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Stress pathophysiology Content of the practical = examination questions • Stress and General adaptation syndrome characteristics, phases, regulatory mechanisms. Eustress. Distress. • Psychosomatic disturbances. Iatrogenic diseases. • Pain and stress. Stress-reaction (general adaptation syndrome) is common both for humans and animals Dental Fear It is estimated that as many as 75% of US adults experience some degree of dental fear, from mild to severe. Approximately 5 to 10 percent of U.S. adults are considered to experience dental phobia; that is, they are so fearful of receiving dental treatment that they avoid dental care at all costs What is stress? • Physiological or biological stress is an organism's response to a stressor such as an environmental condition or a stimulus. Stress is a body's method of reacting to a challenge. • Stressor – any influence which is a THREAT to psychological or biological homeostasis Constancy of the Internal Environment (Homeostasis) 1. Constancy in an open system, such as our bodies represent, requires mechanisms that act to maintain this constancy. 2. Steady-state conditions require that any tendency toward change automatically meets with factors that resist change. An increase in blood sugar results in thirst as the body attempts to dilute the concentration of sugar in the extracellular fluid. Cannon W.B. (1932). The wisdom of the body (pp. 299–300). New York: W.W. Norton. Homeostasis (cont.) 3. The regulating system that determines the homeostatic state consists of a number of cooperating mechanisms acting simultaneously or successively. Blood sugar is regulated by insulin, glucagon, and other hormones that control its release from the liver or its uptake by the tissues. 4. Homeostasis does not occur by chance, but is the result of organized self-government. Cannon W.B. (1932). The wisdom of the body (pp. 299–300). New York: W.W. Norton. History of research As a young medical student, Selye noticed that patients with diverse disease conditions had many signs and symptoms in common. He observed that “whether a man suffers from a loss of blood, an infectious disease, or advanced cancer, he loses his appetite, his muscular strength, and his ambition to accomplish anything; usually the patient also loses weight and even his facial expression betrays that he is ill.” Selye referred to this as the “syndrome of just being sick.” Selye noted a triad: • adrenal cortex enlargement, • atrophy of the thymus gland and other lymphoid structures • development of bleeding ulcers in the stomach and duodenal lining. • appeared in rats he was using for his studies. These same three changes developed in response to many different or nonspecific experimental challenges. Other definitions of stress? • Stress results from the ‘interaction between, or misfit of, environmental opportunities and demands, and individuals needs and abilities, and expectations, elicit reactions’. • In its negative sense, stress is defined as “physical, mental or emotional strain or tension; a condition or feeling experienced when a person perceives that demands exceed the personal and social resources that individuals are able to mobilize • Levi L. 1987 Definitions and the Conceptual Aspects of Health in Relation to Work. In Psychosocial Factors at Work and Their Relation to Health. R. Kalimo, M.A. El-Batawi and C.L. Cooper, eds. WHO, Geneva. Sutherland V.J. and C.L. Cooper. 1990 Understanding Stress: A Psychological Perspective for Health Professionals. London: Chapman and Hall. Types of stress • Acute vs chronic • Acute stress is defined as a single exposure on the scale of minutes to hours without cycles of recovery and reexposure • Physical (burns, trauma, noise, infection), • Psychological (emotional) – all factors that demand significant changes of behavior Eustress vs Distress • Selye indicated that not all stress was detrimental; hence, he coined the terms eustress and distress. • Eustress - mild, brief, and controllable -perceived as positive stimuli to emotional and intellectual growth and development. Distress - severe, protracted, and uncontrolled situations of psychological and physical distress that are disruptive of health Classic Stages of Stress • Stage 1 Alarm • Shock phase (1): During this phase, the body can endure changes such as hypovolemia, hypoosmolarity, hyponatremia, hypochloremia, hypoglycemia - the stressor effect. This phase resembles Addison's disease. The organism's resistance to the stressor drops temporarily below the normal range and some level of shock (e.g. circulatory shock) may be experienced. • = prevalent effects of the stressor • Can lasts seconds-days, if stressor is tolerable → phase 2 or if stressor is small, phase 1 is not registered Stress: Stage1 Alarm (phase 2) • Antishock phase: • When the threat or stressor is identified or realized, the body starts to respond and is in a state of alarm. During this stage, the locus coeruleus/sympathetic nervous system is activated and catecholamines such as adrenaline are being produced, The result is: • increased muscular tonus, • increased blood pressure due to peripheral vasoconstriction and tachycardia, • and increased glucose in blood. • There is also some activation of the HPA axis, producing glucocorticoids (hence the fight-or-flight response. • cortisol, aka the S-hormone or stress-hormone). Stress Stage 2 • Resistance • increased secretion of glucocorticoids play a major role, intensifying the systemic response—they have lypolytic, catabolic and antianabolic effects: increased glucose, fat and aminoacid/protein concentration in blood. Moreover, they cause lymphocytopenia, eosinopenia, neutrophilia and polycythemia. In high doses, cortisol begins to act as a mineralocorticoid (aldosteron) and brings the body to a state similar to hyperaldosteronism. Although the body begins to try to adapt to the strains or demands of the environment, the body cannot keep this up indefinitely, so its resources are gradually depleted. Stress Stage 3 Recovery or Exhaustion: • Recovery stage follows when the system's compensation mechanisms have successfully overcome the stressor effect (or have completely eliminated the factor which caused the stress). The high glucose, fat and aminoacid levels in blood prove useful for anabolic reactions, restoration of homeostasis and regeneration of cells. Exhaustion • Exhaustion is the alternative third stage in the GAS model. • All of the body's resources are eventually depleted and the body is unable to maintain normal function. The initial autonomic nervous system symptoms may reappear (sweating, raised heart rate, etc.). If stage three is extended, long-term damage may result (prolonged vasoconstriction results in ischemia which in turn leads to cell necrosis), as the body's immune system becomes exhausted, and bodily functions become impaired, resulting in decompensation. PRE - START of stress Stressors Physical 1) harmful environmental stimuli (fumes, high levels of radiation, unfavorable climate, cold or hot climate, etc.); 2) Disturbances of physiological processes in the body, such as in various diseases, including - infectious, physical overload, etc.; Psychological 3) the need for rapid information processing, ie work in a shortage of time; 4) work in terms of risk to their own lives or the lives of others; 5) perceived threat to life; 6) isolation and imprisonment; 7) ostracism (exile, persecutions), pressure group; 8) lack of control over events; 9) lack of purpose in life; 10) deprivation - lack of stimuli. 11) the threat of "death" of one of the inner psychic parts Stressors of civilized people: are the acute or chronic? Holmes- Rahe Stress Inventory Evolutionary role of stress: what do you need to survive? CNS mechanism of stress Brain cortex Stimulus receptor Reticular formation Hypothalamus Limbic system Threat = Stress Parasympathetic activation 1 Sympathetic activation (150 ms – minutes - hours) 2 Adrenaline reaction (sec – minutes – hours … 10 times longer then 1st) 3 ACTH – cortisol + TTH + STH + aldosterone + vasopressin + angiotensinogen (appr 10 sec. - hours – days – weeks) ACTH • ACTH is recepted not only by cells of the adrenal glands, but by many nerve cells of the brain, and one of its important functions is to consolidate memory, ie transfer information from short-term to long-term memory. Low/moderate levels of stress in most cases improves memory, while a high level - on the contrary, worsen. Glucocorticoids, GABA and opioids reduce the secretion ACTH CRH serotonin, acetylcholine, IL 1 and IL6. Structure of adrenal gland • https://upload.wikimedia.org/wikipedia/commons/thumb/c/ca/1818_The_Adrenal_Glands.jp g/600px-1818_The_Adrenal_Glands.jpg Mechanism of steroid hormones’ action Hypothalamic-PituitaryAdrenal Axis. The response to stress begins in the brain. The hypothalamus is the control center in the brain for many hormones including corticotropinreleasing hormone (CRH). ACTH, Adrenocorticotropic hormone. Stress Interactions PHYSIOLOGIC EFFECTS OF CATECHOLAMINES PHYSIOLOGIC EFFECTS OF CATECHOLAMINES (cont.) PHYSIOLOGIC EFFECTS OF CORTISOL Carbohydrate and lipid metabolism Diminishes peripheral uptake and utilization of glucose; promotes gluconeogenesis in liver metabolism cells; enhances gluconeogenic response to other hormones; promotes lipolysis in adipose tissue Protein metabolism Increases protein synthesis in liver and decreases protein synthesis (including immunoglobulin synthesis) in muscle, lymphoid tissue, adipose tissue, skin, and bone; increases plasma level of amino acids; stimulates deamination in liver Anti-inflammatory effects (systemic effects) Proinflammatory effects (possible local effects) High levels of cortisol used in drug therapy suppress inflammatory response; inhibit proinflammatory activity of many growth factors and cytokines; however, over time some individuals may develop tolerance to glucocorticoids, causingan increased susceptibility to both inflammatory and autoimmune disease Cortisol levels released during stress response may increase proinflammatory effects PHYSIOLOGIC EFFECTS OF CORTISOL (Immune effects) Treatment levels of glucocorticoids are immunosuppressive; thus, they are valuable agents used in numerous diseases; the T-cell or innate immunity system is particularly affected by these larger doses of glucocorticoids with suppression of Th1 function or innate immunity; stress can cause a different pattern of immune response; these nontherapeutic levels can suppress innate (Th1) and increase adaptive (Th2) immunity—the so-called Th1 to Th2 shift; several factors influence this complex physiology and include long-term adaptations, reproductive hormones (i.e., overall, androgens suppress and estrogens stimulate immune responses), defects of hypothalamic-pituitary-adrenal axis, histamine generated responses, and acute vs. chronic stress; thus stress seems to cause a Th2 shift systemically whereas locally, under certain conditions, it can induce proinflammatory activities and by these mechanisms may influence onset or course of infections and autoimmune/inflammatory, allergic, and neoplastic diseases PHYSIOLOGIC EFFECTS OF CORTISOL (cont.) Digestive function Promotes gastric secretion Lipid metabolism Lipolysis in extremities and lipogenesis in face and trunk Urinary function Enhances excretion of calcium Connective tissue function Muscle function Decreases proliferation of fibroblasts in connective tissue (thus delaying healing) Maintains normal contractility and maximal work output for skeletal and cardiac muscle Bone function Decreases bone formation Vascular Maintains normal blood pressure; permits increased system/myocardial responsiveness of arterioles to constrictive action of function adrenergic stimulation; optimizes myocardial performance Central nervous system function Somehow modulates perceptual and emotional functioning; essential for normal arousal and initiation of daytime activity Possible synergism Suppresses maternal immune system to prevent rejection of with estrogen in fetus? pregnancy? Levels of cortisol and melatonin cycle throughout the day “Trier Social Stress Test” (TSST). The researchers asked the participants to conduct a 5-minute speech task and a 5minute mental arithmetic task in front of an audience. Effect of Corticotropin-Releasing Hormone (CRH)—Mast Cell—Histamine Axis, Cortisol, and Catecholamines on the Th1/Th2 Balance—Innate and Adaptive Immunity. 3 phase: Somatotropin + Thyrotropin • ST somatomedin insulin resistance Glucose+FFA • TT T3+T4 sensitivity of tissues to Epi+NorEpi Energy production heart contractility blood pressure OTHER HORMONES THAT INFLUENCE THE STRESS RESPONSE β-Endorphins (endogenous opiates) Pituitary and hypothalamus Growth hormone (GH, somatotropin) Anterior pituitary gland Oxytocin Hypothalamus Testosterone Leydig cells in testes Estrogen Ovaries Substance P (SP) Produced by a neuropeptide classified as tachykinin (increases heart rate subsequent to lowering blood pressure) found in brain, as well as nerves innervating secondary lymphoid tissues Activates endorphin (opiate) receptors on peripheral sensory nerves, leading to pain relief or analgesia Hemorrhage increases levels to inhibit blood pressure or delay compensatory changes that would increase blood pressure1 Affects protein, lipid, and carbohydrate metabolism Counters effects of insulin Involved in tissue repair May participate in growth and function of immune system 2 Levels increase after a variety of stressful stimuli (cardiac catheterization, electroshock therapy, gastroscopy, surgery, fever, physical exercise) Increased levels associated with psychologic stimuli (taking examinations, viewing violent or sexually arousing films, certain psychologic performance tests) Prolonged stress (chronic stress) suppresses growth hormone Promotes bonding and social attachment In animals associated with reduced hypothalamic-pituitary-adrenal (HPA) activation levels and reduced anxiety4 Regulates male secondary sex characteristics and libido Levels decrease after stressful stimuli (anesthesia, surgery, marathon running, mountain climbing)5 Decreased by psychologic stimuli; however, some data indicate that psychologic stress associated with competition (e.g., pistol shooting) increases both testosterone and cortisol levels, especially in athletes older than 45 years6 Markedly reduced in individuals with respiratory failure, burns, and congestive heart failure7 Decreased levels occur during aging and are associated with a lower cortisol responsiveness to stress-induced inflammation8 Works in concert with oxytocin, exerting a calming effect during stressful situations9 SP increases in response to stress; receptors for SP are found on membranes of both T and B cells, mononuclear phagocytic cells, and mast cells; proinflammatory activity induces release of histamine from mast cells during stress response; causes smooth muscle contraction, causes macrophages and T cells to release cytokines, and increases antibody production OTHER HORMONES THAT INFLUENCE THE STRESS RESPONSE Melatonin Produced by pineal gland Increases during stress response; release is suppressed by light and increased in the dark; receptors have been identified on lymphoid cells, possibly higher density of receptors on T cells than B cells; suppression of lymphocyte function by trauma was reversed by melatonin10 Prolactin Anterior pituitary gland; numerous extrapituitary tissue sites Increases in response to many stressful stimuli (including procedures such as gastroscopy, proctoscopy, pelvic examination, and surgery)3 Requires more intense stimuli than those leading to increases in catecholamine or cortisol levels Levels show little change after exercise Somatostatin (SOM) Produced by sensory nerve terminals found in and released from lymphoid cells and hypothalamus Vasoactive intestinal peptide (VIP) Found in neurons of central nervous system (CNS) and in peripheral nerves Natural killer (NK) function and immunoglobulin synthesis are decreased by SOM; growth hormone secretion decreased by SOM Calcitonin gene–related peptide (CGRP) Found in spinal cord motor neurons and in sensory neurons near dendritic cells of skin and in primary and secondary lymphoid tissues CGRP receptors are present on T and B lymphocytes; thus it is likely that CGRP can modulate immune function; CGRP may enhance acute inflammatory response because it is a vasodilator; maturation of immune B lymphocytes is inhibited by CGRP; IL-1 is inhibited by CGRP, which is important for activation of T cells; it has been shown to interfere with lymphocyte activation Neuropeptide Y (NPY) Present in neurons of CNS and in neurons throughout body; co-localized in nerve terminals in lymphatic tissues with norepinephrine Lymphocytes have receptors for NPY and thus may modulate their function; 11 several lines of evidence suggest that NPY is a neurotransmitter and neurohormone involved in stress response; increased levels of NPY occur in plasma in response to severe or prolonged stress; it may be responsible for stress-induced regional vasoconstriction (splanchnic, coronary, and cerebral); it may also increase platelet aggregation2 VIP increases during stress; VIP-containing nerves are located in both primary and secondary lymphoid tissues, around blood vessels, and in gastrointestinal tract; VIP receptors are on both T and B cells; VIP may influence lymphocyte maturation; cytokine production by T cells is modified by VIP; B cells and antibody production are influenced by VIP Stress-limiting systems Reduce the intensity of their effects on target organs. These mechanisms include: • GABA-ergic system • Endogenous opioids • Prostaglandins, • Antioxidant system and • Parasympathetic nervous system. Factors, affecting adaptation to stress Diagnosis of Stress • Heart rate variability testing - defines the state of stress regulatory systems by measuring RR intervals during long time (>5 min) • The content in blood / urine / saliva of: glucocorticoids / catecholamines and their metabolites • The questionnaires and inventories, scales to determine anxiety and anxiety Psychosomatic diseases Psychologic stress may cause or exacerbate (worsen) several disease states, which are called PSYCHOSOMATIC (≠in ICD10 or DSM-V) In 1950 Alexander published a work that described seven conditions thought particularly to have a psychosomatic aspect. These were reverently referred to as the "Holy Seven" in the following years. 1) gastric ulceration, 2) ulcerative colitis, 3) bronchial asthma, 4) essential hypertension, 5) eczema, 6) hyperthyroidism and 7) rheumatoid arthritis Psychoneuroimmunology • 1975 - The possibility of conditional reflex regulation of the immune system • The animals were given water with saccharin and immunosuppressants, producing a conditioned reflex. • After a while immunosuppression observed when giving water with saccharin, even without immunosuppressive drugs http://www.stress.org/stress-effects/ 50 common signs and symptoms of stress 1. Frequent headaches, jaw clenching or pain 2. Gritting, grinding teeth 3. Stuttering or stammering 4. Tremors, trembling of lips, hands 5. Neck ache, back pain, muscle spasms 6. Light headedness, faintness, dizziness 7. Ringing, buzzing or “popping sounds 8. Frequent blushing, sweating 9. Cold or sweaty hands, feet 10. Dry mouth, problems swallowing 11. Frequent colds, infections, herpes sores 12. Rashes, itching, hives, “goose bumps” 13. Unexplained or frequent “allergy” attacks 14. Heartburn, stomach pain, nausea 15. Excess belching, flatulence Stress-related diseases Stress-related disease Stress Pain Symptoms of TMJ problems Some people notice that when stressed, they grind their teeth - particularly at night and this can put pressure on the TMJ. The usual symptoms of TMJ problems are pain, which may be felt as earache, clunking of the jaw, or limitation of movement, causing difficulty in opening the mouth. Other symptoms that may arise are swelling of the joint, headaches, neck pain and tinnitus. Psychosocial factors in TMJ dysfunction • Emotional stress (anxiety, depression, anger) may increase pain by causing autonomic, visceral and skeletal activity and by reduced inhibition via the descending pathways of the limbic system. • The interactions of these biological systems have been described as a vicious "anxiety-pain-tension" cycle which is thought to be frequently involved in TMD. • stress and anxiety grinding of teeth + sustained muscular contraction in the face pain further anxiety prolonged muscular spasm at trigger points+ vasoconstriction, ischemia and release of pain mediators. • The pain discourages use of the masticatory system (a similar phenomenon in other chronic pain conditions is termed "fear avoidance" behavior), which leads to reduced muscle flexibility, tone, strength and endurance. This manifests as limited mouth opening and a sensation that the teeth are not fitting properly • https://en.wikipedia.org/wiki/Temporomandibular_joint_dysfunction Personal traits TMJD • Persons with TMD have a higher prevalence of psychological disorders than people without TMD. People with TMD have been shown to have higher levels of anxiety, depression, somatization and sleep deprivation, and these could be considered important risk factors for the development of TMD. In the 6 months before the onset, 50–70% of people with TMD report experiencing stressful life events (e.g. involving work, money, health or relationship loss). It has been postulated that such events induce anxiety and cause increased jaw muscle activity. Muscular hyperactivity has also been shown in people with TMD whilst taking examinations or watching horror films. • https://en.wikipedia.org/wiki/Temporomandibular_joint_dysfunction Mouth Ulcers The exact cause of most mouth ulcers is unknown. Stress or tissue injury is thought to be the cause of simple mouth ulcers. http://www.webmd.boots.com/oral-health/guide/mouth-ulcers Stress ulcer • - single or multiple mucosal defects which can become complicated by upper gastrointestinal bleeding during the physiologic stress of serious illness. Ordinary peptic ulcers are found commonly in the gastric antrum and the duodenum whereas stress ulcers are found commonly in fundic mucosa and can be located anywhere within the stomach and proximal duodenum. Psychological Stress Inflammation • Appels A. 2000 - anxiety and depression cause increased production of inflammatory cytokines, particularly IL-6 (the level of which is prognostically important in morbidity, mortality, aging). • During anxiety disorders the number of receptors for IL-2 is reduced in lymphocytes an increase in sick days due to acute respiratory infections (La Via MF 1996). Connection between psychology and specific immunity • Kemeny M, 1989 Depressive symptoms are associated with a decrease in the number of T-helper cells which provide Tcell immunity (MD-8) that is developed to increase the frequency of herpes relapse after 6 months. Stress and immunity • Students who responded to the session with more anxiety, more often demonstrated lack of response to immunization against hepatitis B. • During the session wound on the oral mucosa healed by 40% longer. • In individuals who care for disabled immunity disorders can last for years. E.g. level of antibodies against pneumococcus is falling faster after immunization Stress and leukocytes • Studying the effect of stressful intensive care unit (ICU) shifts on medical residents, biologist Matthias Nahrendorf of Harvard Medical School in Boston recently found that blood samples taken when the doctors were most stressed out had the highest levels of neutrophils and monocytes. http://www.sciencemag.org/news/2014/06/how-stress-can-clog-your-arteries Stress and atherosclerosis In mice living with chronic stress, (Nahrendorf) atherosclerotic plaques more closely resemble plaques known to be most at risk of rupturing and causing a heart attack or stroke. When the scientists blocked the β3 adrenoreceptor, though, stressed mice not only had fewer of atherosclerotic plaques, but also had reduced levels of the active immune cells in their plaques, pinpointing β3 as a key link between stress and atheroscelerosis http://www.sciencemag.org/news/2014/06/how-stress-can-clog-your-arteries Iatrogenic disease • Iatrogenic disease is defined as any medical, therapeutic, diagnostic, or prophylactic action that, unintentionally, causes symptoms that need treatment, call for hospital admission, increase hospital stay, cause permanent incapacity or injury, or lead to death. • Can you propose some examples? The diseases we cause: Iatrogenic illness in a department of internal medicine Sofia Madeira, Miguel Melo, João Porto, Sílvia Monteiro, J.M. Pereira de Moura, M.B. Alexandrino J.J. Alves Moura European Journal of Internal Medicine 18 (2007) 391–399 Causes of iatrogenesis include: • side effects of possible drug interactions • complications arising from a procedure or treatment • medical error • negligence • unexamined instrument design[clarification needed] • anxiety or annoyance in the physician or treatment provider in relation to medical procedures or treatments • unnecessary treatment for profit Additional sources http://www.stress.org/education/ http://www.drlam.com/articles/adrenalexhaustion.asp 1. Amico JA et al: J Neuroendocrinol 16(4):319–324, 2004. 2. Rabin BS: The nervous system—immune system connection. In Stress, immune function, and health: the connection, New York, 1999, Wiley-Liss. 3. Rohleder N et al: J Neuroimmunol 126(1-2):69–77, 2002. 4. Marucha PT, Kiecolt-Glaser JK, Favagehi M: Psychosom Med 60(3):362– 365, 1998. 5. Chesnokova V, Melmed S: Endocrinology 143(5):1571–1574, 2002. 6. Guezennec CY et al: Int J Sports Med 16(6):368–372, 1995. 7. Bauer-Wu SM: Clin J Oncol Nurs 6(3):167–170, 2002. 8. Bauer-Wu SM: Clin J Oncol Nurs 6(4):243–246, 2002. 9. Repka-Ramirez MS, Baraniuk JN: Clin Allergy Immunol 17:1–17, 2002. 10. Maestroni GJ: Adv Exp Med Biol 460:396, 1999. 11. Petito JM, Huang Z, McCarthy DB: J Neuroimmunol 54:81, 1994. Thank you for attention!