The Respiratory System L18 & 19 - Chemical and Neuronal Control Mechanisms - Gas Transport & Exchange

Question 1

Basic structure of the respiratory epithelium

Answer 1

The airways are lined by a thin layer of epithelial cells:
-Type varies by location
-Protect and help clear the airways of inhaled microbes and debris
-in the alveolar ducts and alveoli, these cells are important for gas exchange

Question 2

The purpose of the respiratory system?

Answer 2

Primary purpose: gas exchange. The provision of O2 to and removal of CO2 from tissues
Regulation of acid-base status by controlling CO2-pH blood / kidney
Activation or deactivation of circulating mediators
-Activation of angiotensin 1 to angiotensin 2
-Deactivation of bradykinin, serotonin, noradrenaline
Filtering microthrombi and other debris from blood
Speech
Breathing (or ventilation) is the process of moving air into and out of the lungs to facilitate gas exchange, this means taking oxygen and eliminate carbon dioxide.

Question 3

Partial pressure of oxygen

Answer 3

PO2
If atmospheric pressure is 100 kPa and normal atmospheric air 21% O2
PO2 is 21 kPa

Question 4

Partial pressure of CO2

Answer 4

PCO2
Normal air 0.04 % CO2 = 0.04 kPa

Question 5

partial pressure of arterial oxygen

Answer 5

PaO2
normally about 80 - 100 mm Hg
(NOTE: PAO2 Alveolar oxygen)

Question 6

partial pressure of arterial CO2

Answer 6

PaCO2
normally about 40 mm Hg

Question 7

respiratory control center

Answer 7

The master controller of the respiration is in the brainstem in the medulla. The medulla is the primaryrespiratory control center. The principal function is to send signals to the muscles that control respiration that causes breathing to happen

Question 8

neuronal control of breathing

Answer 8

Nerve impulses generated within the medulla will travel through the spinal cord down for the motor neurons which will induce contraction of the respiratory muscles, to the external intercostal muscles and the diaphragm. When these muscles contract they will raise the rib cage and flatten the diaphragm which reduces the pressure within the alvioli so will draws air into the lungs

When the lung are full, it will activate a signal to prevent the lungs to over-inflate. These signals are sent by mechano receptors also called stretch receptors in the lungs which will sense how extended the Airways are. When these receptors are on will send a feedback signal to the upper brainstem in the medulla to stop breathing in. These feedback loop maintain a basic rhythm of respiration at rest condition. Bread in –lung full – switch off

But our needs and demand for oxygen, and hence ventilation, changes depends on your activities. Therefore there are additional mechanisms to control breathing.
We have Chemoreceptor which sense oxygen, carbon dioxide and pH levels in the blood and send input to the medulla which modifies the rate and depth of breathing so that, under normal conditions, arterialPCo2, pH, andPo2remain relatively constant.

But we can consusly start breathing faster or slower. For example I’m breathing rapidly before the body actually sensed I need more oxygen

Question 9

neural control of respiration

Answer 9

Central rhythm generator in medulla- located in the medulla and the pons which are part of the brain stem
Receptors in respiratory tract causing sneezing, coughing and hyperpnoea
Nociceptors

Question 10

Chemical control of respiration

Answer 10

Central and peripheral chemoreceptors which sense oxygen, carbon dioxide and pH levels

Question 11

Two types of mechanisms regulate breathing

Answer 11

neural control and chemical control

Question 12

inspiration center

Answer 12

automatically generates impulses in rhythmic waves

Question 13

Neuronal control of breathing- medulla

Answer 13

Automatic control by respiratory centers in brainstem

medulla
Ventral and Dorsal Respiratory Group - Respiratory Centers
-Discharge rhythmically
-efferent neurons to motor nerves
-receives afferent input from periphery and pons
-Little activity in expiratory center at rest

Question 14

Neuronal control of breathing- pons

Answer 14

-Apneustic centre
Prolongs medullary centre firing
Hence depth of breathing increased

-pneumotaxic centre
Inhibits apneustic centre
Controls rate of breathing

Question 15

If now we cut between the ponds and medulla

Answer 15

so you separate the pneumotaxic center from the medullary centre you get more irregular breathing because you lost the feedback mechanisms breathing continuous.

Question 16

If now we cut between the medulla and the spine

Answer 16

we stop breathing because there’s not neural imput from the hindbrain down

Question 17

Central control of ventilation

Answer 17

Transection above pons:
loss of voluntary control

Transection above medulla:
loss of feedback regulation from pons
breathing continues

Transection of spinal cord:
breathing abolished

Question 18

Rhythmic discharge of pre-Bötzinger complex

Answer 18

Region of the ventral respiratory group in the medulla
Spontaneous rhythmic discharge
Stimulates rhythmic discharge of motor nerves

Question 19

Pre-Botzinger complex destroyed by

Answer 19

targeted toxin
Loss of regular rhythm and CO2 responsiveness

Question 20

Voluntary control of breathing

Answer 20

via cerebral cortex
Sends signals direct to respiratory motor neurones
Sensitive to
temperature
Emotion

Ondine’s Curse’
Loss of automatic control

Question 21

Lung transplant

Answer 21

Motor innervation is to skeletal muscles, so ventilation maintained
Preservation of cough from tracheal stimulation
Loss of cough stimulation from lower airway
Loss of Hering-Breuer reflex

Because certain nerve connections to thelungsare cut during the procedure,transplantrecipientscannotfeel the need tocoughor feel when their newlungsare becoming congested
Clinically, theloss ofboth thecoughreflex and impaired mucocillary function plus the useofimmunosuppressive agents places

Question 22

Chemical Control of Respiration

Answer 22

1-Central chemoreceptors
[H+]
2-Peripheral chemoreceptors – Carotid and Aortic Bodies
Primary peripheral signal is
Also some input from H+

Question 23

Blood PCO2 has a

Answer 23

bigger influence on ventilation than pH

Question 24

within the cerebrospinal fluid

Answer 24

HCO3- & H+ do not easily cross the BBB
CO2 - uncharged
does cross BBB and dissociates in CSF

Question 25

Henderson-Hasselbalch equation

Answer 25

ph=pK+log hco3/alpha times pco2
α = solubility coefficient (0.03 mmol/L/mmHg)
pK is the negative log of the dissociation constant for carbonic acid (6.1)

Increase in CSF PCO2=> decrease CSF pH
H+ Stimulates central chemoreceptors
Increase in ventilation
Reduction in blood PCO2

i.e. CO2in blood (not H+) regulates ventilation by its effect on CSF [H+]

Question 26

Peripheral control respiration – O2

Answer 26

Fall in O2 Stimulates glomus cells in carotid and aortic bodies
Contain O2 sensitive K+ channels and dopamine

O2 fall
O2 sensitive K+ channels CLOSE
Depolarisation
DA release
Stimulates afferent fibres
Signals to medulla

Question 27

Nerve firing

Answer 27

increases at low PaO2

Question 28

Ventilation increases

Answer 28

as PaO2 falls
Arterial CO2 levels kept stable

Question 29

Regulation of CO2 during sustainable exercise

Answer 29

Ventilation increases prior to rise in blood CO2
Anticipatory stimulation – higher CNS
Arterial PCO2 levels fall
As exercise proceeds, more CO2 generated
CO2 passes from muscles into venous blood
Efficiently removed in lung
When exercise ceases, ventilation falls rapidly

Question 30

Respiratory stimulants

Answer 30

· Acetazolamide
Carbonic anhydrase inhibitor. Stimulates respiration by creating mild metabolic acidosis via decreased renal reabsorption of bicarbonate and hence reduced acid buffering

		CO2 + H2O           H2CO3                   H+  + HCO3-

Carotid bodies respond to decreased pH (although fall O2 is primary drive)
Doxapram
Closes K+ channels on glomus cell (carotid body)
Glomus cell depolarises
- sends afferent signals to medullary respiratory centre
Central action at high dose
Use in respiratory failure (rarely)

Caffeine (& other xanthines)
Non-specific CNS stimulation, including respiratory centre
Bronchodilator (via phosphodiesterase inhibition?)
Used in sleep apnoea and premature babies

Question 31

Respiratory depressants

Answer 31

Majority of drugs with depressant action on CNS
Central chemoreceptors are very sensitive
Narcotic analgesics
Opiates affect sensitivity to CO2 at low doses, direct suppression of respiratory centre at higher doses
m opioid receptor effects on medulla
barbiturates
Alcohol
H1 antagonists

Question 32

Why do we breathe?

Answer 32

O2 needed for aerobic respiration
Krebs’ cycle cannot proceed without regeneration of NAD+
Electron Transport Chain crucially dependent on O2
ATP generated by respiration required for all active processes
Active transport
Ionic gradients
Nutrient uptake
Anabolic reactions
Muscle contraction
Phosphorylation of targets
Precursor for cAMP
O2 also needed to pay ‘oxygen debt’ after bursts of anaerobic metabolism

Question 33

How Do We Transport Oxygen to the Tissues?

Answer 33

Most O2 is carried bound to haemoglobin (Hb) in the red blood cells

Oxygen is insoluble in water!

The binding of O2in hemoglobin is cooperative

Question 34

Haemoglobin (Hb)

Answer 34

Haemoglobin is a tetramer
4 oxygen-binding haem groups
Binding of 1 O2 to Hb increases affinity for next molecule of O2 to bind
Conversely, loss of O2 from saturated Hb gets easier as O2 is lost
Cooperative

Question 35

Oxygen Transport

Answer 35

Normally almost all O2 (97%) transported in red blood cells bound to haemoglobin (as HbO2)
Hb fully saturated at normal O2 (alveolar 104 mmHg)
Still 90% saturated at 60 mmHg
Total amount of oxygen in arterial blood
= O2 bound to haemoglobin
+ O2 dissolved in blood

Depends on
Saturation of haemoglobin
PO2

Question 36

Myoglobin (Mb)

Answer 36

Role in O2 storage and transport in metabolically active cells
Skeletal and cardiac muscle
Does not bind cooperatively
Single O2 binding site
high affinity
affinity not affected by pH or CO2

So is able to capture O2 released by Hb

Question 37

CO2 Transport

Answer 37

1) CO2 transported mainly (70%) as HCO3-
2) 7% as dissolved CO2
3) 23% as carbamino haemoglobin (HbCO2)

CO2 from tissues diffuses into plasma
Most of this (85%) enters red blood cells and is converted to bicarbonate by carbonic anhydrase

When CO2 production increased (exercise or disease)
Fraction of CO2 increases relative to HCO3-
CO2 in CSF increases
Dissociates in CSF and H+ detection by central chemoreceptors

Question 38

Basic structure: Alveoli and their epithelium

Answer 38

Close approximation between alveolar epithelium and capillary endothelium and fusion of their basement membranes facilitates gas exchange.
The wall is formed from very thin, unciliated squamous epithelial cells (type 1 with a few type 2 pneumocytes which secrete surfactant to reduce surface tension).

Question 39

PCO2 higher in

Answer 39

veins than alveolus and systemic arterial blood

Question 40

PO2 almost same

Answer 40

in alveolus and pulmonary vein, but much higher than in systemic veins (and hence the pulmonary artery)

Question 41

The high PO2in the lungs causes the blood to release CO2

Answer 41

O2 binding to Hb makes Hb more acidic
Less formation of Hb.CO2
Excess H+ binds bicarbonate to form carbonic acid
CO2 released

Question 42

Hypoxaemia

Answer 42

(Low blood O2)
Shunting: An area with perfusion but no ventilation
Anatomical
Unventilated alveoli
Ventilation-perfusion mismatch
Diffusion abnormalities
thickened alveolar wall
Hypoventilation
Neuronal defect or muscle weakness
Obstruction
drug-induced

Question 43

Hypercapnia

Answer 43

Increased CO2)
An area with ventilation but no perfusion is termed “dead space”.
Increased “dead space”
pulmonary embolus
Hypoventilation

Question 44

Physiological response to low inspired O2

Answer 44

Increased ventilation (immediate)
Driven by peripheral chemosensors
Not sustained
Pulmonary vasoconstriction (rapid and sustained)
Homeostatic mechanism designed to shunt blood away from poorly ventilated areas
Not useful if the whole lung is hypoxic!
Increased haematocrit (red cell fraction of blood > 50%)
Activation of the transcription factor HIF (hypoxia inducible factors)
HIF regulates transcription of many genes
Erythropoetin production by kidneys
EPO stimulates bone marrow to make red blood cells

Question 45

Altitude sickness

Answer 45

Chronic mountain sickness
Low PO2 that cannot be matched by ventilation
Increased erythropoetin production in the kidney
Too high haematocrit
Viscous blood
Increased load on right heart
Acetazolamide (carbonic anhydrase inhibitor) inhibits kidney EPO production
Additional effect to the increased ventilation discussed earlier
Acute mountain sickness
Lowlanders moving rapidly to altitude >2500m
Flu-like symptoms, hangover
Breathlessness
Hypoxic pulmonary vasoconstriction
Pulmonary & cerebral oedema (serious!)

Question 46

Genetic adaptations of high altitude populations

Answer 46

Tibetans hypoxaemic (similar to non-altitude populations) at altitude compared with Andeans

Compensation by increased O2 uptake by tissues
Increased muscle capillaries
High myoglobin levels (oxygen binding molecule in muscles)
Myoglobin gene polymorphism

Question 47

Key Points

Answer 47

Ventilation controlled by medulla and pons
Central and peripheral sensors to match demand with supply
O2 transported principally as HbO2
CO2 transported mainly as HCO3-
Physiological and pathological adaptations occur at altitude