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Physiological Regulation, Adaptation, and Survival

Physiological Regulation, Adaptation, and Survival. Claude A. Piantadosi, M.D. Professor of Medicine Duke University Medical Center Durham, N.C. USA. Physiology of extreme environments. Objectives

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Physiological Regulation, Adaptation, and Survival

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  1. Physiological Regulation, Adaptation, and Survival Claude A. Piantadosi, M.D. Professor of Medicine Duke University Medical Center Durham, N.C. USA

  2. Physiology of extreme environments • Objectives • Learn common physiological principles involved in defense of homeostasis in extreme environments • Survival limits • Time at DT, DP, DG, D Sv • Cold, heat, high • Efforts to adapt • Tolerance, adaptation, and resilience • Requirements • Water and energy • Vulnerable populations • Very young • Very sick • Very old

  3. Physiology of extreme environments • Survival Biology— Definitions • Homeostasis • `Stability of inner medium is actively regulated • Claude Bernard’s “milieu-interieur” • Walter Cannon’s “Wisdom of the Body” • Stress and strain • An external force—stressor or adaptagent—sufficiently intense to exceed a threshold and invoke a biological response produces strain.

  4. Physiology of extreme environments • General Adaptation Syndrome (Hans Seyle;1907–1982) • Stress is a “non-specific response by the body to any demand,” physical or psychological. • General Adaptation Syndrome represents timed development of the “stress response” to the prolonged action of stressors • initial “alarm reaction” or “shock” phase • second “resistance” or “contra-shock” stage • final “exhaustion” stage

  5. Physiology of extreme environments • Survival Biology— Definitions • Tolerance • Adaptation to a stimulus of constant intensity allows the intensity of the response to decrease over time. Also called habituation. • Fatigue • A diminishing strength of response under the repeated or prolonged influence of a constant stimulus

  6. Physiology of extreme environments • Survival Biology— Definitions • Adaptation • Any functional, structural or molecular change that occurs in the individual as a result of a change in environment • Accommodation, acclimation, acclimatization • We acclimatize to complex environments • Maladaptation • Disease

  7. Physiology of Extreme Environments • Survival analysis • “Time to event” analysis • In medicine, estimate of differences in time until death of patient or cohort • Kaplan-Meier plot displays observed cumulative survival function for individual data • Analog in engineering sciences is "reliability analysis" or "failure-time analysis” • Predicts time for mechanical or electronic components to break down

  8. Physiology of extreme environments Kaplan-Meier Plot 1.00 0.75 Drug Probability of Survival 0.50 .025 Placebo 0 0 6 12 18 24 Survival time (months)

  9. Stress and acclimation Positive acclimation Negative acclimation Physiology of extreme environments High Intensity of stress or strain Low 0 1 2 3 4 Short  Time to tolerance failure  Long

  10. Human survival analysis Physiology of extreme environments 1.00 0.75 Probability of Survival 0.50 Acclimation 0.25 0 0 1 2 3 4 5 6 7 Survival time (arbitrary interval)

  11. Heat shock factors (HSF) Uncoupling proteins (UCP) Hypoxia-inducible factors (HIF) Anti-oxidant response (ARE) Neuroendocrine cells Stalk Posterior pituitary (Neurohypophysis) Anterior pituitary Hormone-secreting cells Programmed cell stress responses Long term Adaptation Slow Adaptation—the “Master” Gland Heat stress AVP Cold stress Generalized stress responses (Adrenal-rapid) ACTH TSH Fast • Integrated NE stress response— HPA axis • Fight or Flight

  12. Physiology of extreme environments • Some things to think about: • How long can you live without water? • Can you adapt to water deprivation? • How long can you live without food? • Which is harder to adapt to— heat or cold? • What is cold water and why is it so dangerous? • What limits exercise capacity at altitude? • What is limits altitude acclimatization in humans?

  13. Physiology of extreme environments • News Headlines • Missing Hiker Ate Ants, Centipedes to Survive • 27-year-old Oregon man is recovering from a broken ankle and five days lost on Mt Adams… • Survivor claims he was lost at sea for 13 months • 37 year old Salvadoran man lived on fish, birds and turtles before washing ashore on the remote Marshall Islands thousands of miles away…

  14. Physiology of Extreme Environments

  15. Physiology of Extreme Environments

  16. Physiology of extreme environments • Resilience: ability to maintain normal physical and psychological function when exposed to even extraordinary levels of stress and trauma (avoidance of serious mental and physical illness) Russo, SJ et al. Nat Neurosci 15: 1475, 2012

  17. Physiology of extreme environments • Development of stress resilience • Stress “inoculation” • Environment • Early life experiences • Resilience training • Genetics • Genome • HPA axis • Neuropetides (NPY, 5-HT) • Epigenetic events • K channel induction/ neuronal silencing • DNA methylation • Changes in gene expression • Stress resilience • Active coping (behavioral adaptation) • Increased fitness Modified from Russo, SJ et al. Nat Neurosci 15: 1475, 2012

  18. Antarctica is the world’s greatest desert! Cold; Similar to surface of Mars (-128oF) Dry; Rainfall ~ Sahara (2”/year); 70-90% world’s fresh water High; South polar plateau 9,300 ft (PB 10,500 ft due to polar low; SaO2 ~87%) Physiology of extreme environments

  19. Amundsen at the Pole December 14, 1911 The Race for the Pole 1911-1912 Scott at the Pole Round trip ~1,850 miles “I am just going outside and may be some time.” Captain L. Oates

  20. The Race for the Pole 1911-1912 “Every detail of our food supplies, clothing and depots worked out to perfection... We have missed getting through by a narrow margin which was justifiably within the risk of such a journey." Final journal, Robert F. Scott "I may say that this is the greatest factor—the way in which the expedition is equipped—the way in which every difficulty is foreseen, and precautions taken for meeting or avoiding it. Victory awaits him who has everything in order –luck, people call it. Defeat is certain for him who has neglected to take the necessary precautions in time; this is called bad luck." The South Pole, Roald Amundsen

  21. Why is cold so hard for us? We are tropical creatures; therefore, we adapt better to heat than to cold Migration of mitochondrial genome (mitochondrial Eve) Physiology of extreme environments

  22. Unassisted recovery is not possible Hypothermia— Medical School 37 Hypothermia 35 Start re-warming Confusion Body Temperature (oC) Afterdrop Shivering stops 30 Coma Death 25 Duration of exposure

  23. Skin Freezing Times (Cheek) P. Tikuisis and A. Keefe

  24. Muscle Performance in the Cold

  25. Physiology of extreme environments • Survival in extreme cold • Avoid wind chill— hastens hypothermia • Avoid frostbite— immobilizes • Shivering— requires extra nutrition • Water for drinking— Need fuel to melt ice

  26. Fatal Hypothermia in Water

  27. How do we adapt to the cold? Cold stress Slow Rapid Loss of body heat Conserve/produce heat Shiver Vasoconstriction Habituation Less shivering Less vasoconstriction Costs energy Conserves energy Keeps up (support metabolism) Falls short (add insulation) Hibernation Add body fat Seek shelter Clothing Heating All vertebrates  Behavioral Adaptation Humans only

  28. Cold acclimation— Heat production • Increased heat production • Shivering • Mitochondrial uncoupling • Primarily in brown fat; mainly newborn in humans • Requires a few days b NE G AC ATP cAMP PKA HSL UCP NE- norepinephrine b- receptor G protein AC-adenylate cyclase ATP-adenosine triphosphate ADP-adenosine diphosphate cAMP-cyclic adenosine monophosphate PKA-protein kinase A UCP-uncoupling protein HSL-heat-sensitive lipase H+- hydrogen ion AS- ATP synthase ETC- electron transport chain FFA- free fatty acids FFA H+ UCP ATP H+ AS ETC ADP

  29. Physiology of extreme environments • Cold acclimation— Adding fat • Leptin/Ghrelin • Leptin is an adipokine that controls energy balance and food intake • Decreases body weight by suppressing appetite and by promoting energy expenditure • Targets hypothalamic neurons by binding to LEPRb, long form of leptin receptor • Leptin-responsive neurons connect widely in the brain forming circuitry that controls energy intake and expenditure • Leptin resistance leads to obesity • Ghrelin • GI hormone produced by gastric epithelial cells • Stimulant for appetite and feeding • Strong stimulant of GH secretion from anterior pituitary • Increases feeling of hunger Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab. 297(6):E1247-59, 2009

  30. Leptin/Ghrelin Satiety Hunger Two subpopulations of arcuate (ARC) neurons are leptin responsive [proopriomelanocortin (POMC) neurons and agouti-related protein (AgRP) neurons]

  31. Physiology of extreme environments The Hot Deserts: Sand and Sea Avoiding dehydration

  32. Physiology of extreme environments • Air temperature usually associated with thermal comfort • Determines convective and evaporative heat loss • Mean radiant temperature equally important • In this room, we radiate out to all surfaces and objects and they radiate back in proportion to their temperature • Heat Index • Shade air temperature/humidity interact to give effective temperature (how hot it "feels") • Exposure to sunshine increases heat index by up to 15°F (8°C) • Evaporative cooling (water loss) becomes paramount as Tamb = Tbody

  33. Sweating Panting Physiology of extreme environments Human heat dissipation is typical of tropical creatures Cow Camel Horse Human 100 Heat dissipation (% of total) 0 Bird Dog Cat Pig Goat

  34. Death by dehydration The 100-hour rule of thumb Cool Heat acclimation Hot Water discipline Physiology of extreme environments 1.00 0.75 Probability of Survival 0.50 0.25 0 0 1 2 3 4 5 6 7 Survival time (days)

  35. Exercise time in the heat— acclimatization works Major event is the production of dilute sweat (salt conservation) 100 7 5 % Subjects still exercising 50 3 Day 1 0 75 0 15 30 45 60 Exercise Time (min) Physiology of extreme environments

  36. Physiology of extreme environments • Natural Disaster • Magnitude 7.9 earthquake • May 12, 2008 • Sichuan Province, China • 69,122 dead /18,000 missing persons • Same as wiping out Chapel Hill • 368,500 injured • 15 million displaced Courtesy New York Times

  37. Sichuan Province, May 12, 2008 Mean daily temperature ~75oF (24oC) 26,000-30,000 people buried alive Physiology of extreme environments 10000 6,375 <2.5% survival if trapped more than 2 days <0.1% survival if trapped more than 4 days 1000 Number of People Rescued 165 100 11 10 2 1 1 1 1 1 0 1 2 3 4 5 6 7 8 9 10 Days after Initial Earthquake

  38. Physiology of extreme environments • Port au Prince Haiti, Jan 12, 2010 • Mean daily temperature ~81oF (27oC) • 170,000 dead; unknown number buried alive N=134

  39. Physiology of extreme environments Effect of Dehydration on Performance A B 39 39 95% Plasma volume 95% 97% 97% 100% 100% Body temperature (oC) 38 38 37 37 0 15 30 45 60 0 2.5 5.0 7.5 10 Exercise time (minutes) Sweat production (ml/m2/min)

  40. Physiology of extreme environments Heat Stroke Mortality 100 75 50 42.5oC Cumulative mortality (%) 25 0 37 39 41 43 45 Body temperature (oC)

  41. Physiology of extreme environments Heat Shock Response Phosphorylation MAPK HSF Induction Heat stress Oxidative stress Proteases Heavy metals Inflammation hsp Hsp RNA poly Hsp 70 Nucleus Proteasomal Degradation Hsp 90 ATP Protection at 24 h Increase protein disposal Prevent protein degradation Reduce oxidative stress Prevent apoptosis Repair ion channels Suppress inflammation X Hsp 60/70 (Importation) ADP Mitochondrion

  42. High Altitude Mt Everest 8848m 27’59” N PB 253 mm Hg 1953- P summit 14% K2 (Chogori) 8611m 35’53” N 1954- P summit 16.5%

  43. Physiology of extreme environments Altitude (thousands of feet) 0 10 20 30 Sea level 750 150 Airliner cabin 500 100 Limit human habitation (5,000 m) Inspired PO2 (mmHg) Barometric pressure (mmHg) Mt Everest (8,848 m) 250 50 0 0 8 0 2 4 6 10 Altitude (km)

  44. Physiology of extreme environments • Hypobaric Hypoxia • Unique to mountain environments • Hypoxia disrupts homeostasis leading to complex set of physiological responses • Altitude acclimatization • Hypoxia is the stimulus to acclimatize • Hyperventilation/respiratory alkalosis • Individual differences in ventilation do matter • Correct term is acclimatization because high altitude is also cold and dry and air density is low

  45. 40 Aircraft 30 Altitude (K) Mt Everest Decompression 20 Cabin 10 0 Flight time Altitude acclimatization is real! Physiology of extreme environments 60,000 50,000 40,000 Altitude (feet) Altitude (m) 10,000 Unconscious 30,000 9,000 8,000 7,000 Conscious 20,000 0 5 10 Time (minutes)

  46. Physiology of extreme environments • Benefits of altitude acclimatization • Improved O2 delivery and utilization • Restore mental performance (1-2 days) • Decrease susceptibility to altitude illness (3-5 days) • Improve sleep quality (5-7 days) • Improve work performance (10-14 days)

  47. Physiology of extreme environments • Failure to Adapt • High-altitude diseases • Acute mountain sickness (AMS) • Occurrence 40-60% over 10,000 ft • High altitude pulmonary edema (HAPE) • Occurrence 2% over 10,000 ft • High altitude cerebral edema (HACE) • Occurrence 1:1,000 over 10,000 ft

  48. Adaptation to Altitude—Limits Hypoxia limits exercise capacity Physiology of extreme environments 100 Sea Level 80 60 Zone of Death (8,000 m) Acclimatization complete VO2 max (%) 40 Summit Mt. Everest (8,848 m) 20 Limit PB 240 mmHg (9,250m) 0 0 50 100 150 Inspired PO2 (mmHg) American Medical Expedition to Everest (AMREE 1981)

  49. Physiology of extreme environments Cellular Hypoxia HIF-1a pVHL Hypoxia-inducible factors Normoxia Nucleus O2 PHDs HIF-1a HIF-1b Ubiquitination HRE Proteasomal Degradation Transcription of target genes mRNA Translation HIF-1 Hypoxia Inducible Factor HRE Hypoxia response element pVHL Von Hippel-Lindau protein PH prolyl hydroxylase EPO erythropoietin VEGF vascular endothelial growth factor VEGF EPO

  50. Physiology of Extreme Environments Adaptation to High Altitude Normal Adapted 100 28 20 Altitude Cold CO Blood O2 content (mL/100mL) 15 21 Fever Exercise 2,3 DPG O2 saturation (%) 50 10 14 5 7 0 0 25 50 75 100 PO2 (mmHg)

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