physiological regulation, adaptation, and survival claude a. piantadosi, m.d. professor of medicine...

Physiological Regulation, Adaptation,

and Survival

Claude A. Piantadosi, M.D.Professor of Medicine

Duke University Medical CenterDurham, N.C. USA

Objectives Learn common physiological principles involved in

defense of homeostasis in extreme environments Survival limits

Time at T, P, G, Sv Cold, heat, high

Efforts to adapt Tolerance, adaptation, and resilience Requirements

Water and energy Vulnerable populations

Very young Very sick Very old

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.


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

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


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

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

Physiology of Extreme Environments

Survival time (months)

Pro

babi

lity

of S

urvi

val

0 6 12 18 24

0

.025

0.50

0.75

1.00

Placebo

Drug

Kaplan-Meier Plot



Stress and acclimation

Short Time to tolerance failure Long

Intensity of stress or strain

Low

High

0 1 2 3 4

Positive acclimation

Negative acclimation


Human survival analysis

Survival time (arbitrary interval)

Pro

babi

lity

of S

urvi

val

0 1 2 3 40

0.25

0.50

0.75

1.00

5 6 7

Acclimation

Adaptation—the “Master” Gland

Integrated NE stress response— HPA axis Fight or Flight

ACTHTSH

AVP

Cold stress

Heat stress

Generalized stress

responses(Adrenal-rapid)

Programmed cell stress responses

Long term Adaptation

Slow

Heat shock factors (HSF)Uncoupling proteins (UCP)

Hypoxia-inducible factors (HIF) Anti-oxidant response (ARE)Stalk

Neuroendocrinecells

Hormone-secretingcells

Anterior pituitaryPosterior pituitary

(Neurohypophysis)

Fast

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?

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…

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

Physiology of extreme environments Development of stress resilience

Modified from Russo, SJ et al. Nat Neurosci 15: 1475, 2012

Stress “inoculation”•Environment •Early life experiences•Resilience training

Stress resilience•Active coping (behavioral adaptation)•Increased fitness

Epigenetic events•K channel induction/ neuronal silencing•DNA methylation•Changes in gene expression

Genetics•Genome•HPA axis•Neuropetides (NPY, 5-HT)


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%)

The Race for the Pole 1911-1912Amundsen at the Pole

December 14, 1911

“I am just going outside and may be some time.”Captain L. Oates

Round trip ~1,850 milesScott at the Pole

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


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)

Hypothermia— Medical School

37

Duration of exposure

Bo

dy T

em

pera

ture

(oC

)

Death

35

30

25

Unassisted recovery is not possible

Start re-warming

Afterdrop

Hypothermia

Shivering stops

Coma

Confusion

Skin Freezing Times (Cheek)

P. Tikuisis and A. Keefe

Muscle Performance in the Cold

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

Fatal Hypothermia in Water

How do we adapt to the cold?

Rapid Loss of body heat

Conserve/produce heat Shiver

Vasoconstriction

HabituationLess shivering

Less vasoconstriction

Slow

Cold stress

Conserves energyCosts energy

Keeps up(support metabolism)

Falls short(add insulation)

ClothingHeating

Add body fat Seek shelter

All vertebrates Behavioral Adaptation Humans only

Hibernation

Cold acclimation— Heat production

NE- norepinephrine- receptorG protein AC-adenylate cyclase ATP-adenosine triphosphateADP-adenosine diphosphatecAMP-cyclic adenosine monophosphate PKA-protein kinase AUCP-uncoupling proteinHSL-heat-sensitive lipase H+- hydrogen ionAS- ATP synthaseETC- electron transport chainFFA- free fatty acids

GAC

UCP

UCP

HSL

ETC

AS

NE

ATP

cAMPATP

ADP

H+

H+

FFA

Increased heat production Shivering Mitochondrial uncoupling

Primarily in brown fat; mainly newborn in humans

Requires a few days

PKA

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


Leptin/Ghrelin

Two subpopulations of arcuate (ARC) neurons are leptin responsive [proopriomelanocortin (POMC) neurons and agouti-related protein (AgRP) neurons]

Satiety Hunger

The Hot Deserts: Sand and Sea


Avoiding dehydration

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


He

at d

issi

pa

tion

(% o

f to

tal)

Bird

Human

Dog Pig

Camel

Goat

Horse

Cat

Cow

PantingSweating

0

100

Human heat dissipation is typical of tropical creatures


Death by dehydration The 100-hour rule of thumb

Survival time (days)

Pro

babi

lity

of S

urvi

val

0 1 2 3 40

0.25

0.50

0.75

1.00

5 6 7

Hot

Cool

Heat acclimation

Water discipline


Exercise time in the heat— acclimatization works Major event is the production of dilute sweat (salt conservation)

Exercise Time (min)

0 15 30 45 60 75

Day1

3

5

7

% Subjects still exercising

100

0

50


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


Sichuan Province, May 12, 2008 Mean daily temperature ~75oF (24oC) 26,000-30,000 people buried alive

6,375

165

11

21 1 1 1

1

10

100

1000

10000

0 1 2 3 4 5 6 7 8 9 10

Number of People Rescued

Days after Initial Earthquake

<2.5% survival if trapped more than 2 days<0.1% survival if trapped more than 4 days

Physiology of extreme environments Port au Prince Haiti, Jan 12, 2010

Mean daily temperature ~81oF (27oC) 170,000 dead; unknown number buried alive

Haiti Earthquake 1-12-10

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Days after Earthquake

Nu

mb

er

of

Su

rviv

ors

N=134


Bo

dy te

mpe

ratu

re (

oC

)

100%

97%95%

37

38

39

Exercise time (minutes)0 15 30 45 60

APlasma volume

Sweat production (ml/m2/min)0 5.0 107.52.5

37

38

39B

100%

97%95%

Effect of Dehydration on Performance


Body temperature (oC)

Cum

ulat

ive

mor

talit

y (%

)

0

100

37 39 41 43 45

50

75

25

42.5oC

Heat Stroke Mortality


ProteasomalDegradation

HSF

ATP

ADP

Hsp

InductionHeat stress

Oxidative stressProteases

Heavy metalsInflammation

Mitochondrion

hsp

Hsp 60/70(Importation)

Hsp 90

Hsp 70

XProtection at 24 h

Increase protein disposalPrevent protein degradation

Reduce oxidative stressPrevent apoptosis

Repair ion channelsSuppress inflammation

PhosphorylationMAPK

Heat Shock Response

RNA

poly

Nucleus

High Altitude

Mt Everest 8848m27’59” N PB 253 mm Hg1953- P summit 14%

K2 (Chogori) 8611m35’53” N1954- P summit 16.5%

Altitude (km)

Ba

rom

etr

ic p

ress

ure

(m

mH

g)

0

0 2 4 6 10

500

250

750

8

Mt Everest (8,848 m)

Limit human habitation(5,000 m)

Sea level

Inspire

d P

O2

(mm

Hg

)

150

50

0

100

Altitude (thousands of feet)

Airliner cabin

3020100


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

Altitude acclimatization is real!

Time (minutes)

40,000

20,000

60,000

0 5 10

30,000

50,000

Alti

tud

e (

fee

t)

40

20

30

10

0

Cabin

Aircraft

Alti

tude

(K

)

Decompression

Flight time

Conscious

Unconscious10,0009,0008,0007,000

Altitude (m)

Mt Everest


Benefits of altitude acclimatizationImproved 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)


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


Adaptation to Altitude—Limits Hypoxia limits exercise capacity

American Medical Expedition to Everest (AMREE 1981)

1501005000

20

40

60

80

100

VO

2 m

ax

(%)

Inspired PO2 (mmHg)

Summit Mt. Everest (8,848 m)

Sea Level

Limit PB 240 mmHg (9,250m)

Zone of Death (8,000 m)Acclimatization complete


ProteasomalDegradation

EPO

Cellular HypoxiaHIF-1

NormoxiaNucleus

pVHL

Ubiquitination

Translation

Transcriptionof target genes

HRE

HIF-1

HIF-1

mRNA

HIF-1 Hypoxia Inducible FactorHRE Hypoxia response elementpVHL Von Hippel-Lindau protein

PH prolyl hydroxylaseEPO erythropoietin

VEGF vascular endothelial growth factor

PHDsO2

Hypoxia-inducible factors

VEGF


0 25 50 75 1000

50

100

PO2 (mmHg)

O2 s

atur

atio

n (

%)

AltitudeColdCO Fever

Exercise2,3 DPG

5

10

15

20

7

14

21

28

Blood O

2 content (m

L/100mL)

Normal Adapted

Adaptation to High Altitude

Piccard and Kipfer

Beyond the Limits Hard

ShellEngineering

Physiology of Extreme Environments First line of defense

Integrated stress response (generalized adaptation syndrome— fast)

Cellular/molecular adaptations (slow) Underlie integrated physiological response Redundancy/overlap in pathways Reversible

Behavioral adaptation Sensing environmental cues Knowledge and preparation Hard shell engineering

physiological regulation, adaptation, and survival claude a. piantadosi, m.d. professor of medicine...

Documents