Presentation on theme: "Cardiomyocytes form a SYNCITIUM to respond essentially as one big cell. Contractile signals at one site are transmitted quickly and easily to neighboring."— Presentation transcript:
Cardiomyocytes form a SYNCITIUM to respond essentially as one big cell. Contractile signals at one site are transmitted quickly and easily to neighboring cells. Cardiac musculature is arranged in bands so that contraction results in a twist that generates greater force than simple contraction.
Circulatory anatomy is discussed in lab, but you need to know it here too. The conduction system stimulates cardiac muscle contraction in a coordinated way that leads to regular changes in vessel and heart-chamber blood pressure. Understand this diagram, and you know a LOT of cardiac physiology!!! On average, at rest, the cardiac cycle is about 0.8 sec, during which fluid moves from atria to ventricles and is then pumped out. Isovolumetric contraction
SA node is also called “pacemaker” because it depolarizes (spontaneously) more rapidly than any other region of the heart. The SA node has no stable resting potential. Its depolarization comes from a slow inward flow of Ca 2+ ions — Na + influx is involved at the start. AP occurs when voltage- gated Ca 2+ channels reach threshold. Repolarization occurs by increased outward flow of K + ions. AV depolarization is also slow via Ca 2+ ions. 1.HR increase comes from inhibiting vagus nerve release of acetylcholine (ACh) and stimulating release of norepinephrine (NE) from sympathetic neurons. 2.NE increases inward both Na + and Ca 2+ currents 3.T 3 and epinephrine increase HR (tachycardia) 4.Hyperkalemia slows SA firing and can even stop it. 5.Ca 2+ -channel blockers cause bradycardia by slowing inward Ca 2+ currents. 6.We’ll look at other hormones like ADH and angiotensin when we study the kidney.
Precapillary sphincter muscles ring arterioles and can constrict to regulate blood flow through different tissues. Relaxation dilates vessels and increases flow (vasodilation), while vasoconstriction decreases flow. Vasodilation occurs in response to hypoxia, hypercapnia (CO 2 ) and lower pH. Since the vascular system is closed, pressure is affected by TOTAL diameter of vessels, as well as local diameter. Nitric oxide (NO) is an important local regulator of blood pressure. Type II and III nitric oxide synthases produce NO from endothelial cell arginine. Blood shearing releases Ca 2+ to active cNOS (constitutive). Many other substances activate iNOS (inducible). NO relaxes smooth muscles and leads to vasodilation, increased flow and O 2 delivery. iNOS is activated by bacterial endotoxins and inflammatory factors, leading to 1000-fold increase in NO during inflammation!!
Pressure in the arteries is defined as CO x total peripheral resistance (diameter). Cardiac output is determined by extracellular fluid volume, blood volume, vessel compliance and resistance. Control of normal pressure over long periods of time (weeks to months) primarily reflects kidney system (renin-angiotensin) regulation of pressure and water-salt balance. Total peripheral resistance reflects vascular structure and local autoregulatory systems (NO, sphincters). Short-term control (seconds to days) is through neuroendocrine systems, arterial chemo- and baroreceptors, and the autonomic NS (sympathetic & parasympathetic NS). CO x total peripheral resistance
Immune Systems Cells interact to maintain the integrity of an organism
Two dominant themes in all healthcare today are GENETICS— especially cancer genomics and development genetics —and IMMUNOLOGY
Immunity is a complex set of processes that involve 1. an array of specialized MOLECULES involved in ligand- receptor bindings, some involving free molecules and some involving cell membrane receptors. Antibodies, antigens, cell receptors, complement proteins, Toll-like receptors, interleukins, cytokines, and more… 2. an array of IMMUNITY CELLS that have key membrane receptors that recognize millions of different “foreign” ligands called antigens, either in isolation or on cell or virus surfaces. B-lymphocytes, T-lymphocytes, TH1 helper cells, TH2 helper cells, T17 lymphocytes, Dendritic cells, Natural Killer cells (NK cells), plasma cells, memory cells.
3. movements of cells and molecules through blood, lymphatics, lymph nodes, and surfaces where pathogens are most likely found — skin, intestine, respiratory system. 4. cell-cell interactions after phagocytic cells capture pathogens and present them to effector and regulatory cells that then launch reactions against antigens. 5. development of immunity cells from an immature “naïve” status before encountering antigens to mature “effector” cells that bind and remove foreign cells and molecules 6. ALL OF THESE WORK SIMULATANEOUSLY!!!
Phagocytosis of several bacteria (green) by a cell of the immune system – a macrophage
Immunity usually divided into two aspects Innate immunity starts with passive physical structures and mechanisms (skin, pH, mucus), then uses general physiological processes (inflammation, phagocytosis, scavenging cells [NK cells], enzyme cascades, membrane disruption) to neutralize and destroy foreign cells. Adaptive immunity utilizes specific ligand-receptor associations to launch A) neutralizing pathogen-receptor binding and B) destruction of pathogenic/abnormal cells. Innate and adaptive immune systems interact and employ several parallel processes at the same time. Except for structural complexes like mucus, skin or clots, both innate and adaptive immune processes involve ligand- receptor binding as critical signaling steps. Pathogens evolve rapidly, and often evade effective ligand- receptor recognition, thereby leading to illnesses and, of course, death. IMMUNITY DOES NOT ALWAYS WORK!!!
Innate immunity is evolutionarily older than adaptive immunity. It reacts to common characteristics held by many pathogens. Adaptive immunity responds to specific characteristics of one type of pathogen, often developing a memory of the reaction so that a second encounter launches a quicker reaction.
Ligand-Receptor Binding in Immune Reactions Ligands that cause an immune response are called ANTIGENS. After binding to certain receptors, they generate antigenic (immune) reactions. Not all antigens are pathogens, and not all antigens are foreign molecules [i.e. self-antigens] Membrane-bound antigens of a cell are called cell-surface antigens. Other antigens may be secreted as “free or soluble antigens”. Hydrolysis of cells or large antigenic molecules can generate dozens of smaller unique antigens. Receptors for antigens are found as circulating antibodies or cell-surface receptors. A good way to approach immunology is to look at the many receptors of immune systems, the cells that produce them, and the events that follow antigen-receptor binding.
A closer look at the inflammatory response. Underneath epithelial surfaces are MAST CELLS that release a variety of chemical signals: HISTAMINE, prostaglandins, TNF (tumor necrosis factor ) that increases inducible nitric oxid synthase (iNOS) locally increasing vasodilation and capillary permeability, induces endothelial adhesion molecules, stimulates fibroblasts to synthesize collagen (re-epithelialization). Local vasodilation results in increased pressure and fluid leakage, leading to swelling and redness. Swelling lowers access by bacteria to circulatory system. NEUTROPHILS release H 2 O 2 as well as phagocytize bacteria, usually dying in the process — PUS!
Swelling and redness — classic signs of inflammation Inflammation can occur internally as well as on the skin. Internal inflammation can be more serious, leading to internal scarring & swelling
Classic Innate Immune Reaction 1.Physical barrier (e.g. skin) may also release microbicidal molecules such as lysozyme, which can kill a microorganism directly, and defensins. Fingers have lysozyme in their secretions. 2.Re-epithelialization occurs rapidly after a break, with daughter cells generated just behind the wound front. 3.Microbial clearance through ciliary movement (bronchi), sweat, fluid flow. 4.INFLAMMATION. Epithelial cells release chemokines and lipids and express adhesion receptors that launch initial wave of neutrophil extravasion to injury site, followed by macrophages. Intact barrier Disrupted barrier Cathelicidins prevent bacterial adhesions
From an ecosystem perspective, consumers of other cells/organisms are predators that disrupt their prey’s metabolism (at best) or kill them. Microbial predators are called PATHOGENS, the unseen sources of sickness, illness, disease and destruction…bad things, evil, instruments of the devil, God’s wrath, and just plain nasty. Biologically, they’re cellular or molecular predators. The PATHOLOGICAL conditions generated are diseases, infections (coming from the environment), curses, punishments, morbidities, mortalities, a disruption of the good and normal, of “health”. Along with the evolution of pathogens, organisms have co-evolved complex systems that neutralize many pathogens and limit their scope, an INNATE immune system. An ADAPTIVE immune system evolved with vertebrates. It’s activated against specific pathogens, usually shows a memory against those specific pathogens, and adapts with elaborate regulatory steps to distinguish external pathogens from internal “self” cells and molecules. Here’s an overview of an innate and adaptive response to a pathogen. specific general predator
INNATE ADAPTIVE monocyte macrophage Major cells of innate and adaptive immunity. Some cells clearly overlap both systems. Immune systems operate simultaneously. Dendritic cells and macrophages phagocytize microbial cells after recognizing cell-surface antigens. After phagocytosis and digestion, dendritic cells and macrophages generate a wide array of individual microbial antigens, which they then “present” to other immune cells to start an immune response. All these cells have receptors for free antigens. Some cells (e.g. granulocytes) release toxic chemicals that kill pathogenic cells. T H1 T H2
Innate immunity relies on detection of a microbial infection (first discovered in insects). Key receptors have evolved to recognize and bind evolutionarily conserved molecules unique to microbes. Toll proteins bind these microbial molecules and activate inflammatory and innate immune responses. Binding to Toll- like receptors on dendritic cells — major surveyors of epithelial areas like skin and gut — triggers their maturation and can launch steps of the adaptive immune system. After phagocytic cells recognize common cell- surface antigens on microbes, phagocytosis leads to individual pathogen cell digestion and release of pathogen molecular debris. Pathogen debris
Toll-like receptors recognize a variety of common microbial molecules. Several different TLRs bind different Pathogen-associated Molecular Patterns (PAMPs). Key PAMPs include lipopolysaccharides, peptidoglycan (found in bacterial membranes), dsRNA (found in many virus), flagellin (a protein found in bacterial flagella), lipoteichoic acid (found in Gram-positive bacteria). See Fig 35.4 in your book, p 713. Binding of PAMPs by TLRs on dendritic cells upregulates co-stimulatory molecules CD80 and CD86 as well as MHC-II molecules and dendritic cell maturation. Dendritic cell is an ANTIGEN PRESENTING CELL that will lead to the activation of T-lymphocytes.
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