Exam II Study Guide PDF

Exam II 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? Physical: State of tension that can lead to disruption or that threatens homeostasis Psychological: nervousnes...

Exam II 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? Physical: State of tension that can lead to disruption or that threatens homeostasis Psychological: nervousness, fatigue, anxiety General: Feeling of self-doubt about being able to cope w/ some situation over a period of time ○ Individualized Healthy Stressors ○ Demanding mental & physical activities that enhance mental & physical alertness ○ Eg: exercise, learning Purpose of Stress ○ Trigger adaptation to make us stronger and better capable of coping w/ other forms of stress 2) What were the three observations Selye made in terms of the physical effects of chronic stress in his animals? Explain the general adaptation syndrome. Physical effects of chronic stress in animals (Hans Selye) - Enlargement of Adrenal cortex - Shrinking of lymphatic organs (thymus, spleen)à immunity-related organs - Stomach & duodenal ulcers General Adaptation Syndrome (GAS) - 3 components: o Alarm reaction – mobilization of stress response § High corticosteroid activity § Low resistance to stress o Stage of resistance – repeated exposure to stressor leads to adaptation & resistance § Low corticosteroid activity § High resistance to stress § Individuals regularly move between first 2 stages to adapt to everyday stress o Stage of exhaustion – occurs when adaptation fails & leads to disease/potential death § Increasing corticosteroids activity § Plummeting resistance to stress Small amount of stress induces large stress response 1 3) What are the basic steps to the human stress response (depicted in Slide 3) 1. Stressorà real/perceived negative physiologic/emotional/cognitive stimuli a. “Thinking brain”à Pre-frontal cortex b. “Feeling & reactive brain” i. Emotional brain ii. Triggers physiological stress response 1. Adrenal cortexà releases cortisol 2. Sympathetic nervous systemà flight-or-fight response 4) What structures in the brain are involved in a human stress response? What are their functions? Limbic System – Emotional Brainà Allows us to feel and react Prefrontal cortex (frontal lobe) ○ “Limbic cortex”, “thinking brain” Make observations and sends that info to the limbic system to be evaluated for emotional content ○ Judgement, insight, motivation, mood, emotional reactions Hippocampus ○ Declarative memoryà raw faces and figures ○ Short-term memory / learning Important because it helps us to remember the stressful event Amygdala ○ Critical to coordinated response to stress (esp. w/ emotional content)àmobilizes a reaction to a stressor ○ Integrates behavioral reactions that are important for survival ○ Conditioned emotional responses ○ Stimulation can produce a rage reaction ○ 2 modes: Silent Panic Hypothalamus ○ Primary input for limbic systemà connection between thinking/feeling and stress response output ○ Connected to anterior pituitary hormone output & sympathetic nervous system Rapid stimulation of SNS Stimulate adrenal cortex to synthesize and release cortisol ○ Regulates body temp, appetite, sexual responses Olfactory bulb ○ Smell ○ Connection between olfactory bulb and hippocampus ○ Associating smell w/ emotion (good or bad) 2 5) What are the two output systems and physiological effects of the human stress response? Sympathetic -Adreno-Medullary (SAM) Axis Rapid response Catecholamines release ­HR Bronchodilation → ­ perfusion Liver: glycogenolysis →­ blood glucose Adrenal medulla ○ Release epinephrine & norepinephrine → long lived response Hypothalamic-Pituitary-Adrenal (HPA) Axis Slower responseàCRH → ACTH → cortisol released ­ blood glucose levels ○ Breakdown muscle → AA → gluconeogenesis in liver → glucose ○ Antagonize insulin receptors-à inhibiting glucose uptake ○ Enhance glycogen breakdown in liver to form glucose ­ calciumà for muscle contraction ○ Micro breakdown of bone → release Ca2+ ­ calcium excretion à counterbalance ­calcium levels Na+ retention, K+ loss Vasoconstrictionà ­BP Immunosuppressant & anti-inflammatory responseà mobilize energy ­excitability of brain 3 Part 3: Black Americans more prone to health issues because of racism 8) How many black Americans die prematurely every day? - Over 200 black Americans 9) What has Dr. David Williams’ research found? What is the everyday discrimination scale? - Racism itself can be a killer - Everyday discrimination scale o 9 item questionnaires measuring the amount of dignity is affected on daily basis o The higher the score = have a broad range of adverse health conditions § HTN, DM, CVD, poorer mental health 10) How did the life expectancy of White vs. Black Yale 1970 graduates differ? What does this illustrate? - Black graduates were 3x more likely to die prematurely than white classmates - Illustrates magnitude of racial disparities in health 11) How does Dr. Williams describe the phenomenon of “weathering”? - Weathering is used to describe this effect on African Americans - Imagineà o Constant dripping of water from a roof onto sidewalk § If this happens occasionally then is no big deal § But if constantly dripping onto the sidewalk the concrete will bill become weathered It erodes from constant exposure to adversity - Research shows that all these stressors are “weathering” AAs the same way 12) How does a person’s address affect their health and their life expectancy? - 20–25-year gap in life expectancy based on the communities we live in - 3 Key Pillars o Community wellness, community health, & sense of community spirit o Accessible, affordable housing o Education - Improving housing conditionsà improves health outcomes o Access to healthy foods is the key à by some individuals taking housing vouchers and moving to better neighborhoods they were able to see low rates of obesity and diabetes risk with no health interventions 4 Part 4: “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”? - “Weathering” à cumulative stress and adversity experienced by Black individuals in a race- conscious society leads to earlier deterioration of their health compared to White individuals 14) What is Allostasis and Allostatic Load? - Allostasis: body’s adaptive response to stress o The body’s attempt to maintain homeostasis through changes in response to stressors - Allostatic load: Physiological burden imposed by stress response to multiple biological systems o Causing weathering, premature aging/death, diseases in AA communities 15) How is Allostatic Load measured? - Measuring Primary Mediators and Secondary Effects - Primary stress hormones released in response to stress o Norepinephrine o Epinephrine o cortisol o dehydroepiandrosterone sulfate (DHEAS) - Secondary Effects o Elevated BP o Cholesterol levels o Hgb A1C levels o Waist-to-hip ratio - Individuals receive a point for each biomarker reading beyond a high-risk thresholdà then added together to get the total allostatic load score 16) What are the key findings of the study? - Blacks have a higher Allostatic Load Score (particularly at 35-64yrs of age) - Racial differences were not explained by poverty - Nonpoor blacks have higher scores than poor whites - AA women had higher allostatic load scores compared with everybody else o Experience double jeopardyà racial and gender discrimination - For white men vs womenà no differences in allostatic load - Blacks experience earlier health deterioration 5  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. - The more adversity/stress experienced by peopleàhigher their allostatic loadàgreater risk for diseases - Dose response provides strong support for the weathering hypothesis and highlights how social inequalities can become embodied in population health disparities over the life course o The systemic drivers of racial inequity need to be addressed to improve the health of marginalized populations 6 Immune System: Structure and Normal Function Pathogen Entry Steps: 7 1. What are the cells of the immune system and where do they come from? Red Bone marrowà Pluripotent Hematopoietic Stem Cell 8 Cell Type Mediator Function o Lysosomal Enzyme o Inflammation activatoràPhagocytosis o Prostaglandin o Some release in EC spaceà pathogen injuryà also causes host tissue injury o Leukotrienes o Circulate bloodstream Neutrophils o ROS released EC o Contain lysosomal enzymes o PAF o 1st responders in infectionà inducible cellsà ­w/ presence of infection o PAFà ­platelet aggregation, ­vasodilation & ­vascular permeability, ­leukocyte adhesion, ­chemotaxis o Prostaglandin o Circulate bloodstream o Leukotrienes o Extracellular killing of bacteria and parasites o PAF o Plays role in allergic reactions. Eosinophils o PAFà ­platelet aggregation, ­vasodilation & ­vascular permeability, ­leukocyte adhesion, ­chemotaxis o Histamine o Activators of inflammation o NCF o Filled with inflammatory mediator histamine o ECF o Released during allergic reactions o Prostaglandin o Circulates in bloodstream Basophils o Leukotrienes o PAFà ­platelet aggregation, ­vasodilation & ­vascular permeability, ­leukocyte adhesion, ­chemotaxis o PAF o Attract neutrophils and eosinophils to injury site Monocytes/Macrophages o Lysosomal Enzyme o Inflammation activatoràPhagocytosisà APC - Tissue macrophages o ROS released EC o Some release in EC spaceà pathogen injuryà also causes host tissue injury - Circulating monocytes o Nitrous Oxide o Activation of bactericidal mechanisms o Communicate w/ adaptive immune system o Critical for inflammatory responsesà ­vasodilation, dec platelet aggregation and leukocyte adhesion o Circulating monocytesà activated by inflammation to become macrophages o Tissue macrophagesà Resident in connective and endothelial tissues throughout the body o Histamine o Aid in blood clotting to prevent bleeding. o Serotonin o Fragments of cells o Prostaglandin o Circulates in bloodstream Platelets o ROS released EC Erythrocytes (Red Blood Cells) o Erythrocyte o Transport oxygen from the lungs to tissues and return carbon dioxide to the lungs. o Histamine o Activators of inflammationà via vasodilation+ swelling of blood vessels o NCF o Filled with inflammatory mediators (e.g. histamine) à immediate released o ECF o Leukotrienes releasedà vascular effects; Prostaglandinsà vascular effects and pain = both are delyaed released Mast Cells o Resident in connective and endothelial tissues throughout the body o Attract neutrophils and eosinophils to injury site à immediate released o Antigen-Presenting o Capture and present antigens to T-cells to initiate adaptive immune response. Cell (APC) in lymph o Phagocytic cell nodes o Constantly monitors ECF for pathogens & traps antigens Dendritic Cellsà o Communicate w/ adaptive immune system Myeloid or Lymphoid o Resident in connective and endothelial tissues throughout the body B cells o Lymphocyte o Made and matured in bone marrowà housed in secondary lymphoid tissue o Produce antibodies that neutralize pathogens o Lymphocyte o Made in bone marrowà mature in thymus to naïve T-cells w/ receptorà housed in secondary lymphoid tissue o Recognize and kill infected cells or help other immune cells T cells o Include helper (CD4) and cytotoxic T cells (CD8) Natural Killer Cells Lymphocyte o Part of the innate immune systemàact without prior exposureà in both blood stream and 2nd lymphoid tissue o Fights intracellular pathogensà like viruses o Kills w/o specificity 1 Defense barriers 2. What events can initiate a local inflammatory response? Event Description Infection by Pathogens - Macrophages recognize pathogensà triggers an immune response - Causes release cytokinesàinitiates inflammation Tissue Injury - Physical damage-à release cytokinesàinitiates inflammation Allergic Reactions - Exposure to allergens àprovoke a local inflammatory response Autoimmune Reactions - Immune system mistakenly attacks the body’s own tissuesàcausing inflammation. Toxins or Irritants - Presence of chemical irritants, toxins, or foreign substancesàtrigger an inflammatory response. Necrosis (Cell Death) - Cell death due to injury, ischemia, or other factors releases cell contentsà trigger local inflammation. 1  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? Macrophages and dendritic cells are typically the first cells to recognize pathogens. Pro-inflammatory cytokines releasedà triggering inflammation activation or cell injury Activators Function/Effects Macrophages Local Effects: NK cells - ↑ Vasodilation: Expands blood vessels, increasing blood flow to the infection site. TNF - α Mast cells - ↑ Vascular Permeability: Allows immune cells and proteins to leave the bloodstream and enter tissues. Injured cells - ↑ Leukocyte Adhesion: Promotes the adhesion of leukocytes to endothelial cells. - Attraction of Monocytes and Neutrophils: Recruits these immune cells to the site of infection or injury. - Activation of Macrophages: Enhances phagocytosis to engulf and destroy pathogens. Systemic Effects: - ↑ CRH (Corticotropin-Releasing Hormone): Triggers the release of cortisol, modulating the stress and immune response. - Fever: Acts on the hypothalamus to increase body temperature. - ↓ Appetite: Reduces appetite as part of the body’s inflammatory response. - ↑ Liver Production of Acute-Phase Proteins: Stimulates production of proteins to enhance immune function - CRP: Enhances opsonization and pathogen clearance. - MBL: Activates complement and aids pathogen recognition. IL-1 Macrophages Local Effects: Injured cells - ↑ Vascular Permeability: Increases the ability of immune cells and proteins to pass into tissues. - ↑ Leukocyte Recruitment: Promotes the expression of adhesion molecules on endothelial cells, enhancing leukocyte migration to the infection site. - ↑ Macrophage and Neutrophil Activation: Activates and recruits these cells for pathogen clearance. - Amplifies the Inflammatory Response: Stimulates the production of other pro-inflammatory cytokines (like TNF-α) and chemokines to further enhance immune response. Systemic Effects: - Fever: Acts on the hypothalamus to raise body temperature, inhibiting pathogen replication. - ↑ Acute-Phase Proteins: - CRP: Enhances opsonization and pathogen clearance. - MBL: Activates complement and aids pathogen recognition. - ↓ Appetite and Fatigue: Triggers sickness behavior, reducing energy expenditure and promoting rest during infection. - ↑ CRHà increase cortisol levels - Inducer for production of IL-6 IL-6 Macrophages Local Effects: ECs - Supports Leukocyte Recruitment: Helps in recruiting neutrophils and lymphocytes to the site of inflammation. - Promotes T and B Cell Differentiation: Helps in the activation and maturation of T cells and B cells, which are crucial for the adaptive immune response. - Anti-inflammatory Role: In chronic inflammation, IL-6 can promote tissue repair and transition from acute to resolving inflammation. Systemic Effects: - ↑ CRH: Stimulates CRH release from the hypothalamus, leading to cortisol production. - Fever: Raises body temperature to inhibit pathogen growth. - ↓ Appetite: Reduces appetite during infection to conserve energy. - ↑ Acute-Phase Proteins: - CRP: Enhances opsonization and pathogen clearance. - MBL: Activates complement and aids pathogen recognition. - Autocrine IL-6 Production: Promotes its own production to sustain the immune response. IL-8 In response toLocal Effect (CXCL8) pro-inflammatory - Chemotaxis: acts as a chemokine, attracting neutrophils to the site of infection or inflammation response (TNF-a, - Activation of Neutrophils: Enhances neutrophil activity, promoting their ability to engulf and destroy IL-1,etc.) pathogens through phagocytosis. IL-12 Macrophages Local Effect Dendritic cells - Activation of NK Cells and T Cellsà NK cells and CD4+ T cells to produce IFN-γ (interferon-gamma), which enhances the immune response - Promotes the differentiation of naïve CD4+ T cells which will be involved in cell-mediated immunity - Enhances Cytotoxicity: Boosts the cytotoxic activityàaiding in the destruction of infected or abnormal cells. 2  4. What are the vascular and cellular events of acute inflammation and in what sequence do they occur? Injury/Presence of Pathogen Inflammation Triggersà Injured tissue releases cytokines → activate macrophages Injury activates mast cells → mast cell releases pro-inflammatory mediators Macrophages detect/ingest pathogen → macrophage releases pro-inflammatory mediators Activated macrophages stimulate mast cells → mast cell releases pro-inflammatory mediators Mast cell triggered byà injury, interleukin I, complement proteins, and IgE (hypersensitivity reactions) Vascular Migration Cell migration Attack of Pathogens - Occurs in the microcirculation - Chemotaxis migration of - Pathogens system leukocytes to area phagocytized/destroyed via o 1st: Leukocytes extracellular killing using o 2nd: Monocytes → enzymes and ROS macrophages - Marginationà vasodilationà blood - Phagocytic cells carry flow slowsà leukocytes accumulate along antigen thru lymph fluid to the blood vessel walls nearest lymph node - Adhesion (Adhere to endothelial cells in the blood vessels liningà move out into the tissue to track down pathogens - Transmigrationsà leukocytes squeeze through and migrate to affected tissue - Vasodilation → redness, heat at site of inflammation - Inc permeability → immune cells leak into surrounding tissuesà albumin leakà edema - Delayed vascular stasisà helps immune cells get to affected area while controlling blood flow - Exudate of fluidà fibrinogen and other plasma proteins + fluid move into tissuesà isolated pathogen and dilute toxinsà pain and swelling 3 5. What role do Mast Cells play in inflammation? - Release Histamine o Causes vasodilation and increased vascular permeability, leading to redness and swelling - Secrete Cytokines/Chemokines o Attract and activate other immune cells (neutrophils, macrophages, etc.) o Prolong inflammation and contribute to pain and swelling - Activate Complement o Helps opsonize pathogens and recruits additional immune cells - Initiate Early Inflammation o Act as first responders to injury or infection 6. What part of the immune system is a natural defense against cancerous growth? - NK Cells (innate immunity) and Cytotoxic T Cells (CD8+ T cells) (adaptive immunity) are the primary cells responsible for identifying and killing cancer cells. - Macrophages, Helper T cells, and Dendritic cells support the process by either directly attacking cancer cells or enhancing the overall immune response. 4 7. What is the complement system and what are the possible pathways by which it can be activated? - Complement System o Part of innate immunity o Made of many circulating plasma proteins that activate in cascade of enzymatic rxns to accomplish 3 purposes § (1) Promote inflammation § (2) Directly kill pathogenà enzymes create holes in cellsà swell and degradeà membrane-attack complex § (3) Tag pathogen for later killing (opsonization) § Opsins (tagged pathogens) formed and destroyed o Activated in 3 waysà which forms C3 convertase which activate the system: § (1) Presence of pathogenà Classical Pathway C1 binds to antigen-antibody complexes § (2) Activated as part of systemic inflammatory responseà MB-Lectin Pathway Mannose-bind lectins bind mannose on pathogen surfaces § (3) Activated by adaptive immunity (antibody-mediated)à Alternative Pathway C3 spontaneously binds to pathogen surface 5  8. How does the complement system interact with both innate and acquired immunity? - Interaction with Innate Immunity: o Can be activated directly by pathogens without prior exposure, plays role in: § Opsonization: Opsins formed (via coating pathogens)à easier for phagocytes (such as macrophages and neutrophils) to recognize and engulf. § Chemotaxis: Attract immune cells like neutrophils to the site of infectionà helping amplify inflammatory response. § Cell Lysis: Forms membrane attack complex (MAC), which creates pores in the membranes of pathogens, leading to their destruction. - Interaction with Acquired (Adaptive) Immunity: o Also interacts with the adaptive immune system: § Classical Pathway Activation: This pathway is triggered when complement proteins bind to antibodies (IgG or IgM) that are already attached to pathogens, linking the complement system to antibody-mediated immunity. § Enhancing B Cell Responses: Complement receptors on B cells help in their activation and enhance their ability to produce antibodies. § Antigen Presentation: The complement system helps clear immune complexes (antigen- antibody complexes), which is important for proper antigen presentation to T cells, aiding in the adaptive immune response. - Dual interaction helps bridge the innate and acquired immune systems, making the complement system a critical component in both rapid and specific immune responses. Innate Immune System Adaptive Immune System - First line of defense and non-specific - Specific and slower to respondà provides long- - Structural/chemical barriers lasting immunity - Phagocytic/Scavenger cellsà Macrophages and - B lymphocytes – (antibody-mediated immunity) Dendritic cells - T lymphocytes (cell-mediated immunity) - Inflammation o Both learn from experience - Plasma protein systems o As we encounter more pathogensà they are o E.g.: compliment system, clotting system to attack more rapidly and effectively to kinin system avoid illness - APCs- o Macrophages à present antigens to T-cells trigger system o Dendritic cells à most efficient antigen- presenting cells o Presents antigens to T-cells in lymphoidà triggers systemà initiating production of pathogen0specific T-cells and B-cells 6  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? Cells Responsible for Function Inflammatory Mediators’ Function Collateral Damage Mediators Responsible for Collateral Damage Neutrophils First respondersà Reactive Oxygen Destroys pathogens, but can damage release (ROS) Species (ROS) cellular membranes, proteins, and proteolytic enzymes to DNA of healthy cells kill pathogens Lysosomal Enzymes Degrade extracellular matrix to remove damaged tissue, but can harm healthy tissue Macrophages Release cytokines, ROS, Cytokines (TNF-α, IL- Promote inflammation and recruit and nitric oxide (NO) to 1) immune cells, but excess can cause kill pathogens tissue damage Nitric Oxide (NO) Has antimicrobial effects but can cause oxidative stress and tissue damage Natural Killer (NK) Release cytotoxic ROS and Cytotoxic Destroy infected cells, but nearby Cells granules to destroy granules healthy cells may be damaged infected or abnormal cells Cytotoxic T Cells Target and kill infected Perforin and Create pores in infected cells, (CD8+ T cells) cells with perforin and Granzymes leading to apoptosis, but can also granzymes affect nearby healthy cells Complement System Activates immune Complement Proteins Kills pathogens but can lead to host responses and forms the (MAC) cell damage if not well regulated membrane attack complex (MAC) 10. What cells in the immune system defend against extracellular pathogens? Cell Type Immune System Function in Defending Against Extracellular Pathogens Neutrophils Innate - Phagocytose and destroy bacteria and fungi using enzymes and reactive oxygen species (ROS). Macrophages Innate - Engulf and digest pathogens through phagocytosis. - Present antigens to T cells. Dendritic Cells Innate - Capture extracellular pathogens and present their antigens to T cells to initiate adaptive immunity. Eosinophils Innate - Attack large extracellular parasites (e.g., worms) by releasing toxic granules. Basophils/Mast Innate - Release histamine and other inflammatory mediators, particularly in Cells allergic reactions and parasitic infections. B Cells Adaptive - Produce antibodies that neutralize pathogens, opsonize them for phagocytosis, and activate the complement system. Helper T Cells Adaptive - Stimulate B cells to produce antibodies and recruit eosinophils to fight extracellular pathogens. - Enhance neutrophil response to bacterial and fungal infections. 7  11. What cells in the immune system defend against intracellular pathogens? Immune Cell Immune Response Type Function Against Intracellular Pathogens Natural Killer (NK) Cells Innate - Detect and kill virus-infected cells with reduced MHC class I expression - Release perforin and granzymes to induce apoptosis in infected cells Macrophages Innate - Engulf and digest pathogens - Activated by IFN-γ to kill intracellular pathogens within phagosome Cytotoxic T Cells (CD8+ Adaptive - Recognize and kill infected cells presenting T cells) antigens on MHC class I molecules - Release perforin and granzymes to destroy intracellular pathogens via apoptosis Helper T Cells (CD4+ T Adaptive - Produce IFN-γ to activate macrophages and cells) cytotoxic T cells - Enhance macrophage ability to kill intracellular pathogens (e.g., bacteria) 12. What are the subtypes of T cells, what surface markers do they express, and what are their respective functions? T-cells ○ Leave bone marrow without surface markers → mature thymus gland to get CD4 or CD8 surface marker with T-cell receptorà naïve T-cell ○ CD4àT helper cell Controls immune responses & coordinates adaptive response Surface markers CD4 T-cell receptor à ○ CD8 Cytotoxic T cell Attacks and searches for pathogens Surface markers CD8 T-cell receptor - B-cells Form & mature in bone marrowà producing a targeted immune response, creating immunological memory Reside in lymphatic tissue (lymph node, spleen) to stay Function ○ Antibody production (key function). ○ Antigen presentation to activate T cells. ○ Formation of memory B cells for long-term immunity. ○ Neutralization of pathogens and opsonization for destruction by phagocytes. 8  13. What are the relevant metabolites of Arachidonic Acid in relation to acute inflammation and what are their respective functions? - Arachidonic acid: o Key in the inflammatory response and its metabolites are necessary for acute inflammation regulation - Metabolized two ways: o Cyclooxygenase (COX) pathway o Lipoxygenase (LOX) pathway - Tx: o NSAID (including ASA)à COX 1 and 2 inhibitorsà prevent formation of prostaglandins o Steroids/Corticosteroidsà block phospholipase C which prevent formation of arachidonic acidà production of leukotrienes and prostaglandins blocked Metabolite Pathway Function Prostaglandins COX Pathway - Vasodilation, increased vascular permeability, induce pain and fever - Cause edema Leukotrienes LOX Pathway - Chemotaxis: Attracts and activates neutrophils - Bronchoconstriction, increase vascular permeability, key in asthma and allergic reactions 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 o Systemic reaction triggered by inflammation due to infection, injury, or trauma o mobilizes the body’s defenses to limit damage and promote healing. - Triggers o Pro-inflammatory cytokines like IL-1, IL-6, and TNF-α, released by macrophages and neutrophils o Cytokine releaseà ↑ Liver Production of Acute-Phase Proteins § Stimulates production of proteins to enhance immune function CRP: Enhances opsonization and pathogen clearance MBL: Activates complement and aids pathogen recognition 9 10 11  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). Cytokine Target Organ/Tissue Activators Function/Effects IL-1 Hypothalamus, liver, bone marrow - Macrophages - Induces fever (hypothalamus) - NK cells - Stimulates acute phase protein production - Mast cells (liver) - Injured cells IL-6 Liver, bone marrow, fat/muscle - Macrophages - Promotes synthesis of acute phase proteins - Injured cells (liver) - Stimulates production of leukocytes TNF-α Hypothalamus, liver, adipose tissue - Macrophages - Induces fever - ECs - Stimulates fat and muscle catabolism to mobilize energy 16. Under what conditions are interferons released? From what cells? What functions do the interferons perform? - Interferons o Signaling proteins that inhibit viral replication and activate immune cells o Released during viral infections. § Produced by virus-infected cellsà mainly macrophages, dendritic cells, and fibroblasts. o Functions: § Interferon-α/β: Inhibit viral replication, degrade viral RNA, and increase MHC class I expression to improve antigen presentation. § Interferon-γ: Activates NK cells and enhances the immune response. 12 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? 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 o On all cells, except RBCs o Found inside cells o Indicate virus infected, non-self, abnormal self-cells o Randomly attach to another proteinà take protein to the surfaceà displays itàRecognized by cytotoxic T cells (CD8) & NK cellsà determine if harmful or not § If harmfulà destruction - MHC II o Only on: § Antigen-presenting cells (macrophages, dendritic cells, B cells) o Display antigen-à recognized by CD4à activate adaptive immune response 13 19. What cells function as the antigen-presenting cells? - Dendritic Cellsà primary function APC o highly specialized o Phagocytic cells - Macrophages - B-lymphocyteà APC but in a very specific way o Few bacteria can immediately activate a B-ell § à typically, a B cell has by a CD4 cell - Pathogens are either in the ICF (virus) or in ECF (bacteriaà e.g. TB, Malaria or leprosy) 14 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 is the process by which B and T lymphocytes develop a wide variety of antigen receptors through gene rearrangement - It occurs during lymphocyte maturation in the bone marrow (for B cells) and the thymus (for T cells). - Central tolerance in the central lymphoid organs (bone marrow and thymus) eliminates self-reactive lymphocytes, ensuring that B and T cells capable of recognizing self-antigens are destroyed, preventing autoimmune responses 15 21. What are “plasma cells” and what role do they play in immunity? - Plasma cells are differentiated B cells that secrete large amounts of antibodies. Antibody Function IgG - Most abundant antibody - neutralizing toxins - opsonizing pathogens - activating the complement system - Sensitization for killing by NK cells - 2nd antibodies produce when you encounter a pathogen - 1st antibody when encountering the same pathogen for the 2nd time - Crosses the placenta to fetus - Binds phagocytes IgA - Confers passive immunity between mom and fetus via breast milk IgM - First antibody produced during an immune response - Effective at forming complexes with antigens and activating the complement system o Makes you feel sick due to this activation - 1st antibodies produced when an encountering a pathogen IgE - Involved in allergic reactions - Binds to allergens and triggers the release of histamine from mast cells and basophils - Provides protection against parasitic infections. IgD - Plays a role in activating B cells - They play a central role in humoral immunity, the part of the immune response that involves antibodies circulating in body fluids. - Plasma cells are essential for: o neutralizing pathogensà marking them for destruction o activating other components of the immune system. - By producing antibodies, plasma cells help the immune system identify and eliminate harmful invaders, preventing infections from spreading or becoming severe. 16 22. Explain a scenario in which a B lymphocyte could act as an antigen presenting cell. - B lymphocyte can act as an antigen-presenting cell (APC) by binding a specific antigen with its receptor, internalizing ità and present the protein on MHC class II molecules surfaceà helper T cells recognize the antigenà activates both CD8 T cell + B cellà antibody production, immune memory formation and pathogen destruction 17  23. What is the difference between primary and secondary lymphoid structures? What is significant about the placement of secondary lymphoid structures? Lymphoid Structure Type Function Bone Marrow Primaryà where o Produces all blood cellsà lymphocytes are including lymphocytes formed/mature o Maturation site for B cells Thymus Primary o Maturation site for T cells Lymph Secondaryà o Filters lymph Nodes where o Traps antigens lymphocytes o Activates lymphocytes reside and are o Connected via lymphatic activated system containing lymph fluid in extracellular space o Distributed throughout the body to filter lymph and catch pathogens. Spleen Secondary o Filters blood o Traps antigens o Activates lymphocytes o Connected via lymphatic system containing lymph fluid in extracellular space o Positioned to filter blood and respond to blood-borne pathogens. o Red pulpà removes old and damaged RBCs o White pulpà Lymphocytes an initiated immune response to blood-borne antigens Mucosa-associated lymphoid tissue (MALT) Secondary o Traps antigens entering via - Tonsils mucosal surfaces (e.g., tonsils, - Peyer’s Peyer’s patches). Patches o Connected via lymphatic (GI) system containing lymph fluid - Appendix in extracellular space o Located in mucosal areas (digestive, respiratory) for rapid response to pathogens 18  24. Describe and compare the various “lines of defense” involved in an innate immune response. Line of Components Function Additional Notes Defense Barrier o Physical barriers: o Prevent pathogens o 1st line of defense in innate immune System Skin, mucous membranes from entering the body by response o Chemical barriers: creating a protective barrier o Physically block pathogens from entering Stomach acid, enzymes in the body. saliva, antimicrobial proteins o Chemical barriers kill or inhibit pathogens. o Microbial barriers: o Microbial flora outcompete harmful Normal microbiota pathogens o Non-specific o Continuous Inflammation o Acute o Increases blood flow o Increases blood flow to the site of infection inflammationà Immediate to infection site or injury, delivering immune cells and protein and short-lived o Recruits immune o Chronic inflammationàpathological and cellsàcauses redness, harmful à can lead to fibrosis swelling, and heat to contain and eliminate the pathogen. Phagocytic o Neutrophils o Engulf and destroy o 2nd line of defense after bypass of the barrier Cells o Macrophages pathogens through system phagocytosis. o Phagocytosis Plasma o Formed in the liver o Plasma proteins that o Enhances the body’s ability to contain and Protein o Clotting system: either prevent the spread of fight infection. Systems Prevents bleeding and traps infection or actively help o Clottingà prevents pathogen from pathogens destroy pathogens. spreading via clotting o Complement o Apart of acute phase o Thrombin also promotes system: Enhances pathogen response inflammation via ­ leukocyte destruction through adhesion, ­ prostaglandin, ­PAF, phagocytosis and cell lysis ­NO o Kinin system: o ComplementàEnhances immune response Promotes vasodilation and o Kininà Increases permeability and increases vascular promotes inflammation permeability Acute Phase o Systemic o Systemic o Part of the broader inflammation response, Response Inflammatory response: inflammatory response: often caused by cytokines due to infection of tissue o Fever o mobilizes the immune injury o Aches system o Helps fight off pathogens by raising body o Fatigue o raises body temperature and promoting immune activity temperature (fever) to inhibit pathogen growth o triggers general malaise. Natural Killer o NK cells o NK cells target and o Fight abnormal host cells and viral Cells & o Interferons destroy virus-infected and infections without prior exposure. Interferons cancer cells o Interferons alert neighboring cells to o Interferons are presence of pathogen signaling proteins that inhibit viral replication and activate immune cells. 19  Study Questions Normal Function of the Cardiovascular System I 1) Describe in detail (including valves) the path that blood takes as it enters the heart from the Vena cava until its final entrance into the Aorta. Steps of Blood Flow Deoxygenated blood from superior/inferior vena cava → Right Atrium Tricuspid valve (R. AV Valve) Right Ventricle Pulmonary valve →Pulmonary arteries → pulmonary circulation Oxygenated blood from pulmonary veins → Left Atrium Mitral valve (L. AV Valve) Left Ventricle Aortic valve → Aorta → systemic circulation 20 2) Review the structure of the heart valves. Between which two structures do we find valves? Between which two structures in the heart do we NOT find valves? - Regulates blood flow and prevention of backflow between different chambers and blood vessels - Between Atria & Ventricles (AV Valve) o Location: § Tricuspid (Right side) § Mitral/Bicuspid (Left side) o Structures: § Leaflets anchored to papillary muscles (w/in ventricles) via chordae tendineae Prevents inverting and backflow o Function: § Atria contractà valves openàblood flows into ventricles § Ventricles contact (systole)à Valves close (preventing backflow into atria) - Between Ventricles & Main Arteries à Semilunar Valves o Location: § Pulmonaryà /b/ RV and pulmonary artery § Aorticà /b/ LV and aorta o Structure: § Unanchored 3-moon-shaped cusps o Function: § Ventricles contractà cusps forced open by pressureà blood flows into pulmonary artery and aorta § When ventricles relaxà blood fills cuspsà pressure from filled cusps cause them to closeà prevent backflow into ventricles - No Valves Found: o Between b/c blood flow is managed by pressure gradient § Vena Cava and RA § Pulmonary veins and LA 21 3) Describe the structure and function of the pericardial sac? - Structure o Fibrous Pericardium § Outermost layer; dense connective tissue § Anchors heart w/in chest o Serous Pericardium § Epicardium (Visceral) Directly covers myocardium Contains autonomic gangliaà nerves that regulate heart function § Parietal Lines the inner surface of fibrous pericardium o Pericardial Fluid § Secreted by serous layers (in pericardial cavity) - Function o Protection § Barrier from infections or inflammation that might be spread from nearby organs o Anchorage o Lubrication § Pericardial fluidà ¯ friction between heart and surrounding structures during heartbeatsà allowing smooth movement o Prevents overexpansion 4) What are the unique structural features of cardiac muscle? - Striated o Intracellular proteins organized patternà generates force for contraction o Striations are found only in cardiac & skeletal muscle - Branching pattern - Intercalated discs o Attach one muscle cell to anotherà physically anchors and electrically couples’ cells o Physical anchors § Desmosomes- Protein anchor cells together § Gap Junctions- Ion channels that allow AP to diffuse between cellsàelectrically coupled cellsà allow rapid spread throughout musclesà cell contract ALL AT ONCE o Critical important for function 22  5) Consider the gap junctions located in the intercalated disks of cardiac muscle. Think about some consequences of selective blockade of those junctions. - Loss of Synchronized Contractionà leading to inefficient or irregular HRà reducing hearts blood pump ability - Arrhythmiasà irregular propagation of impulsesà atrial fibrillation or ventricular tachycardiaà reduce CO and could be life-threatening - Impaired AP Conductionà blocked gap junctionsà slow/stop AP spreadà prolonged contraction timesà delaying/stopping atria and ventricles sequential contractionàsudden cardiac death - Increased Risk of Heart Failureà persistent asynchrony and arrhythmiasà decreases COà potential lead to HF over time - Potential Metabolic Disturbancesà blocking junctions disrupts metabolic signaling (ATP and ions) between cellsà imbalances w/in myocardiumà cellular stress and damageà ­ cardiac dysfunction 6) Describe and explain the ionic basis of the action potential in the autorhythmic cells in the heart. Autorhythmic Cells (1%) Fire APs spontaneously (fire w/o external source) and at a particular frequency Stimulate CM cells to move from stage 0 Never maintain stable resting potentialà b/c of leak Na+ channels Connected via Purkinje fibers Pacesetter Steps 1. -60 mVàall voltage ion channels open 2. Leak Na+ channelsàNa+ entersàslow depolarization towards threshold 3. As depolarization gets closer threshold potentialàTransient Ca2+ channels (T type; Voltage gated channels) open then closeàsome Ca2+ inàbrings membrane to threshold potential 4. At threshold (-40 mV) àLong type Ca2+ channel opensàCa2+ in for longer periodà AP rises 5. At peak 0-5 mVà L type Ca2+ channel closes 6. K+ channels open → repolarization back to -60 mV 23  7) Describe and explain the ionic basis of the action potential in the cardiac muscle cells? Contractile Cardiac Muscle Cell (99%) - Requires stimulation from external source - Wider APà more time in depolarized stateà allows AP spread to cardiac muscles cellsà all cells contract at same time Steps - Phase 4àResting membrane potential - Phase 0àRapid Depolarization o Triggered by external stimuli o Voltage-gated Na+ channels openà rushes in (for short period) - Phase 1àNa+ Channels Close o Membrane peaksà the slightly drops o Voltage-gated Ca2+ & K+ channels open § Ca2+ in § K+ out - Phase 2àPlateau Phase o Sustained depolarization due to opposing directions of Ca2+ in & K+ out o Allows for all cardiac muscle cells to fire APs at same time to contract same time - Phase 3: Repolarization o Ca2+ channels close o K+ continues going outà repolarization - Phase 4àResting membrane potential 8) Where are the autorhythmic cells located in the heart? What is the direction of flow of the action potential? - Locations: ○ SA Nodeà RA Left Atria (Interatrial pathway) AV Node (Internodal pathway) 70-80 AP/min → fastest rate Pacemaker of heart → determines HR ○ AV Nodeà Near Septum in RA 40-60 AP/min ○ Bundle of His (L & R branches) 20-40 AP/minà determined by slow rate of depolarization phase Located in Intraventricular Septum muscle between ventricles Connected to Purkinje fibersàpenetrates L/R ventricular muscle - Direction of Flow of the AP 1. SA Node to 2 locations at same timeàatrial contractionà blood moves to ventricles 2. Spread through atriaàAV nodal delay a. 100msec after SA firingà allows for max filling of ventricles 3. AV node fires 4. Propagation to Bundle of Hisà Purkinje Fibersà ventricle contraction 24 9) Why is the Sinoatrial node considered the pacemaker of the heart? What area of the heart would become the pacemaker if the SA node stopped functioning? - SA node considered pacemaker of the heart because its rapid depolarization rateà à allows pacesetting for the entire heartàinitiates each heartbeat and directing the timing of atrial and ventricular contractions. - If SA node failsà AV node takes over as a secondary pacemaker - If both the SA and AV nodes fail, the Bundle of His or Purkinje fibers act as the heart’s final backup pacemakers o But at a much slower rate 10) What is the purpose of the AV nodal delay? - Allows maximal ventricular filling of blood - Because after AV node fires AP, it goes to bundle of His and causes ventricular contraction 11) If you were to cut off all parasympathetic and sympathetic innervation to the heart, what would heart rate be? Explain why? - 70-80 bpm, it is the natural firing rate of SA node 12) Explain what electrical events happening in the heart generate the waveforms seen in a 12 lead EKG. - P WaveàAtrial Depolarization - PR Intervalà Measures AV nodal delay - QRS complexà Ventricular depolarization - ST Segmentà Ejection of blood from ventricles - T Waveà Ventricular repolarization - TP intervalàDiastole 25  13) If you were to look at a series heart cycles on an EKG, the distance between which two waveforms would decrease if heart rate increased? - R-R interval decreases as HR increases o Clinically used to measure distance between cardiac cycles 14) Review all the electrical and mechanical events of the cardiac cycle. - Graph is only measuring left side of heart, but right side is same thing - Left side higher pressure b/c it’s pumping blood into aorta 1. Ventricular & atrial diastoleà passive filling Blood Flow ○ Blood from superior/inferior vena cava → right atrium → right ventricle ○ Blood from pulmonary vein → left atrium → left ventricle AV valves are open Left Atrial pressure slightly greater than ventricular pressure ○ Allows AV values to stay open 2. Atrial Contraction Atrial pressure still greater than ventricular pressureàAV valve still openà blood goes to ventricles ○ Ventricular volume increases EKG: P wave 3. Isovolumetric ventricular contraction Ventricular pressure becomes greater than atrial pressureàcloses AV valves (EDV) ○ First heart sound (Lub) All valves closed Isovolumetric Ventricular Contraction: ○ Ventricles contractingàsqueezing blood in ventriclesàbuilds up pressure Goal: to increase ventricular pressure to surpass aortic pressure 4. Ventricular Ejection Ventricular pressure > aortic pressureàaortic valve opens Blood leaves L ventricleà Aorta T wave: Repolarization of Ventricles ○ Halfway into T wave: end of ventricular systoleà enter ventricular diastole Ventricular pressure becomes < aortic pressureàaortic valve closes ○ 2nd heart sound (dub) Isovolumetric relaxation ○ All valves closed Ventricular pressure < Aortic pressure Ventricular pressure > Atrial pressure Ventricular pressure becomes < Atrial pressureà Diastole begins again 26 27 28 15) What are the only times during the cardiac cycle that ventricular volume is not changing?’ - Isovolumetric Contraction - Isovolumetric relaxation 16) Describe all the electrical and mechanical events of the cardiac cycle that correspond in time with the QRS complex (and just after, 30-40 msec, the QRS complex) on the EKG? - QRS: Ventricular depolarization Ventricular Pressure > Atrial Pressureà Isovolumetric Contraction ○ AV valve shuts (first heart sound) Ventricular Pressure becomes > Aortic Pressure ○ Aortic Valve opens ○ Leads to ejection phase 29  17) Describe the pressure differences during Isovolumetric contraction between: - Ventricles + Atria ○ Ventricular pressure > atrial pressure Cuspids close - Ventricles + Arteries ○ BUTàVentricular pressure < arterial (aortic) pressure Aorta and pulmonary valves remain close - Ends when ventricle pressure >arterial pressureà Semilunar valves open 18) What is the required change that allows the ventricles to move from Isovolumetric contraction to the ejection phase? - Ventricular pressure must exceed arterial pressure 19) Think of the mechanical events that take place during the second heart sound and answer the following. - What is happening in terms of aortic vs. ventricular pressure? o Aortic pressure is higher than ventricular pressureà closure aortic valve (dub) - What is happening electrically in terms of the EKG? o End of the T wave corresponds to ventricular repolarization and the beginning of diastole - What is happening in terms of the heart valves? o Closure of the aortic and pulmonary valves causes S2, while the AV valves remain closed during isovolumetric relaxation. 20) If a patient had an alteration in his second heart sound (ex. the sound was muffled or involved an abnormal whistle), this would most likely indicate a problem with what structure in the heart? - Semilunar valves (likely aortic valve) 21) A patient with hypertension has a systolic blood pressure of 140mmHg and a diastolic blood pressure of 95mmHg. How high must left ventricular pressure reach in order to end isovolumetric contraction in this patient (give a number value)? - Diastolic BP (95 mmHg) o Represents the pressure in the aorta t the start of ventricular contraction o But LV pressure needs go reach systolic BPà overcome higher resistance caused by HTN - Systolic BP 140mmHgà LV>aortic pressureàends isovolumetric contractionà ejection phase o LV must exceed 140mmHg 30  Study Questions 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. Systemic Circulationà L Side: - Systemic arteries: o Carries fast transport of oxy bloodàorgans o Stores pressure that drives perfusion § Thick and muscular to w/stand pressure - ArteriesàArterioles o Distribute CO depending on demands o Regulate MAP and capillary blood flow § Via vaso-dilation or constriction - ArteriolesàCapillaries o Site of all exchange between tissue & blood o Smallest & most delicate vessels - Systemic Venules o Deoxy blood from organs - Systemic Veins o Return deoxy bloodà heart o Compliant and low resistance § Contain majority of bloodà aka blood reservoir o Valves to prevent backflow Pulmonary Circulationà R Side: - Carries deoxy blood heartà lungsàoxygenatedà back to heart - Pulmonary Artery: Carries deoxy blood - Pulmonary Vein: carries oxy blood - Pulmonary Capillaries o Gas, nutrient and waste exchange occurs 31 2) Review flow dynamics. What factors enhance flow what factors decrease flow. - F = 𝚫P/R o F = flow rate [mL/min] § The blood volume moving through a segment o P = 𝚫pressure gradient § Perfusion Pressure Needed movement of blood o R = resistance § Two sources: Blood Viscosity (hematocrit) à Stable (mostly) o Impacted by ratio of cell to plasma Diameter/radius of vesselsà Major contributor (every changing) o Small changesà big change in resistance - Pressure, Viscosity(thickness), and Diameter (Vasoconstriction/dilation)à affect flow - Enhanced Flow: o ­ pressure௠resistance + vasodilation - Decreased Flow: o ¯ pressureà ­ resistance + vasodilation 3) Review the structure and function of Arteries. How does the structure of the artery wall lend itself to its function? - Structure o Thick, elastic walls w/ muscular layer allow: § Storing pressureàelasticity § Control blood flow § Ensure efficient distribution of oxy blood to tissues o Layers of arteries from inner to outer layer § Endothelium § Connective tissue layeràcollagen & elastic fibers Elastic properties o Energy generated from ventricular diastoleà­ pressureàstretch § Smooth muscle + Sympathetic nerve innervation § External Connective Tissue Cover Inhibit compliance - Major functions o Maintain flow rate from heartàorgans § large diameter = low resistance = high flow rate o Maintain stable blood pressure Force of blood and walls Artery wall stretches during systole Rebounds during diastole → generated perfusion pressure 32 4) Define and explain Systolic vs. Diastolic blood pressure. What is Mean Arterial Pressure? Why is MAP important? - BPà force of blood against vessels o Adequate perfusion o Pressure not too highà vessel damage o Typically obtain noninvasively via brachial artery - Systolic o Maximum pressure generated by ventricular contraction during systole to arteries o ­ Systolic pressureà BP spends more time here - Diastolic o Pressure in blood vessels & arteries when heart at rest o Affecters § Artery wall health § Total blood volume - Mean Arterial Pressure o MAP= diastolic pressure + ⅓ pulse pressure OR 2(DBP) + SBP / 3 o Average pressure in arteries during cardiac cycleà necessary for consistent organ perfusion o Constant perfusion pressure that exists along arteries whether heart activity § Pulse pressure= Systolic pressure - diastolic pressure Potential for perfusion 80-120à min. 80mmHg for adequate tissue perfusion Lower pulse pressure = less blood ventricles can push into aorta 5) Review and understand the steps involved in taking non-invasive arterial blood pressure measurement. - Stethoscope placed at antecubital region, where brachial artery is o First obtain max pressureà add 2-30mmHG - Cuff pressure occludes blood flow - Slow release of cuff pressure to listen for Korotkoff sounds o SystolicàFirst tapping sound § Cuff pressure slightly below systolic o DiastolicàSound disappears § Cuff pressures < diastole - BP is an underestimation 33 6) Compare MAP across the various parts of the vascular tree. - MAP decreases due to resistance o Left ventricle → arteries → arterioles → capillaries → veins 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? - Arterioles o Structure Smooth muscle covering endothelium → enables vasoconstriction/vasodilation Minimal connective tissue Endothelial layer inside ○ Normal tone produced by: Myogenic activity Elastic property of muscle tissue Baseline sympathetic input ○ Function Regulate arterial BPàconstriction/dilation Variably distribution of cardiac output depends on current demands Different organs get different percentages of CO 34  Factors that Cause Arteriolar Vasoconstriction / Vasodilation - Intrinsic – Local factors o Metabolic changesà Chemical (NO or histamine release) or Physical (Temp changes or Myogenic response to stretch) § Detected by endothelium Vasoconstriction Vasodilation Low metabolic activity: High metabolic activity: - ­ O2 - ¯ O2 - ¯ CO2 - ­CO2 - ¯ acidity - ­ acidity - ¯ free adenosine - ­free adenosine (consuming ATP) Arteriole endothelium detects local metabolic Arteriole endothelium detects local metabolic changes → releases endothelin → changes → releases nitric oxide (EDRF)→ vasoconstriction௠flow vasodilationà­ flow - Extrinsicà neuronal/hormonal factors o Sympathetic Nervous Systemà no PNS input § Depends on where the arterial beds reside § Prioritizes blood flow to heart and skeletal muscle § Supply arteriole SM everywhere but brain § Releases Epi or NE Epià release from adrenal medulla o High affinity for beta 2à arterioles on heart and skeletal muscle § Causes bronchodilation in lungs and vasodilation in arteries perfusing skeletal musclesà ­ flow NEà released form adrenal medulla (20%) and postganglionic SN ending o Bind alpha receptorsà arterioles on all other organs § Vasoconstriction௠flow § Helps regulate BP ­ activityà vasoconstriction ¯ activityà vasodilation § Hormones ADH/vasopressin (water retention) and angiotensin 2 (Balance plasma volume and Na+) Both produced by renal system Both cause constriction௠flow 35  8) How do arterioles help regulate mean arterial blood pressure? - Regulate MAP by controlling TPRà via vasoconstriction and vasodilationà able to increase or decrease resistance to blood flowàaffecting MAP - Allowing adjustments of blood flow to meet local tissue demands while also maintaining systemic blood pressure o MAP determined by two main factors: § Cardiac output (CO) CO= Heart Rate (HR) × Stroke Volume (SV) § Total peripheral resistance (TPR) Resistance to blood flow in the vasculature o MAP = CO x TPR § Both MAP and TPR are interrelated and influenced by blood flow ­ flowà vasodilation௠resistance௠TPR + ¯ MAP o ¯SV b/c dilationàcaused PNS input o ¯COà b/c ¯HR ¯flowà vasoconstrictionà­ resistanceà­TRP + ­MAP o SNSà binds alpha receptors constrictà­SV o SNSà binds beta receptors dilationà­SV + HRà ­CO 9) Compare the distribution of cardiac output at rest to during moderate exercise. Discuss some mechanisms by which this distribution changes. - Resting- o CO is primarily distributed to vital organs o CO= 5L - Exercise- o ­ CO (­ 2.5x baselineà12.5L) with the majority directed towardàskeletal muscles and some to the skin for dissipate heat § Heart and lungs ­ blood flow due to ­CO and O2 demand o Body achieves this redistribution via sympathetic stimulation, local metabolic changes, and the muscle pump mechanism o Adjustments allow the body to meet the ­O2 and nutrient demands of active muscles while maintaining essential functions in other areas o Mechanism § ExtrinsicàSNS activation Release Epi/NE from adrenal medulla causing: o Binding B2 receptorsà vasodilation skeletal muscle and heart o Binding aloha receptorsàvasoconstriction all other tissues o ­HR and SVà ­CO o ­Glycogen breakdownà ­ glucose for energy § ExtrinsicàHormonal Release ADH (released from Posterior pituitary) o ­Na+ retention in kidneysà ­H2O retain + maintain BP Aldosterone (adrenal cortex) o ­H2O retention in kidneysà preventing dehydration and maintains BP 36  § Intrinsicà Loss Metabolic Function Active muscles produce metabolic byproducts during exercise (CO2, lactic acid and free adenosine)à Byproducts detected by endothelium (lining of blood vessels) à release NOà local vasodilation in active musclesà ­blood flow to meet ­demand o Despite overall SNS- driven vasoconstriction § Intrinsicà­ Venous Return Muscles contractionsà act as a muscle pumpà ­push back of blood to heart and ­venous return ­venous returnà stretch heart via Frank-Starling Mechanismà ­ SVà ­CO to support ­demand § Intrinsic + ExtrinsicàRedistribution by Arterioles Redistributes cardiac output to match body demands BIG PICTURE - Total ­ CO - ­ blood flow àskeletal muscles, heart sand skin - Brain blood flow remains the same - ¯blood flow to all other organs 10) Review the structure and function of capillaries. How does the structure of capillaries lend itself to its function? - Thin Walls o Made of a single layer of endothelial cells o PurposeàAllow for exchange of gases, nutrients, and wastes - No Smooth Muscle or Connective Tissue o ­flexibility and ­ permeability. - Small Diameter o Blood velocity slows à maximizing opportunity for exchange - Extensive Network o Minimized diffusion distance o Large surface area (reach nearly every cell)à significant space for diffusion - Cross Sectional Area o SA available for diffusion o ­ @ capillary bedsà¯speed/velocity of blood flow through caps. - Gaps and Pores o Everything but cells and plasma able to escape 37  - Metarteriole o Connects an arteriole to a capillary bed o Pathway that can bypass capillariesà directly connect to venules if needed o Partially surrounded by smooth muscleàallowing some control over blood flow into caps - Precapillary Sphincter o Regulates blood flow into caps based on body demand o Controlled by local metabolic activity of tissue § ¯ Metabolic Activity (Rest) Sphincter Constrictsà blood bypasses capillaries bedà restricted flow to capillaries à blood bypasses directly into venule § ­ Metabolic Activity (Exercise) Sphincter Relaxedàblood flows unrestricted into capillaries for nutrient and gas exchange 11) Review capillary bulk flow. Understand the mechanism and function of this passive process. - Passive forces representing net movement of ECF in and out of caps - Regulates distribution of ECF between intravascular (plasma) & interstitial fluid by: o Maintain fluid balance o Supporting BP (limited way) and blood volume o Preventing edema - Drive by pressure gradients (Starling Forces): o Hydrostatic (Pushing) Pressureà Ultrafiltration § Pressure capillary walls § Fluid out of the capillaries § Interstitial hydrostatic pressure → reabsorption § Capillary blood pressure → ultrafiltration § Net reabsorb/filtrationà dependent by Cap BPà which is determined by blood flow via capillaries or metarterioles ­ metabolic activityà ­ cap blood flowàforced ULTRAFILTRATION ¯ metabolic activityà restricted cap blood flowà metarterioles direct to venulesàforced REABSORPTION o Osmotic (Oncotic) (Pulling) Pressureà Reabsorption § Created by plasma proteins (mainly albumin) § Draws water into the capillaries § Capillary Oncotic Pressureà Reabsorption Determined by albumin levels Critical for maintaining plasma volume Remains stable in healthy pt § Interstitial Oncotic Pressureà Ultrafiltration Caused by albumin leakà otherwise not a factor o Hypervolemiaà ­ cap BPà net FILTRATIONà fluid pushed to interstitial spaceà preventing dramatic ­BP o Hypovolemiaà ¯ cap BPà net REABSORPTIONà fluid pushed to intravascular spaceà preventing dramatic ¯BP - Normally ultrafiltration > reabsorptionà Cap BP > Cap Oncotic and Interstitial Hydrostatic 38 12) Review the structure and function of Veins. How does the structure of veins lend itself to its function? - Function: o Deoxy blood tissuesà heart § Except pulmonary veinà carries oxy blood lungsà heart o Blood Reservoir § Holds 60-70% of bloody flow @ rest - How Structure Support Function: o ­Compliance (Stretch) & ­Capacitance o Thin walls + large lumenà accommodates volume o Valvesà prevent BACKFLOW § Flows back to heart even against gravity o ¯ Smooth Muscle= ¯ Structural Rigidityàadaptable to changes in blood volume and pressureà allows for blood storage 13) What is Venous Return? What factors contribute to the maintenance of venous return? - Venous Capacity o Ability to hold blood and store blood o Dependent on: § Vein Compliance ­ Complianceà ­ Capacity ¯Compliance௠Capacity § Body position Standing/sittingà­venous pooling (esp. legs)à ­venous capacityà ¯venous returnà¯CO + MAPàOrthostatic Hypotension/Syncope Laying downà ¯venous capacityà easier venous return to heart § SNS Activation Exercise or Stressà¯venous capacityà­venous return to heart and active muscles § Blood Volume ­blood volume à ­ pressureà ­complianceà ­ capacity ¯ blood volume à ¯ pressureà ¯compliance௠capacity - Venous Return o Flow of blood back into RA of heartà affecting EDV (End Diastolic Volume) and SV (Stroke Volume) o Dependent On 1. SNS Vasoconstrictionà caused by exercise or stress a. ¯ venous capacityà ­venous return to heart and active muscles 2. Skeletal Muscle Activity a. Contractions (esp. legs)à compress veinsà push blood back toward heart 3. Effect of Venous Valves a. Valves ensure venous return toward heart and prevention backflow 4. Respiratory activity a. Thoracic Cavity Pressure > Abdominal Cavity Pressure i. Inhalationà diaphragm moves downward + pleural space w/in TC< atmospheric pressureà causing ¯ Thoracic Cavity Pressure and ­ Abdominal Cavity Pressureà ­ blood into TC 5. Cardiac suction a. W/ each heartbeatà ventricular contractionà­ atrial volumeà– atrial pressure à venous return b. During diastoleà ventricular relax + atria expandà ¯ atrial + ventricular pressureà ventricular fillingà maintain venous return c. Critical for maintaining steady blood flow to heart and supporting CO 39 40 14) What are all the factors contributing to MAP? What happens if MAP is too low? What happens if MAP is too high? - Blood Pressure o MAPàMain driving force in supplying blood to tissues=Perfusion Pressure § MAP= CO X TPR § Too low = inadequate perfusion § Too high = increased workload on heart, damage to blood vessels → ¯tissue perfusion 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 o Baroreceptorà monitors to moment BP changes § Adapts to sustain persistent change (few minutes_ § Measures based stretch of artery wall in Aortic Arch and Carotid Sinus) § Sensory (­ or ¯ BP) à baroreceptors detect changeà ­ or ¯ firing rateà signals to Medulla Oblongata (control center) à initial ANS (PNS or SNS) depending on signalà ­ or ¯ MAP ­MAP: ­BPà­arterial wall stretchesà­ baroreceptors firingà ­PNS + ¯SNS à­ vasodilationà ¯CO (HR, SV) + ¯TPRà ¯MAP + BP ¯MAP: ¯BPà ¯arterial wall stretchesà ¯baroreceptors firingà ­SNS +¯PNSàvasoconstrictionà­CO (HR, SV) + ­TPRà­MAP + BP 41 16) What is the system for the long-term control of MAP? Explain how this system operates. - Controlled via renal system - Influences plasma volume via renin release and RAASà that control o Thirst mechanism o Urine Output o Salt balance - Too ¯BPà ¯plasma volume - Too­BPà ­plasma volume Critical Thinking Questions: 17) Consider the following relationships: - SV = EDV – ESV - CO = SV X HR - MAP = CO X TPR - 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. - SEE PAGE 41 - E.g. Question: someone has infection and & it becomes septic. Cytokines & inflammatory mediators released and BP drops. What factors are most directly caused in the change in BP? o TPR 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 - Purpose: o Efficient exchange o Enhanced diffusion o Fluid exchange - How: o F (constant)= Surface Area x Velocity § Causes inverse relationship because of the constant ○ ­ Surface Areaàvelocity ¯ while maintaining constant flow rate 42 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