Patho Exam PDF

Study Questions Human Stress Response Part 1: The Human Stress Response Asynchronous Lecture 1) What are some ways we can define stress? What are examples of “healthy stressors”? What is the purpose of stress? For humans to survive the...

Study Questions Human Stress Response Part 1: The Human Stress Response Asynchronous Lecture 1) What are some ways we can define stress? What are examples of “healthy stressors”? What is the purpose of stress? For humans to survive they must adapt biologically to their environment Environmental stressors can be overwhelming and detrimental or healthy Healthy stressors include demanding mental and physical activities that enhance mental and physical alertness (exercise, learning, etc.) Stress = state of tension that can lead to disruption or that threatens homeostasis Psychologic phenomenon of stress is closely allied to nervousness, fatigue, and anxiety In general terms, stress has been defined as a feeling of self-doubt about being able to cope with some situation over a period of time Purpose of stress is to trigger adaptation and through that adaptation we get healthier and stronger 2) What were the three observations Selye made in terms of the physical effects of chronic stress in his animals? Physical effects of chronic stress in his animals: o 1) Enlargement of the Adrenal cortex § Release of cortisol à cellular changes including hypertrophy and hyperplasia of the Adrenal cortex due to increase functional demand o 2) Shrinking of the lymphatic organs (thymus, spleen, etc.) § When people are in chronic stress activation, they have impaired immune function o 3) Stomach and duodenal ulcers § When we are in a stress response, blood is not going to the GI tract but instead it is going to the skeletal muscle, heart, lungs, etc. because we are either going to fight or flee 3) What are the basic steps to the human stress response (depicted in Slide 3) “Thinking brain” and “feeling and reacting brain” 1. Stressor (real or perceived) viewed as a negative physiologic, emotional, or cognitive stimuli, “thinking brain” will recognize stressor 2. “Thinking brain” will activate “feeling and reacting brain” 3. “Feeling and reacting brain” will activate the two outputs for the stress response: the Sympathetic Nervous System and the adrenal cortex/the release of cortisol 4. Start to see physical manifestations of active stress response o Cortisol o Increased BP o Increased HR o Pupils dilate o Increased RR o Blood flow gets diverted from GI tract, and into the brain and heart instead 4) What structures in the brain are involved in a human stress response? What are their functions? “Thinking brain” = the prefrontal cortex o Located in the frontal lobe; involved in judgment, insight, motivation, mood, and emotional reactions § Prefrontal cortex recognizes stressors; activates the stress response AND turns off the stress response  § Therapy is about trying to modify the prefrontal cortex to produce healthier stress responses; ex. People with trauma “Feeling and reacting brain” = the limbic system o Hippocampus – critical in learning and short-term memory § Interconnected with emotions § We want to remember things that are good for us (good memory/emotions) and things that are bad for us (bad memory/emotions) o Amygdala – critical to coordinated responses to stress, especially with emotional content § Integrates behavioral reactions involving survival § Conditioned emotional responses § Stimulation of amygdala produces a rage reaction, strong fear (Ex. Snake) o Olfactory bulb § Sense of smell important for stress response; recognize smells/food that is dangerous for us o Hypothalamus – primary output; connects the limbic system to the sympathetic NS and endocrine system § Releases CRH which activates the anterior pituitary hormone to release ACTH, which stimulates the adrenal cortex to release cortisol § Regulates body temperature, appetite, and sexual responses 5) What are the two output systems to the human stress response? Sympathetic nervous system – sympathetic nerves that innervate the organs in our body and release NE onto adrenergic receptors + release of mostly Epi from adrenal medulla Endocrine system – specifically the HPA Axis (Hypothalamic- Pituitary-Adrenal Axis) o Hypothalamus releases CRH to the Anterior Pituitary o Anterior Pituitary releases ACTH to the Adrenal cortex o Adrenal cortex releases cortisol (the stress hormone) 6) What physiological effects do the two output systems generate? Stress response = sympathetic NS = fight or flight Heart o Increased HR o Increased contractility Lungs o Bronchodilation Liver o Produces more glucose – liver breaks down more glycogen and undergoes more gluconeogenesis Immunosuppression Breaks down bone to release more Ca2+ to help with muscle contraction Blood vessels o Vasoconstriction of the liver o Vasodilation of the skeletal muscles and heart Brain – increases mental agility Increased secretions – salivary, sweat Increased insulin secretion – breaks down more fat Mydriasis (pupil dilation) – good for far vision  Less urination – sphincter contraction, detrusor relaxation 7) Explain the general adaptation syndrome. Describes the stages of activation of the stress response 3 Stages: o 1. Alarm stage § First exposed to a new stressor – resistance to stress decreases, cortisol levels increase § Activation of stress response § Overtime body adapts to stress response, move into resistance stage o 2. Resistance stage § Same stimuli but body has adapted § Resistance to stress increases, so cortisol levels decrease § Body able to meet the physical challenge without the need for a stress response § Healthy relationship of stress = moving back and forth between alarm and resistance § Key = have a BREAK from the stressor; adaptation occurs during that period of rest when stress goes away, and we can prepare for the next time we are exposed to the stressor o 3. Exhaustion stage § If stressor is unrelenting, go from alarm to exhaustion stage § Stress becomes maladaptive – develop ulcers, immune system down, emotional lability § Resistance to stress decreases, cortisol levels increase Part 2: Black Americans more prone to health issues because of racism 8) How many black Americans die prematurely every day? Around 200 – a plane full of people every day 9) What has Dr. David Williams’ research found? What is the everyday discrimination scale? Tool created by Dr. David Williams that has been validated to measure the experience of racism daily o More statements you identify with = more racism you experience = poorer health outcomes, regardless of financial status or education level Correlated with life expectancy and likelihood of developing chronic diseases (diabetes, hypertension, heard disease etc.) 10) How did the life expectancy of White vs. Black Yale 1970 graduates differ? What does this illustrate? Black Yale students of his class were 3x more likely to have died by the time graduation came around Life expectancy gap of 20-25 years between African Americans and Caucasians 11) How does Dr. Williams describe the phenomenon of “weathering”? Constant stressor of racism/adversity (interpersonal and structural) causes activation of stress response that results in premature aging overtime 12) How does a person’s address affect their health and their life expectancy? Your address influences if you have access to affordable housing, gyms, hospitals, quality education, healthy food, etc.  Close ties to government redlining o Structural racism prevents AAs to have addresses that allow them to have good health and prosperity Part 3: “Weathering” and the Age Patterns of Allostatic Load Scores Among Black. And Whites in the United States 13) How does Geronimus et al describe the idea of “weathering”? Early health deterioration because of the cumulative impact of repeated experience with social or economic adversity and political marginalization 14) What is Allostasis and Allostatic Load? Allostasis = how our body adapts to the presence of chronic stress to maintain stability (as opposed to homeostasis, which strives to maintain optimal health) Chronic stressor = BP goes up, but body cannot maintain old set point o Instead, body starts to operate under new altered set point (allostasis) – higher, able to maintain, but causes cumulative damage to body Allostatic Load = physiological burden imposed by stress; how far away the new set point is from the old set point (ability for new set point to take on more stress) o Causes weathering! o If allostatic load is very high, you live with much higher level of stress o Disproportionately higher rates of disease in POC = higher allostatic load 15) How is Allostatic Load measured? 2 categories of biomarkers: o 1. Primary mediators § Substances in the body that release in response to stress § Ex. NE, Epi, Cortisol, DHEA-S o 2. The effects that results from the actions of primary mediators § Ex. Elevated systolic and diastolic BP, cholesterol levels, glycated hemoglobin levels, waist-to-hip ratio § Waist-to-hip ratio = comparing someone’s waist measurement to their hip measurement Level of cortisol/stress activation tends to cause fat deposition higher in the center of the body o Someone with high allostatic load = Waist circumference will be close/equal to hip circumference § Change in response to the primary mediators 16) What are the key findings of the study? In all cases, mean scores of allostatic load for African Americans were statistically significantly higher than the mean score for White people African American women had higher allostatic load scores than African American men and White women in every age group o Gap in scores grew with age from 18 to 64 years, and became especially pronounced after age 30 years § Age 45 = 50% Black women had a high score, age 64 = >80% did § Additive effect of racism and sexism o In contrast, white people reached 50% level as they approached 60 years and never reached levels above 60% Findings were independent of financial and education status  o Ex: If you’re a poor Caucasian, you still have a lower allostatic load than a wealthy African American 17) Describe and defend the idea that there may be a “dose response” effect with respect to weathering, based on the findings of this study. A dose-response curve – the more adversity/stress, the more their allostatic load, the more their risk for disease Increased dose (increased stress) = increased response (increased allostatic load + disease risk/poor health outcomes Trauma and Trauma Disorders Trauma = a distressing event that causes an overwhelming amount of stress and exceeds ability to cope or process emotions o Can be a single acute event, ex. Car crash o Or can be a prolonged time, ex. Poverty, childhood neglect, military combat Trauma Disorders – all share similar symptoms of flashbacks, nightmares, and anxiety, and all interfere with their day-to-day activities o PTSD § Directly experienced a traumatic event or witnessed as it happened to others Heard family or friend was involved Prolonged exposure to graphic details § Symptoms (at least one month) Recurrent, involuntary, and intrusive memories of the experience (nightmares or flashbacks) Intense psychological distress or physical reactions (sweat or heart palpitations) Hypervigilance – constantly on guard Hyperarousal – exaggerated startled response Avoiding environments and situations that remind them of their trauma Thinking and mood are negatively affected o World is dangerous, no one can be trusted o Fear, distress, shame o Acute Stress Disorder § Similar to PTSD, but symptoms only last between 3 days to 1 month following the trauma (time frame difference) o Adjustment Disorder § Stress of life-changing event – divorce, losing a job, illness § Emotional symptoms Anxiety, depression, hopelessness, powerless, suicidal ideation § Behavioral symptoms Aggression, rebellious outbursts § Diagnosis: symptoms must develop within 3 months of a known event and disappear within 6 months after event If symptoms last > 6 months, diagnosed as generalized anxiety disorder o All have altered levels and response to stress hormones (adrenaline and cortisol) § Elevated cortisol, elevated NE, Epi (baseline level is high) o Their stress-related hormone response to a stimuli is exaggerated – disproportionately large response Treatment o Psychotherapy  § For milder cases § Strategies to address and cope with negative beliefs, assumptions or emotions o Lifestyle changes § Regular sleep schedule § Healthy diet § Meditation § Deep breathing § Physical activity o Medication § First-line medications (high yield) SSRIs SNRIs § Prazosin (Alpha-1 blocker) – good for preventing nightmares § But there’s no medications for Acute Stress Disorder A Therapist Breaks Down How Our Bodies Carry Racial Trauma Resmaa Menakem “My Grandmother’s Hands” Racial trauma = the idea that the white body is the human standard, black bodies are deviants of that standard o Woven in and around through every institution White supremacy literally lives in our bodies – our DNA, nervous system, etc. o Stress/trauma = release of adrenaline, cortisol, NE – designed to help you flee and get out of danger and only be in your body for short bursts of time o But if the danger sticks around (like 250 years, slavery/oppression), the levels of adrenaline/cortisol/NE accumulate à allostatic load à DNA expression changes o By the time it reaches the modern generation, people have this vibratory sense that something is off § Trauma in a person can look like personality overtime, trauma in a family can look like family traits overtime, trauma in a people can look like culture overtime White people get advantages of this current structure, if they go against it they will lose things – relationships, access, privilege à less likely to change this structure White body supremacy and neuroscience o Vagus nerve helps us notice environmental stimuli/what is dangerous “gut reactions” o We’ve been wired to think that the black body is impervious to pain o Police interactions – when a police officer sees a black body, they “brace” and it’s the activation of the “lizard brain,” the most primitive part of the brain (amygdala) à fight/flight/freeze/fawn § Their brains have been wired to think that the white body is the supreme standard Healing work o Acknowledge that something has happened and continues to happen, not a figment of imagination – you are not defective, the system/structure makes you believe that you’re fraudulent because you don’t measure up to the white body standard o Turn towards each other as opposed to turning on each other o Not sure if it’s possible for the trauma-inducing environment to go away period, but we still have to work towards healing “Nap” Ministry o Black bodies should rest – their whole life they have been taught to override any rest, any sense of themselves o Reclaim themselves in this way  Study Guide Questions Immune System I 1. What are the cells of the immune system and where do they come from? Cells of the immune system come from the pluripotent hematopoietic stem cell found in the red bone marrow o Gives rise to our RBCs (erythrocytes), platelets (cell fragments), WBCs (leukocytes – cells of our immune system) First step is producing the common lymphoid progenitor cell and the common myeloid progenitor cell o Leukemia comes from either the lymphoid line or the myeloid line o Many more cells that come from the myeloid progenitor cell § Majority of RBCs, platelets, and the majority of our leukocytes are myeloid derived Myeloid-derived cells: o Myeloid progenitor cells are giving rise to our megakaryocyte erythrocyte progenitor cell which then create megakaryocytes (cell that fragments and becomes platelets) and erythroblasts (make RBCs) o Granulocyte macrophage progenitor cell is going to give rise to the monocytes that then become macrophages, the unknown precursor of mast cell which then becomes Mast cells, and also gives rise to neutrophils, eosinophils, and basophils o Macrophages are phagocytic cells which can do phagocytosis (cell eats/engulfs either other cells or debris) § Once the cell is engulfed by the macrophage, the vesicle fuses with the cell’s lysosomes and digests it – one of the items it can digest is the cell’s antigen § The macrophage will then present the antigen on its surface, and it will help the macrophage communicate with the adaptive immune system § Critical cells for our inflammatory responses § Located throughout our body and living in tissue – where pathogens may be found and where they can enter our body § When we get a vaccination in our deltoid muscle, that vaccine gets taken up by a macrophage and it presents it to our adaptive immune system in order to activate an immune response § Monocytes are also circulating in our bloodstream ready to become macrophages when we need it  o Mast cells are also important activators of inflammation – live throughout the tissue of our body and they live close to blood vessels because they are packed with inflammatory mediators like histamine § When they dump out their histamine, we get a fast inflammatory response § Basophils are like mast cells, but they are in the bloodstream, and they can also trigger inflammatory responses and they are also packed with histamine § Mast cells live in tissue, Basophils circulate in the bloodstream o Eosinophils are also circulating in the bloodstream and are very good at extracellular killing by releasing this substance that pokes holes in the plasma membrane or the cell wall of bacteria and kill it § Very important for parasitic worm infections § Play a key role in classic allergic responses o Neutrophils are also phagocytic cells § Very potent/strong entry level foot soldier in our immune system § Circulating in our bloodstream – any sign of injury or infection in our body we get an inflammatory response and neutrophils are the first to migrate to an area of infection/injury and when they get there, they are very messy and cause a lot of damage by releasing oxygen reactive species trying to kill bacteria/pathogens and they leak out lysosomal enzymes and end up doing a lot of collateral damage associated with inflammatory responses o Dendritic cells – most comes from the myeloid line but some comes from the lymphoid line; these cells are also phagocytic cells § Peaceful cell who does not go around killing anyone, he is kind of like a “spy” who is there to constantly monitor extracellular fluid for pathogens and to trap antigens § Job is highly specialized for something called antigen presentation – specialized for activating an adaptive immune response by presenting an antigen § Some of the promising immune therapies for cancer are with dendritic cells Ø Ex: Take a sample of prostate cancer tumor (very specialized per person) and harvest some of the dendritic cells and tumor cells and we will incubate these two cells together so the dendritic cells can eat up your tumor cells. Every cancer tumor has tumor specific antigens so then we take those dendritic cells and put them back into your body and the dendritic cells present to your adaptive immune system the tumor specific antigens and then your immune system starts attacking your prostate cancer Lymphoid-derived cells: o B lymphocytes (adaptive immune system) – formed in the bone marrow and fully mature here too; produce antibodies o T lymphocytes (adaptive immune system) – formed in the bone marrow and then migrate to the thymus gland where they fully mature; also get the receptors for specificity o NK cell (innate immune system) – natural killer lymphocytes are critical for fighting intracellular infections, especially viral infections  § Attacks without specificity § First time you are sick with a virus, NK cells are the ones to attack and fight the infection first – cannot completely clear the body of the virus but it can really keep the viral number from getting out of control; buys time until T lymphocytes can get on the scene and can actually clear the viral infection Organization of the Immune System: 2. What events can initiate a local inflammatory response? Two events that are going to a trigger an inflammatory response: o Presence of a pathogen – if the presence of a pathogenic organism is noticed by the immune system it is going to trigger an inflammatory response, main cell to recognize a pathogenic organism is a macrophage o Cell or tissue injury – anything to cause injury to a cell is going to cause that cell to release cytokines to trigger inflammation 3. If a pathogen manages to slip past an epithelial border without damage to tissue, what are the first cells that recognize it initiate an inflammatory response? By what mechanism is the inflammatory response triggered? Tissue macrophages are the first cells to recognize a pathogen and initiate an inflammatory response (recruits Mast cells):  o Does this usually because it notices that there is a pathogen present; activates the macrophage and releases cytokines (IL-1, TNF-alpha, IL-6, IL-8, IL-12) § IL-1 activates Mast cells and also activates the vascular endothelium (the cells that line the blood vessels) and activates local lymphocytes; pro-inflammatory Ø Systemic effects à fever and producing IL-6 § TNF-alpha activates the vascular endothelium and enhances vascular permeability which leads to the entry of antibodies (IgG); pro-inflammatory Ø Systemic effects à fever, mobilization of metabolites, and shock § IL-6 activates lymphocytes and increases antibody production; pro-inflammatory Ø Systemic effects à fever, induces acute-phase protein production § IL-8 has a chemotactic factor (movement of a cell towards a chemical signal) which recruits neutrophils, basophils, and T cells to site of infection § IL-12 activates NK cells, induces the differentiation of CD4 T cells into TH1 cells Activation of mast cells – mechanisms (occurs in 4 ways) o Injury o IL-1 – any injured cell will release IL-1 o IgE-mediated mechanisms § IgE = antibody-mediated mechanism. Plays a big role in allergies (hypersensitive reaction) § Ex: Pollen is presented to a CD-4 T-cell, which will produce an IgE antibody. The IgE antibody will attach itself to mast cells. This is mast cell sensitization as it now has an antigen binding site for pollen. The next time there is pollen in your body, it will attach itself to the IgE antibodies and trigger a response o Activated complement proteins (C3a and C5a) § Mast cells have secretory granules that include histamine, neutrophil chemotaxic factor, and eosinophil chemotaxic factor Ø When a mast cell is activated, it will have an immediate degranulation – especially histamine. Histamine has very powerful vascular effects. The chemotaxic factors draw more leukocytes to the area. Ø Mast cells also undergo synthesis, where they produce the metabolites of arachidonic acid – leukotrienes and prostaglandins o Strong vascular effects o Prostaglandins produce pain 4. What are the vascular and cellular events of acute inflammation and in what sequence do they occur? Pro-inflammatory mediators (e.g., IL-1, IL-6, TNF-a, leukotrienes, prostaglandins, etc.) will trigger vascular and cellular events simultaneously #1 Damaged tissues release histamines, increasing blood flow to the area – vasodilation #2 Histamines cause capillaries to leak, releasing phagocytes and clotting factors into the wound – albumin is the protein leaking out of the blood vessel and it increases the interstitial oncotic pressure, causing edema #3 Phagocytes engulf bacteria, dead cells, and cellular debris – neutrophils are the first responders to migrate to the area of infection, they adhere to the endothelial wall and squeeze out of the blood vessel (transmigration) and begin phagocytizing the bacteria and causing a big mess #4 Platelets move out of the capillary to seal the wounded area – delayed vascular stasis which helps to keep WBCs in the area 5. What role do Mast Cells play in inflammation? Cellular initiators of inflammation Similar to macrophages, Mast cells live in the tissue, and they are present when there is cell/tissue injury or when a pathogen enters, and they are the ones that recognize these events and release the mediators that cause inflammation Mast cells activation is done by the following: o Direct injury to mast cells will activate them o IL-1 is released by other cells in the tissue (e.g., macrophages) to activate mast cells  o Complement system can activate mast cells o IgE antibodies can also activate mast cells (“mast cell sensitization” aka Type 1 hypersensitivity reaction) While macrophages tend to live in the reticular connective tissue, Mast cells tend to live close to the circulatory system and it is usually very close to the blood vessels because what they release (histamines, chemotactic factors) have a big impact on the circulatory system during an inflammatory response Also, long-term, will synthesize and release leukotrienes and prostaglandins to vasodilate and produce pain 6. What part of the immune system is a natural defense against cancerous growth? Two cells of the adaptive immune system – CD8 cells and NK cells o NK cells à kill abnormal cells without any prompting § Kills cells that are non-self o CD8 cells à need priming for killing § Needs antigen presentation for CD8 T cell to be activated 7. What is the complement system and what are the possible pathways by which it can be activated? Complement system = made up of many circulating plasma proteins that activate in a cascade of enzymatic reactions to accomplish three purposes o Very important tool of the innate immune system Purposes: o (1) Promotes inflammation o (2) Directly kill pathogen § Forms a membrane attack complex which is a pore and inserts itself into the cell wall of a bacterial cell – water gets into the bacteria, and it dies o (3) Tag pathogen for later killing (opsonization) Three ways to activate complement system: o (1) Presence of a pathogen – bumps up against a lot of complement proteins in the bloodstream and can activate the complement system o (2) As part of a systemic inflammatory response – acute-phase response o (3) Can be activated by adaptive immunity (antibody-mediated) Activation of the C3 convertase will activate the rest of the complement proteins. There are three pathways for C3 to be activated: o Classical pathway § Bump into pathogen directly: C1 attaches directly to pathogen surface (bump into each other) -leads to activation of C3 § Systemic response: CRP (released by liver) attaches to pathogen surface, makes it more likely for C1 to bind, activates the cascade  § Antibody mediated response: Antibody (IgM) attaches to C1 surface, making it more likely to attach to a pathogen o MB-Lectin pathway § MBL attaches to pathogen surface, which causes C2 to attach, which triggers the cascade o Alternative pathway § C3 convertase spontaneously attaches to pathogen surface, directly triggering the pathway From these three C3 activation pathways, will cause C3 convertase to be activated. Results in: o C3a and C5a: act as pro-inflammatory mediators o C3b: act as opsins for opsonization o Group of complement proteins that when activated, they assemble to form a pore called the membrane-attack complex § Lysis of certain pathogens and cells by punching a hole into the bacterial surface, water rushes in, and destroys the bacteria 8. How does the complement system interact with both innate and acquired immunity? There are antibodies in the acquired immune system that are specialized in activating the complement system to fight specific pathogens 9. The process of inflammation tends to bring about some degree of damage to otherwise healthy local tissue. What cells are responsible for this “collateral damage”? What inflammatory mediators are responsible? Two cells responsible for “collateral damage” à neutrophils and macrophages Mediators that are responsible include the release of reactive oxygen species and the leaking of lysosomal enzymes o These help to fight bacteria, but also can spillover onto healthy tissue and cause damage 10. What cells in the immune system defend against extracellular pathogens? All immune cells can defend against extracellular pathogens, though NK and CD8 are better for intracellular pathogens 11. What cells in the immune system defend against intracellular pathogens? NK cells T lymphocytes o CD8 – CD4 needs to be presented first 12. What are the subtypes of T cells, what surface markers do they express, and what are their respective functions? CD4 “helper T-cells” – Recognize antigens and initiate an adaptive immunity response CD8 “cytotoxic T-cells” – Can seek and destroy, especially cancerous cells 13. What are the relevant metabolites of Arachidonic Acid in relation to acute inflammation and what are their respective functions? Two key metabolites of Arachidonic acid are leukotrienes and prostaglandins o Potent inflammatory mediators o Always produced locally by cells  Leukotrienes à causes vasoconstriction, increased permeability, and chemotaxis of neutrophils; involved in anaphylactic reactions Prostaglandins à causes vasodilation, edema, platelet aggregation, pain; protective roles include increase mucus production in stomach to prevent ulcers Arachidonic acid is derived from the membrane phospholipids via phospholipase o Every cell in the body is able to produce Arachidonic acid Arachidonic acid is converted to prostaglandin via cyclooxygenase o Many prostaglandins are pro-inflammatory causing vasodilation, edema, and some also cause pain Arachidonic acid is converted to leukotrienes via 5-lipoxygenase o Many leukotrienes are pro-inflammatory causing vasodilation, attraction of neutrophils (chemotactic attractants), and also play a role in patients with anaphylaxis All anti-inflammatory medications are targeting these metabolites of arachidonic acid o Two specific kinds: § Steroidal anti-inflammatory drugs (cortisol, cortisone, corticosteroids, etc.) those drugs are blockers of phospholipase, so they block the production of arachidonic acid and ultimately block both leukotrienes and prostaglandins Ø “Big hammer” § NSAIDs (ex: Aspirin, Ibuprofen, Naproxen) inhibit cyclooxygenase blocking prostaglandin production, but they do not block the formation of leukotrienes; good for minimizing pain caused by inflammation Ø “Little hammer” 14. What is the “acute phase response”? What triggers it? What are the two acute phase response proteins that we spoke about in class and are their respective functions? Acute phase response – basically our systemic inflammatory response, “flu-like symptoms” such as fever, body aches, fatigue, brain fog, etc. are all caused by cytokines that are released during acute inflammation o Ultimate goal: conserve energy to fight infection, make the body a less hospitable environment for the infection, and ramp up the immune system to fight the infection o Decreases viral replication, bacterial replication The infection when it started triggered a local inflammatory response, but the pathogen managed to proliferate, the size of the inflammatory response increased All the chemical mediators (especially cytokines), their concentrations became larger and larger  o Cytokines IL-1, IL-6, TNF-alpha elicit a systemic response (affects multiple organs) § Liver à they increase acute phase response proteins MBL (Mannose binding Lectin) and CRP (C-reactive proteins) Ø Their function is to activate the complement system which promotes further inflammation Sepsis is the acute inflammatory response gone haywire. What makes it so damaging is that the infection has spread to the bloodstream. It’s primarily bacteremia o LPS (lipopolysaccharide) – component of the bacterial cell wall, they have an endotoxin that when it enters the bloodstream, it interacts with many components of the immune system and able to trigger huge responses § Interacts with endothelium – lining of the blood vessels Ø Will release tissue factor and the mediator that gets active with vascular injury à pro-coagulant effect, induces lots of blood clotting à microvascular occlusion o Most dangerous coagulopathy = Disseminated Intravascular Coagulation (DIC) à so much activation of the clotting cascade that it consumes all your clotting factors, left with no more clotting factors and it results in hemorrhage Ø Triggers release of cytokines (especially IL-1 and TNF- alpha), causes blood clots, vasodilation, increased permeability à drop in blood pressure à septic shock § Interacts with neutrophils – also releases cytokines § Interacts with monocytes – also releases cytokines § Interacts with liver macrophages – also releases cytokines § Having bacteria in circulation is going to activate the complement system, triggering a ton of inflammation o The immune response is what kills people in sepsis, not the bacterial infection § Vascular effects = drop of blood pressure + coagulopathy à drop in perfusion of organs à septic shock and multiple organ failure 15. Which cytokines are primarily involved in mediating the acute phase response? For each cytokine briefly describe the: target organ/tissue and primary effect(s). IL-1, IL-6, and TNF-alpha Once the concentration of IL-1, IL-6, and TNF-alpha reached a critical concentration in the bloodstream, they are now able to bind to distant receptors o So, they are now binding to receptors throughout the body o Brain (hypothalamus, our thermostat) à that’s how the cytokines trigger fever (a non-specific systemic symptom) o Also trigger “sickness behavior” – feeling fatigue, listlessness, lack of energy § It’s meant to slow you down, make you rest, conserve your energy to fight the infection o Also act on bone marrow to trigger the production of more leukocytes § Elevation of neutrophils and monocytes to help fight the infection § Leukocytosis = increase in WBC production o Also act on fat and muscle to stimulate the mobilization of protein, amino acids, and fat so that your body can increase metabolism (breakdown muscles) so that it can generate a fever o Also act on dendritic cells to migrate to local lymph nodes in case those dendritic cells have caught an antigen and can present it to a CD4 T cell in a lymph node o Also act on the liver to increase the production of acute phase response proteins CRP and MBL § These proteins were involved in increasing the likelihood of activation of the complement system à promotes further inflammation 16. Under what conditions are interferons released? From what cells? What functions do the interferons perform? Viral infections will cause interferons to be released o Double stranded RNA is a telltale sign of a viral infection o When infected host cell detects this, it will release interferon alpha and beta – multiple functions: § Produces enzymes that degrades viral RNA and therefore block viral replication § Increase production of MHCI – they allow for better antigen presentation to the NK cells and CD8 T cells § Activates NK cells Ø Migrate and kill virus-infected cells Ø Release interferon-y which potentiates the effects of interferon alpha & beta Ø NK cells can also be activated by macrophage-derived cytokines – they may already be active before the cells recognize that they’re infected with virus 17. When someone is infected with a strain of virus for the first time, what parts of the immune system fight the infection before a T cell response can be mounted? Interferon and NK cells. They help control, but they can’t clear the virus. Note: that’s why we don’t tend to see elevated neutrophils if it’s a viral infection 18. What are the Major Histocompatibility Complex molecules? Which cells possess class I and II MHCs and what function do these molecules play in immunity? MHC I – on all cells of our body except for RBCs o Proteins that start off inside of cells and they attach randomly to other proteins that the cell is making, and they carry those proteins to the surface of the cell, and they basically display that protein in the air and the immune cells that recognize MHC I are the cytotoxic and NK cells MHC II – on three types of antigen presenting cells: macrophages, dendritic cells, B cells o In addition to having MHC I, they also have MHC II o So, when a macrophage for example phagocytizes a bacteria, it is going to take that bacteria inside itself, digest it, rips off the antigen, attaches it to its MHC II, and then displays that antigen at the surface of its cell § It is a specific CD4 Helper T cell that recognizes the antigen on the MHC II and activates an adaptive immune response and immune memory Ø Elicit the specific cytotoxic T-cells (CD8) to replicate into effector T-cells that go out to seek and destroy infected “self’ cells Ø Elicit the specific B-cells to make copies of itself o Half will be sent out to search for the pathogen (B effector cells will make plasma cells, which then search for the pathogen) o Half will turn into memory cells to be stored for a future response 19. What cells function as the antigen-presenting cells? Macrophages, dendritic cells, and B lymphocytes 20. What is the “generation of clonal diversity” with respect to B and T lymphocytes? When does it occur? How do the central lymphoid organs ensure that no B or T lymphocytes carrying the self-antigen receptor survives? Generation of clonal diversity = large populations of B lymphocytes and T lymphocytes that are exactly alike except for the antigen binding site of their T cell receptors and B cell receptors o Location of the generation of clonal diversity: § B cells à bone marrow § T cells à thymus gland o Those receptors are able to respond to any antigen you may encounter in nature before you even encounter it. The match may not be exact, but it is going to be good enough. You will have a T cell receptor or B cell receptor that is good enough to stick to an antigen on any pathogen in nature  Clonal selection à when the antigen presenting cell (APC) presents a particular antigen to that very particular helper T cell, now that helper T cell can find the specific B cell and the specific T cell Clonal expansion à stimulate those cells to make lots of copies of the right B and T cells in order to fight the current infection and future infections o Random recombination of genes that is going to produce slightly different antigen binding sites § Runs the risk of creating T cell receptor that binds to healthy “self” cells (autoreactive) Clonal deletion à delete any clone that is autoreactive, do not want it to leave the bone marrow or thymus 21. What are “plasma cells” and what role do they play in immunity? Plasma cells are daughter cells of B-cells When B-cells are activated, they replicate and make B effector cells which make plasma cells The plasma cells create antibodies, which then go out to find the pathogen (by searching for the antigen site) 22. Explain a scenario in which a B lymphocyte could act as an antigen presenting cell. If a mature, naïve B-cell is leaving the bone marrow and traveling through the bloodstream to get to its final destination in the lymphatic tissue, it could run into a pathogen, gobble it up, and present an antigen to a CD4 T-cell to activate an adaptive immune response  Study Guide Questions Immune System II 1) What does MHC mean? What are the differences between 1 and 2? a) They are proteins to recognize self vs nonself. It stands for Major Histocompatibility Complex. b) MHC1 are recognized by Cytotoxic T cells and NK cells. i) As RBC have no nucleus, so they have no MHC. ii) Cytotoxic T cells and NK cells recognize the MHC, they judge whether the protein attached to the MHC is harmful or not, and destroy based on: (1) Is the cell normal (2) Is the cell virus infected (a) Cell helps via sending out Interferons (3) Is the cell non-self (4) Is the self abnormal c) MHC2 is an additional protein complex, recognized by CD4 T-cell i) This is carried by Antigen-presenting cells (1) Macrophages (2) Dendritic cells (3) B cells ii) It triggers the adaptive immune response iii) Antigen of the destroyed pathogen is attached to the MHC2 complex, CD4 T-cell does two things (1) Recognizes the MHC2 complex (2) Recognizes the pathogenic antigen 2) How is Helper T cell activated? Once activated, what does it do? a) The APC (macrophage, B-lymphocyte, and dendritic cell) uses the MHC2 complex with the pathogen’s antigen attached, and it goes to find the Helper T-Cell (CD4 T-Cell) b) Helper- T Cell (CD4 T-Cell) will activate B cell and T cell, proliferating both memory and effector for each B-cell and T-cell that is activated 3) What are the necessary steps to have a robust immune response to combat various pathogens? a) There are three main steps that are: generation of clonal diversity, clonal selection, and clonal expansion i) Generation of clonal diversity (1) Occurs in early childhood, where the “library” of both B and T-cells are created (2) There is a production of both T- and B cell with all possible receptors for antigen ii) Clonal selection (1) The individual, specific, B or T cell is selected based on pathogen presence iii) Clonal expansion (1) The selected B or T cell is proliferated to attack 4) Where does clonal diversity occur for the T-cell? What is clonal deletion? a) It starts in the thymus gland (Thymus-cell, T-cell)  b) A pre-T cell has migrated from the bone marrow to the thymus i) It does not have a function b/c it lacks a marker CD4 or CD8 ii) It does not have T-cell receptor so it doesn’t have it specificity for an antigen c) Once it enters the thymus, it receives a marker and then its receptors d) It gains its receptor (specificity) through a random arrangement of genes i) This gives the possibility of creating an antigen that’ll hurt the body, thus, an autoimmune disease ii) To combat this, we have clonal deletion (1) As the T-cell develops in the thymus, we have these cortical epithelial cells and medullary cells that display a variety of self-antigens (2) If that T-cell attaches to it, it means its autoreactive, the T-cell won’t leave the Thymus, and will be deleted (3) This will create self-tolerance and prevent autoimmune diseases 5) Where does clonal diversity occur for the B-cell? What genes determine the diversity of both B-cell and T cell? What is the role of stromal cells in clonal deletion? a) Similar process happens in the Bone marrow b) Random arrangement of cells from the V genes, J genes, and C gene is created c) Stromal cells ensure that there is self-tolerance and prevent autoimmune diseases i) If a B-cell attaches to a stromal cell, it will be deleted 6) What four classes of pathogen do our immune system protect us against? What is special about intracellular bacteria? a) Bacteria, virus, parasites, fungi b) Intracellular bacteria are very crafty b/c it avoids phagocytosis by infecting macrophages i) It resides in macrophages but is destroyed by a specific subtype of CD4 T cell that kills it and kills antigen c) Very few types of bacteria are like this but they include leprosy and TB 7) When are B-lymphocytes an APC? a) Once the B-lymphocyte has left the bone marrow (it’s primary lymphoid tissue), it has received its specificity through clonal diversity b) It will travel to it’s secondary lymphoid tissue to reside there and if, in the rare occasion, it interacts with its specific pathogen c) B Cells will need to find CD4 T cell in order to become fully activated d) Once it finds CD4 T Cell, the T cell will release IL 4,5, and 6 to trigger B-cell clonal expansion i) One set of cells will become memory cells and effector cells (1) Effector cells will continue on to become plasma 8) What is the normal series of activation for CD8 T-cells? What APC is an exception? a) APC ⇒ CD4 ⇒ via IL2⇒ CD8 cell proliferation b) Macrophage needs to activate CD4 first i) CD4, when activated, will release IL2 and activate cell proliferation for that CD8 c) A dendritic cell is an expert APC, it can activate a CD8 (effector T Cell, cytotoxic cell) and later active a CD4 cell 9) How do cytotoxic cells kill pathogens? a) CD8 T -Cells particpate in cell-to-cell combat, i) Cytotoxic T cell bind to the viral-infected cell ii) Cytotoxic T cell releases the protein perforin, which makes lesions in the cell membrane iii) The infected cell lyses and dies 10) How do B-cells fight pathogens? a) Antibodies work via i) Opsonization: tag an organism for phagocytosis ii) Neutralization: antibodies bind to pathogen and prevent it from doing harm (1) Does this w/ a virus, but really hard to do so (2) Virus has to be in ECF in order for antigens to attach, but viruses spend a minority of their time in the ECF iii) Activate complement system: makes you feel sick b/c inflammation will occur 11) What is the structure of immunoglobulins? a) The red is antigen binding site (giving its specificity) b) The blue is a class of antibody which gives it a function 12) What are the different types of immunoglobins for? a) IgM: best for activating compliMent system (the big messy hammer) i) “Many compliments” so you feel it ii) 🙂 First wave of antibodies with first exposure to antigens iii) Desired in first exposure and acute phase of infection (1) Low affinity so it attaches (if it ain’t broke, don’t fix it) (2) But through the course of sickness, higher infinity (IgG) b) IgG: these antibodies “Gotcha you” this second time around i) Second wave of antibodies with first exposure ii) After that, second exposure you still have IgG in system from previous experience, so you have a greater IgG and a small wave of IgM c) IgA: Passive immunity i) Breast milk from mom to child d) IgE: i) Seasonal allergiEs and/or parasites e) IgD: i) Surface receptor on B-lymphocyte 13) What is the difference between affinity vs avidity? How does it play in maturation? a) Avidity: Amount of binding sites i) Collectively strong ii) Like having 10 arms of 2 year olds, it adds up b) Affinity: strength of binding sites i) You have two arms, but have the strength of an adult c) Your body finds a new antigen. IgM is activated, the binding is weak, they have low affinity but high avidity. As you fight the disease via compliment system, it has bought you time to find the more perfect match (high affinity) immunoglobins, so the next time you fight it it’s with IgGs. The end.  Study Questions Week 8 Normal Function of the Cardiovascular System II 1. Review the parts of the vascular tree. Note the differences in function of the various branches and the differences in pulmonary vs. systemic circulation. Vascular tree = a set of blood vessels with bifurcation (branches), allows for vast perfusion of all the organs 2 major circulation routes: ○ Systemic circulation – carries blood away from the heart towards the organs for perfusion, then carries blood back to the heart ○ Pulmonary circulation – carries blood away from the heart towards the lungs for oxygenation, and then carries blood back to the heart Has pulmonary arteries, arterioles, capillaries, venules, and veins Pulmonary capillaries = the site for gas exchange between the air sacs of the lungs and pulmonary capillary blood Where blood gets oxygenated Biggest difference between pulmonary and systemic circulation is the blood oxygenation in arteries and veins ○ Arteries always carry blood away from the heart ○ Veins always carry blood towards the heart ○ However, depending on the circulation route they carry either oxygenated or deoxygenated blood The pulmonary artery carries deoxygenated (oxygen-poor) blood away from the heart towards the lungs The aorta (major systemic artery) carries oxygenated (oxygen-rich) blood away from the heart towards the body Systemic arteries ○ Arteries Large vessels Function = fast transport of blood from the heart to the organs Also storing pressure that drives perfusion ○ Arterioles As systemic arteries go throughout body, they get smaller and branch into arterioles – a gateway for organ perfusion Arterioles have 2 major functions: Variably distributing cardiac output based on the body’s demands ○ Different organs get different % of cardiac output Regulate mean arterial pressure (MAP) ○ Capillaries Arterioles branch off further and flow into systemic capillaries Purpose = The site for all gas exchange and all exchange between tissue and the blood Gas exchange = O2, CO2 All other exchange = glucose, amino acids, free fatty acids, hormones, cytokines (chemical messengers)  Smallest, most delicate of our blood vessels ○ Venules From the capillaries blood flows into tiny vein-like vessels called venules Drain blood away from organs and into the systemic veins Systemic veins ○ Function = return blood to the heart ○ They are considered capacitance vessels → they have walls that expand readily, compliant, don’t have much elastic recoil (like a reservoir) Majority of blood volume is flowing through systemic veins If we have a need to increase our CO, then we increase the return of blood to the heart from the systemic veins 2. Review flow dynamics. What factors enhance flow what factors decrease flow. Circulatory system = movement of a liquid through tubing → flow dynamics F = ΔP/R ○ F = flow rate through vessel (mL/min) ○ ΔP = pressure gradient ○ R = resistance of blood vessel ○ Flow is directly proportional to the change in pressure and inversely proportional to the resistance of blood vessel Fluids travel down pressure gradients ○ Blood flowing from location A = 50 mmHg to location B = 10 mmHg ○ The larger the pressure gradient (bigger the discrepancy between pressure A and pressure B), the faster the flow rate ○ Pressure in our blood vessels that creates perfusion originates from the contraction of the ventricles (ventricular systole) If our ventricles stop contracting, the heart stops generating that force, the pressure is lost, and blood flow stops This is why in CPR quality compressions are more important than breaths because you are creating an artificial ventricular systole (generating force and pressure to get blood moving) Flow rate is inversely proportional to the resistance to blood flow ○ Resistance comes from two places: Blood viscosity – how thick the fluid is Looking at hematocrit (Hct) levels Viscosity is ratio of plasma to blood cells In a healthy person, this is a constant value (not changing from moment to moment) Radius/diameter of the blood vessel Contributing profoundly to the resistance of blood flow Changes all the time Changes in radius will have dramatic effect on the blood flow If radius gets smaller, resistance to blood flow exponentially increases (to the 4th power) ○ Resistance = 1/x4 ○ Flow = x4 ○ Ex: Vessel 1 and Vessel 2 – Vessel 2 is twice the size as Vessel 1 Radius in Vessel 2 is 2x that of Vessel 1 Resistance in Vessel 2 = 1/16 that of Vessel 1  Flow in Vessel 2 = 16 times that of Vessel 1 Blood flow in Vessel 1 = 1 mL/min Blood flow in Vessel 2 = 16 mL/min 3. Review the structure and function of Arteries. How does the structure of the artery wall lend itself to its function? Arteries are large blood vessels that are highly muscular and perform two major duties ○ 1. Fast transport from the heart to tissues (large diameter vessels = flow rate is very high) ○ 2. Store pressure and provide driving force for flow when heart is resting (elastic walls) Stores at the stretch of the artery wall Elastic recoil is the driving force for flow Structure of the artery wall: ○ Endothelium Innermost layer made of epithelial tissue The only layer that you see throughout the vascular tree Endothelial cells are flat squamous looking, with gaps in between them ○ Connective tissue layer On top of the endothelium, made of collagen and elastin fibers Then enters the smooth muscle with multiple layers ○ Sympathetic nervous system (nerve tissue) forms a netting around the smooth muscle Parasympathetic nervous system does not provide any nervous innervation to the smooth muscle of blood vessels But there are muscarinic receptors on the smooth muscle ○ External connective tissue covering Circulatory root (tiny little arteries) come in to provide oxygenated blood to the layers of tissue in the arterial walls Tiny little veins that carry this blood away from the cells within the wall of the artery Sympathetic postganglionic fibers that lead to the nerve netting The smooth muscle and connective tissue layer (collagen and elastin fibers) gives the artery wall its elastic properties Compliance and Distensibility ○ Distensibility = the extent to which something can be stretched ○ Compliance = the force or effort that needs to occur for something to be stretched Arteries are distensible but not compliant – will have significant elastic recoil Stretch of the artery is coming from the pressure/force generated from ventricular systole of the heart When the heart is at rest, the elastic recoil generates that pressure that drives perfusion down the arteries and rest of the vascular tree Similar to thick broccoli band (very stretchable, but you have to put in a lot of work to stretch it and there is a lot of recoil) Veins are not distensible but very compliant Similar to super thin rubber bands (not as stretchable before it breaks, but you can stretch it and there’s not a lot of recoil) 4. Define and explain Systolic vs. Diastolic blood pressure. What is Mean Arterial Pressure? Why is MAP important? Arterial blood pressure = force of blood against the vessel wall ○ A good indicator of blood flow and perfusion ○ If it’s adequately high, this means blood is flowing towards our organs and tissues Blood pressure is changing, vacillates between a peak pressure and trough (low) pressure Peak pressure = systolic blood pressure ○ It is the pressure in the arteries generated by ventricular systole (contraction of the heart) ○ Diseased arteries will have greater systolic BP Trough pressure = diastolic blood pressure ○ It is the pressure in the arteries generated at ventricular diastole ○ Diastolic resting pressure of the arteries depends on: 1. Health of the artery wall 2. Total blood volume – the lower the blood volume, the lower diastolic BP; a stiff, diseased artery wall will have a higher diastolic BP Higher diastolic BP, the harder the heart has to work to open the aortic valve and the greater pressure it has to generate in the systolic ventricular systole in order to have an adequate pulse pressure Mean Arterial Pressure ○ Blood vessels are spending a short amount of time in systole, spend a larger amount of time in diastolic range ○ Need a weighted average that gives more weight to diastolic pressure ○ MAP = diastolic pressure + 1/3 pulse pressure Pulse pressure = mathematical difference between SBP and DBP Ex: 120-80 = 40 mmHg → MAP = 80 + 1/3(40) = 93 mmHg ○ Why is MAP important? Will tell us the basic perfusion pressure at all times Able to evaluate how well blood flows through your body and whether it’s reaching your organs/tissues No matter how much systolic and diastolic are changing, if MAP is adequate for perfusion, then we know the organs are getting enough blood flow 5. Review and understand the steps involved in taking non-invasive arterial blood pressure measurement. Non-invasive arterial blood pressure measurement involves an inflatable cuff, pressure-recording device, and stethoscope ○ No risk of bleeding (otherwise you have to puncture artery to get pressure) ○ Downside: risk for error or false reading ○ Measuring the brachial artery ○ Pressure being read is the squeezing pressure on top of the artery ○ Stethoscope placed on antecubital region, that place is where the brachial artery comes closest to the skin Taking manual BP steps 1-5:  ○ 1. Occlude blood flow Put cuff on arm, inflate the cuff – squeeze brachial artery with more pressure than the pressure of blood flow through the brachial artery, this will occlude the brachial artery First feel radial pulse, inflate it until you can’t feel the pulse, then inflate the cuff 20-30 mmHg more ○ 2. Slowly let go of squeezing pressure (deflate the cuff), then you will hear the first tap on the stethoscope First tap (needle’s first jump) = systolic blood pressure, blood is pushing through the artery with more pressure than the cuff squeeze; pressure of blood in artery > cuff squeeze ○ 3. Taps will get softer overtime because the pressure squeezing on the artery is less and less, blood flow through the artery becomes less forceful ○ 4. Cuff pressure continues to decrease until it is lower than diastolic pressure ○ 5. When cuff squeeze < pressure of blood in artery, you hear the first silence (needle stops jumping) = diastolic blood pressure 6. Compare MAP across the various parts of the vascular tree. MAP drops as it goes throughout the vascular tree: left ventricle → large Arteries → arterioles → capillaries → venules and veins Depending on where you are measuring, different arteries in the body will present different arterial pressures ○ Multiple MAPs depending on location, but all these pressures will start to go down as it enters arterioles, capillaries, venules, and veins By capillaries, there’s no pulsating change in pressure 7. Review the structure and function of arterioles. Compare extrinsic vs. intrinsic control of arteriolar diameter. What factors cause vasoconstriction vs. vasodilation? What effect will each have on flow?  Structure of arterioles: ○ Endothelium with smooth muscle fiber on top of it, and that’s it ○ Also have sympathetic nerves that innervate the arterioles ○ No big basement membrane or sheath/connective tissue ○ Changeable diameter – constantly constricting and dilating Function of arterioles ○ 1. Variably distribute cardiac output based on current demands Decides how much cardiac output each organ gets Demands on the tissue and body as a whole ○ 2. Regulate arterial blood pressure All arterioles have normal arteriolar tone ○ Resting diameter produced by myogenic activity (elastic property of the muscle tissue) ○ Baseline sympathetic output Your resting BP is a property of the muscle activity of arterioles and your baseline sympathetic tone Vasoconstriction ○ Smooth muscle contracts, diameter gets smaller ○ Profound decrease of flow Vasodilation ○ Smooth muscle relaxes, diameter gets bigger ○ Profound increase of flow Factors that cause vasoconstriction or vasodilation ○ Intrinsic – local factors Arterioles are located in an organ, needs and conditions of the organ are influencing arteriole diameter Pathological conditions are linked to altered/abnormal intrinsic control of our arteriolar diameter ○ Extrinsic – neuronal or hormonal factors Needs of the entire body determined by our nervous system and endocrine system are influencing arteriole diameter Intrinsic (local) control – changes within tissue ○ Chemical 1. Local metabolic changes** Vasodilation – when tissue is metabolically active ○ Local O2 is low = muscle is consuming O2 at a high rate ○ Local CO2 is high = muscle is generating CO2 at a high rate ○ Local acidity is high = CO2 producing carbonic acid, glycolysis producing lactic acid ○ Local level of free adenosine is high = consumption of ATP results in free floating adenosine ○ Endothelium is sensing these changes and will release nitric oxide as a result  Nitric oxide acts on the smooth muscle of that vessel and cause vasodilation = get more blood flow to replenish O2, remove CO2, carry ATP, carry lactic acid away Vasoconstriction – when muscles are relaxed, tissue is NOT metabolically active ○ Local O2 is high ○ Local CO2 is low ○ Local acidity is low ○ Local free adenosine is low ○ Endothelium will sense this milieu and release endothelin ○ Endothelin will act on smooth muscle and cause vasoconstriction Impaired/loss of local control of arteriolar diameter based on metabolic needs = a lot of circulation/perfusion problems ○ Ex: Ischemic heart disease Local control is all dependent on endothelium – critical part of vascular health ○ Smoking, HTN, high BG, high cholesterol (LDL) injures the endothelium ○ Without a functioning endothelium, you have circulation problems 2. Histamine release Inflammation causes the release of histamine and other inflammatory mediators, those inflammatory mediators tend to cause vasodilation and increase blood flow to the area When something is inflamed, we tend to want to reduce blood flow to the area in order to get that inflammation under control ○ Physical 1. Local application of heat or cold Heat = dilation Cold = constriction This is why when you sprain your ankle, they want you to ice and elevate it to reduce blood flow to the area Wrapping sprained ankle helps reduce blood flow to area, deliver fewer inflammatory mediators (mediators tend to dilate blood vessels) and deliver fewer inflammatory cells (neutrophils and macrophages that bring reactive O2 species, cause more injury and lengthen healing time) Extrinsic control ○ Includes both neuronal and hormonal influences Neuronal – sympathetic nerves innervate the adrenal medulla Release of Epinephrine or Norepinephrine Epi acts on beta 2 adrenergic receptors to cause dilation NE acts on alpha 1 adrenergic receptors to cause constriction Hormonal – vasopressin is released for water balance and angiotensin II is released for plasma  volume (sodium) balance Both cause vasoconstriction ○ Important effect of the sympathetic nervous system Sympathetic nerve fibers supply arteriole smooth muscle everywhere but the brain Increased activity = generalized vasoconstriction Decreased activity = generalized vasodilation ○ Releases NE onto alpha-adrenergic receptors ○ Help regulate blood pressure specifically with TPR influence 8. How do arterioles help regulate mean arterial blood pressure? F = ΔP/R ○ Cardiac output (CO) – Flow ○ Mean Arterial Pressure (MAP) – ΔP ○ Total Peripheral Resistance (TPR) – R The resistance to blood flow across the entire vascular tree Determined by two things – blood viscosity (Hct) and level of constriction, especially in the arteriolar level (constrict vs. dilate) MAP = CO x TPR o Net vasoconstriction = MAP goes up o Net vasodilation = MAP goes down o TPR most influenced by arteriolar resistance 9. Compare the distribution of cardiac output at rest to during moderate exercise. Discuss some mechanisms by which this distribution changes. At rest ○ Total cardiac output is 5,000 mL/min (5 L/min) ○ Distribution of cardiac output from highest to lowest: Digestive tract and liver: 27% (1,350 mL/min) Kidney: 20% (1,000 mL/min) Kidneys actually only need 1% CO to stay alive, but they get the extra 19% because they’re our major filtering organs in our body (along with the liver) Skeletal muscle: 15% (750 mL/min) Bone: 13% (650 mL/min) Brain: 13% (650 mL/min) Skin: 9% (450 mL/min) Heart: 3% (150 mL/min) Without blood going to the heart, nothing can go anywhere During moderate exercise from highest to lowest cardiac output ○ Total cardiac output is now 12,500 mL/min (12.5 L/min) Flow rate has increased threefold – volume per minute How much is being delivered in that timeframe ○ Distribution of cardiac output from highest to lowest – prioritization has changed drastically! Skeletal muscle: 64% (8,000 mL/min) 1,066% increase Needs oxygen and ATP in order to contract and drive the exercise Skin: 13.6% (1,700 mL/min) 370% increase Thermoregulation: all metabolic activity happening in muscle is  generating heat, send more blood to the skin for heat to dissipate into the environment (blood carries the heat) Brain: 5.2% (650 mL/min) No change in amount Does not compromise on how much blood flow it gets Heart: 4.4% (550 mL/min) 367% increase The following organs have decreased CO, but it’s because body does not need their functions during exercise Digestive tract, liver: 4.8% 600 mL/min (56% decrease) Kidneys: 4.4% 550 mL/min (45% decrease) Bone, other: 3.6% 450 mL/min (30% decrease) Mechanisms for distribution changes: ○ Stimulation of the sympathetic nervous system (extrinsic) With moderate exercise, our sympathetic NS turns on Organs with decreased percentage of CO = sympathetic stimulation in their vascular beds caused vasoconstriction and decreased flow Digestive tract, liver Kidneys Bone, other This decrease in blood flow frees up more blood that can be sent to other organs to use Skin – sympathetic system knows we need to dissipate heat for thermoregulation Sympathetic stimulation increases blood flow here Heart – Sympathetic stimulation to the heart = increase HR, contractility → this increases SV and CO Veins – Sympathetic stimulation increases venous return (vasoconstriction) → decreases compliance which means they have a smaller capacity and therefore blood gets returned to the heart, EDV goes up which causes SV and CO to increase ○ For heart and skeletal muscle, it’s a combination of both extrinsic sympathetic stimulation and also increased metabolic demands (intrinsic local control) 10. Review the structure and function of capillaries. How does the structure of capillaries lend itself to its function? Capillaries = sites for exchange of all material between blood and tissues Highly adapted for diffusion Diffusion distance is minimized – all cells in body are super close to a capillary ○ If a cell is too far from a capillary, they’re not getting enough oxygen and they release proangiogenic factors Proangiogenic = stimulate formation of capillaries towards them Thickness of diffusion barrier is minimized ○ Capillaries are just naked endothelial cells, have pores so things can easily diffuse or move out Pores are not big enough for albumin to leak out, unless there’s inflammation ○ Diameter of a capillary is slightly smaller than the diameter of a red blood cell RBCs have to squeeze their way through capillaries – hemoglobin (that has all the O2) has to get as close to the capillary wall as possible so the diffusion distance can be minimized  Tremendous surface area available for diffusion ○ Capillary beds are very small and an enormous number of them ○ Have a huge cross-sectional area that helps maximize diffusion Blood velocity slows through capillary beds ○ F ∝ V x CSA (cross sectional area) ○ As CSA goes up, velocity goes down, and this is what helps flow rate remain the same ○ Purpose of the slowing is to maximize diffusion because it’s the opportunity for exchange with tissue 11. Review capillary bulk flow. Understand the mechanism and function of this passive process. Capillary bulk flow = passive movement of fluid between intravascular space and interstitial space caused by starling forces Purpose of capillary bulk flow = regulating the distribution of ECF between plasma and interstitial fluid ○ Ultra-filtration = fluid moves out of the capillaries and into the interstitial space ○ Reabsorption = fluid moves from the interstitial space into the capillaries Starling forces = 4 pressures (2 from capillaries, 2 from interstitial space) that controls the distribution of fluid between our capillaries and interstitial space ○ 1. Capillary BP – pushing force that comes from inside the capillary Promotes ultra-filtration Can change all the time ○ 2. Capillary oncotic pressure – comes from plasma proteins inside capillaries (mainly albumin) and exerts a pulling force to keep fluid inside the capillary Promotes reabsorption Normally static/unchanging ○ 3. Hydrostatic pressure – pushing force that comes from the interstitial space Promotes reabsorption ○ 4. Interstitial oncotic pressure – albumin comes out into the interstitial space when there is capillary injury and/or inflammation, and that albumin exerts pulling force to keep fluid in interstitial space Promotes ultra-filtration Would normally be 0 (because we’re not normally experiencing inflammation) Normally, capillaries will have constant (net) ultra-filtration going on (U>R) ○ Capillary BP will normally be large enough to overcome capillary OP and hydrostatic pressure → capillaries are leakier in general ○ Why? Because lymphatic vessels are there to collect extra interstitial fluid Fluid gets filtered by immune cells (they live in lymphatic vessels) in case of pathogenic infection, in which the lymphatic system puts the fluid back into circulation But if there is blood loss, blood pressure will go down and cause capillary BP to go down ○ Under this circumstance, (net) reabsorption is greater than ultra-filtration to help offset the blood loss (R>U) 12. Review the structure and function of veins. How does the structure of veins lend itself to its function? Veins are our capacitance vessels that provides a blood reservoir ○ Don’t have a lot of smooth muscle, so when blood enters veins, they tend to expand (very compliant) and don’t have much elastic recoil ○ That’s why there’s a lot of blood at any given moment in our systemic veins Venous capacity = volume of blood that the veins can accommodate Venous return = volume of blood entering each atria from the venous vessels ○ Factors that influence venous return 1. Sympathetically induced venous vasoconstriction  This will reduce venous capacity (volume of blood that veins can accommodate) → blood will get returned to the heart more rapidly 2. Skeletal muscle activity Large veins move through large muscle groups So, when muscles are contracting, they’re milking the blood up the veins and move blood back to the heart ○ Ex: When you’re standing for a long time, you can get a pooling of blood in your legs, and you can feel lightheaded ○ Venous return of blood to the heart goes down, which makes CO go down, and blood flow to the brain go down 3. Effects of venous valves One-way valves! When skeletal muscle contracts, it squeezes on the vein and makes sure all the force moves upward toward the heart ○ Open venous valve permits flow of blood toward heart ○ Closed venous valve prevents backflow of blood 4. Respiratory activity Pressure in thoracic cavity that is slightly less than atmospheric pressure and less than abdominal pressure As blood moves from lower limbs into the abdomen and approaches the thoracic cavity, the sub atmospheric pressure creates a sucking force that encourages blood movement back to the heart 5. Cardiac suction 13. What is Venous Return? What factors contribute to the maintenance of venous return? Venous return = return of blood to the heart ○ Important and it determines end-diastolic volume, which will determine stroke volume and cardiac output Cardiac suction effects venous return ○ When heart is contracting, the atria expand which causes the atrial pressure to go down ○ The atrial pressure dipping down is the suction force and this pulls blood into the atria → enhances venous return 14. What are all the factors contributing to MAP? What happens if MAP is too low? What happens if MAP is too high? MAP = average blood pressure in our arteries throughout the cardiac cycle whether heart is at rest or contracting ○ The main driving force in supplying blood to tissue – our perfusion pressure to the heart MAP is too low = inadequate perfusion MAP is too high = increased workload on the heart; damage to the microcirculation (arterioles, venules, and capillaries) → impairs tissue perfusion Factors contributing to MAP ○ MAP = CO x TPR  CO = SV x HR CO = the volume of blood ejected by the ventricles every minute SV = the volume of blood ejected by the ventricles every cardiac cycle HR = the number of cardiac cycles every minute TPR determined by two things → blood viscosity (Hct) and arteriolar radius (constrict vs. dilate) 15. What is the system for the short-term control of MAP? Explain how this system operates (explain the sensors, the control center, and the effectors). Short-term regulation = baroreceptor reflex ○ Adjust blood pressure to meet the needs of different body positions Adjust HR, SV, and level of vasoconstriction depending on your body position (laying vs standing) ○ Deal with sudden onset of changes in blood pressure ○ Transient effects – can’t deal with long-term problems because it’ll just create a new normal from the baseline they are being presented to, so pressure change will persist Baroreceptors can only correct for blood pressure changes that are not a pathological issue Two baroreceptors: ○ The aortic arch Telling brain about blood pressure going to entire body ○ The carotid sinuses – first bifurcation of the carotid artery Telling brain about blood pressure going to the brain itself When BP is normal = normal firing rate of afferent neurons from these baroreceptors telling brain that blood  pressure is normal BP increases = firing rate increases If increased BP persists for more than a few minutes, the baroreceptor firing rate will go back to normal since they are rapidly adapting BP decreases = firing rate decreases Ex: When responding to increased MAP, there is increased parasympathetic stimulation and decreased sympathetic stimulation Baroreceptor Reflex ○ BP too high → CV Center in Medulla → Increase activity in Vagus nerve → Decreased HR → Decreased CO → Decreased MAP 16. What is the system for the long-term control of MAP? Explain how this system operates. Long term regulation is done by the kidneys through the Renin-Angiotensin Aldosterone system ○ Thirst mechanism ○ Urine output ○ Salt balance ○ Persistent alteration in blood pressure that needs to be corrected JGA Granular Cell Baroreceptors control release of renin Decrease in plasma volume causes decrease in blood pressure, which is sensed by the JGA granular cell baroreceptors ○ Renin is released, which increases circulation of ADH (antidiuretic hormone), thirst, and aldosterone (Na+ reabsorption and retention) ○ All of this is going to expand blood volume and increase BP 17. Consider the following relationships: Understand what each of these parameters mean. Go through and understand the factors that affect each one (ex. Increased contractility, increased venous return, etc.) Understand how each of the parameter affect one another.  SV = stroke volume EDV = end diastolic volume SV = EDV – ESV ESV = end systolic volume CO = SV x HR CO = cardiac output MAP = CO x TPR HR = heart rate MAP = mean arterial pressure TPR = total peripheral resistance Venous return directly affects EDV, which directly affects CO, which directly affects MAP Ex: Vasodilation in sepsis → immediately affects TPR (drop in TPR), which directly affects MAP to go down Ex: Hypovolemic shock → blood volume is not there, immediately affecting venous return Ex: Cardiogenic shock → heart muscle first stops, ESV is immediately affected. The ventricular muscle is no longer contracting, and the heart keeps filling up with blood and can’t be emptied. ○ When ESV goes up, this causes SV to go down ○ Decreased SV causes CO and MAP to go down 18. In which of the vessels in the vascular tree does blood velocity slow down? What purpose (s) does this serve? Explain how blood can slow down so much in these vessels while overall flow rate remains constant. Capillaries is where blood velocity slows down the most Purpose of the slowing is to maximize diffusion because it’s the opportunity for exchange with tissue What causes the blood velocity to slow down? ○ Increase in cross sectional area causes the blood velocity to slow down 19. John gets on a stationary bike in an exercise physiology lab. Strapped to his left thigh is a device that can measure blood flow to a specific region of quadricep muscle tissue. John starts to peddle vigorously and after a few minutes of this rigorous exercise the blood flow gauge reads a three-fold increase in quadricep perfusion. Explain at least two mechanisms that have contributed to this increase in muscle perfusion. His HR increased which caused his CO to increase ○ CO