates nitrogenous toxic waste products from the body like urea or drugs/toxins 5) Secretes 2 hormones: Erythropoctin (stimulates the production of erythrocytes) and Renin which triggers the reabsorption of Na ions. Structure of the Kidney -There are 2 kidneys and they lie in the abdominal cavity. Each is supplied with a large renal artery and vein. -There is a ureter emerging from each kidney connecting it to the bladder. Walls of the bladder are muscular and contain sphincter muscles which regulate flow of urine out of the bladder into the urethra. -There is an outer renal cortex which surrounds the inner kidney medulla which is the deep part of the kidney and is continuous with the renal pelvis and the ureter`s. -The basic functional unit of the kidney is a nephron. There are about a million nephrons in each kidney. A nephron is a hollow tubule and it begins in the upstream end with a cup shaped organ called bowman`s capsule, following this is the proximal tubule and then there is a long Loop of Henle` which dips down into the renal medulla. The next part of the nephron is the distal tubule and this empties into a collecting duct (in the renal medulla). This nephron mentioned above is a juxta-medullary nephron. -A cortical nephron is similar in structure except they don`t have long loops of henle. -Branching of the large renal artery are small arteries and afferent (carrying towards) arteriole and supplies blood to a tuft of capillaries within the Bowman`s capsule called the Glomerulus. Bowman`s capsule is a invaginated blind end of a tubule From the glomerulus the blood is drained in an efferent (carrying away) arteriole. -The efferent arteriole which drains the capillaries is unusual. The efferent arteriole takes the blood from the glomerulus and takes it to another set of capillaries- pertibular capillaries. These capillaries are a network that surrounds the entire nephron and in addition sends long straight loops down into the inner renal medulla. Formation and modification of urine -Overview of excretion: 1) Filtering of plasma such that water, ions and small organic molecules pass into the tubular fluid while proteins and cells do not. 2) Reabsorption (movement of material from the tubular fluid back into the bloodstream-water, ions and glucose. 3) Secretion refers to the selective movement of materials from the peritubular capillaries to the tubular fluid. 4) Excretion is the sum of these three processes. -Pressure gradients required to move fluid. Upstream end of capillaries surrounding the nephron is in the glomerulus and at this end blood pressure is very high because the renal artery is a large artery and the blood is delivered at a high pressure. The osmotic pressure
is relatively low so there is a considerable pressure forcing the fluid to leak out of the capillaries and because the capillary bed is surrounded by Bowman`s capsule, the fluid flows into this capsule. -As the blood moves along this capillary bed, the blood pressure has fallen and the osmotic pressure has risen. At the downstream end, the inwardly directed osmotic pressure is higher than the outwardly directed blood pressure-net movement of fluid into capillary. -Much of the water filtered from the blood, is reabsorbed into the blood without any active transport. However, salts are actively transported back into the blood-this creates an osmotic gradient which furthers pulls more blood back into the blood. -Endothelial cells that make up the capillary wall are leaky and don`t form tight seals. The podocytes in the glomerulus contain finger like processes which interdigitate with each other which form a set of narrow filtration slits-spaces in between the inner processes. Both the pores in the endothelial cells and the filtration slits are filled with an extra cellular matrix material that creates a molecular filter which filter`s the plasma. So, water, ions, small organic molecules pass through these pores and the slits out of the glomerulus into the Bowman`s capsule. However, macromolecules such as proteins and cells are too big to pass through these pores and slits and are retained in the blood. -The presence of proteins in the urine are signs of a serious kidney disease. -The pressure driving the filtration out of the pores and slits is the difference between the outward blood pressure and the inward osmotic pressure (net filtration pressure). -The entire blood volume is filtered 275 times a day. This results in a 180 L of initial filtrate in a 70kg male. The kidney reabsorbs 99% of the water that is filtered. -Osmotic Gradient in the kidney -The yellowness in the diagram represents an osmotic gradient. In the outer cortex, the osmolarity of the extra cellular fluid is around 300 mOsm/L , but as we go deeper into the medulla, the extra cellular fluid becomes more osmotically concentrated due to the presence of salts (NaCl, urea). The deepest part of the inner medulla has an osmolarity about 4 times higher anywhere around the body. -The juxtamedullary is positioned so it has 2 parts: The loop of Henle and the collecting duct traverse into this steep osmotic gradient. The rest of the nephron are up in the cortex. -The kidney can adjust the water permeability of the cells making up the collecting duct depending on physiological conditions. -If the collecting duct is permeable to water, tubular fluid moves down into the more osmotically concentrated inner medulla on its way out to the renal pelvis and ureter. As it moves down, water will diffuse out by osmosis into the more osmotically concentrated surrounding fluid-results with a small amount of osmotically concentrated urine. -If the collecting duct is not permeable to water, then the opposite will happen. Tubular fluid will flow through the collecting duct without the water being reabsorbed- results in a large volume of dilute urine.
Overview of Tubular Function -The fluid filtered into Bowman`s capsule contains desirable components of the plasma that must be returned to the plasma by tubular reabsorption. NaCl and glucose is actively reabsorbed while water and Na is passively reabsorbed. -Active uses ATP against a concentration gradient and passive transport is moving down a concentration gradient. -Epithelial cells that make up the wall of proximal tubule has 2 sides: apical side facing the lumen (that has numerous microvilli) and the side facing the extra cellular fluid is called the basal lateral membrane. Near the apical surface, adjacent epithelial cells are sealed to one another by tight junctions-reduce the leakage of materials between cells. -Movement of material from the lumen to the capillaries have Na, Cl, glucose, amino acids and water reabsorbed. The engine pumping this reabsorption is the Na/K pump which occurs only in the basal lateral membrane. It hydrolyses ATP while pumping Na out of the cell and K into the cell. -Na has to be replaced in the Na/K pump and this Na is coming from across the apical membrane. In the apical membrane, there are sets of Na dependant co transporters. (This is a transport protein that uses the electrochemical gradient to transport other materials across their concentration gradients- Cl, glucose, amino acids). -Extrusion of Na by the Na/K pump drives the inward transport of these important solutes that have to be reabsorbed. As these solutes build up in the cell and leave by a facilitated diffusion transporter-passive across concentration gradient. As the solutes are reabsorbed, it creates an osmotic gradient that favors the movement of water to follow these solutes via aquaporin channels. K has to be released from the apical membrane via a K pump. -The body does need to secrete K in great excess and so it need to reduce K concentration in plasma. -As the solutes are reabsorbed, and the water follows, there is no net change in the osmotic concentration of the tubular fluids because the solutes are moved in proportion. Loop of Henle -The loop of henle has two parts: A descending limb that goes down into the inner medulla and an ascending limb that goes back to the inner cortex. -The function of the Loop of Henle is to create a strong osmotic concentration gradient in the extra cellular fluid. -The mechanism of which this is created depends on regional difference due to different channels and transporters. -The descending limb is permeable to water because they express aquaporins. However, the cells of ascending limb are not permeable to water and tight junctions prevent leakage of water. The tubular fluid as it moves down the descending limb, its progressively moving down more into an environment that is osmotically concentrated. Tubular fluid as it moves down is always hypo-osmotic to the surrounding extracellular fluid. So, water leaves the descending limb by osmosis. This water is carried away by the peritubular capillaries and is reabsorbed.
Regulation of Kidney Function -There are times when the kidney needs to conserve water/salts, and times when the body need to get rid of water/salts depending on your intake. -Antidiuretic hormones -RAA system-Renin angiotensin aldosterone occurs in the distal tubule. -There is a place where the distal tubule lies in the fork between the afferent and efferent arteriole. In this area, there aare specialized cells in the wall of the distal tubule, that form an apparatus known as the juxtaglomerular apparatus (JGA). -The stimulus to this organ is a decrease in blood volume or a decrease in blood pressure to secrete Renin into the blood. Renin is an enzyme that acts as an hormone. It triggers an enzymatic series of conversions of an inactive plasma protein called angiotensinogen into angiotensin 2. -Angiotensin 2 has several effects such as causes constriction of arterioles which raises blood pressure. Due to the constriction of the afferent arteriole, it reduces the blood flow to the glomerular capillaries, so it reduces the amount of water filtered into the tubule and lost in urine. -Angiotensin 2 also acts on the adrenal gland. The outer cortex of the adrenal gland secretes a steroid hormone called aldosterone. This acts on the distal tubules to increase the reabsorption of Na ions and water. -Reabsorption of Na, Cl and water is going to build up blood volume and blood pressure.