The Respiratory System L18 & 19 - Chemical and Neuronal Control Mechanisms - Gas Transport & Exchange Flashcards
Basic structure of the respiratory epithelium
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
The purpose of the respiratory system?
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.
Partial pressure of oxygen
PO2
If atmospheric pressure is 100 kPa and normal atmospheric air 21% O2
PO2 is 21 kPa
Partial pressure of CO2
PCO2
Normal air 0.04 % CO2 = 0.04 kPa
partial pressure of arterial oxygen
PaO2
normally about 80 - 100 mm Hg
(NOTE: PAO2 Alveolar oxygen)
partial pressure of arterial CO2
PaCO2
normally about 40 mm Hg
respiratory control center
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
neuronal control of breathing
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
neural control of respiration
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
Chemical control of respiration
Central and peripheral chemoreceptors which sense oxygen, carbon dioxide and pH levels
Two types of mechanisms regulate breathing
neural control and chemical control
inspiration center
automatically generates impulses in rhythmic waves
Neuronal control of breathing- medulla
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
Neuronal control of breathing- pons
-Apneustic centre
Prolongs medullary centre firing
Hence depth of breathing increased
-pneumotaxic centre
Inhibits apneustic centre
Controls rate of breathing
If now we cut between the ponds and medulla
so you separate the pneumotaxic center from the medullary centre you get more irregular breathing because you lost the feedback mechanisms breathing continuous.
If now we cut between the medulla and the spine
we stop breathing because there’s not neural imput from the hindbrain down
Central control of ventilation
Transection above pons:
loss of voluntary control
Transection above medulla:
loss of feedback regulation from pons
breathing continues
Transection of spinal cord:
breathing abolished
Rhythmic discharge of pre-Bötzinger complex
Region of the ventral respiratory group in the medulla
Spontaneous rhythmic discharge
Stimulates rhythmic discharge of motor nerves
Pre-Botzinger complex destroyed by
targeted toxin
Loss of regular rhythm and CO2 responsiveness
Voluntary control of breathing
via cerebral cortex
Sends signals direct to respiratory motor neurones
Sensitive to
temperature
Emotion
Ondine’s Curse’
Loss of automatic control
Lung transplant
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
Chemical Control of Respiration
1-Central chemoreceptors
[H+]
2-Peripheral chemoreceptors – Carotid and Aortic Bodies
Primary peripheral signal is
Also some input from H+
Blood PCO2 has a
bigger influence on ventilation than pH
within the cerebrospinal fluid
HCO3- & H+ do not easily cross the BBB
CO2 - uncharged
does cross BBB and dissociates in CSF
Henderson-Hasselbalch equation
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+]
Peripheral control respiration – O2
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
Nerve firing
increases at low PaO2
Ventilation increases
as PaO2 falls
Arterial CO2 levels kept stable
Regulation of CO2 during sustainable exercise
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
Respiratory stimulants
· 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
Respiratory depressants
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
Why do we breathe?
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
How Do We Transport Oxygen to the Tissues?
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
Haemoglobin (Hb)
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
Oxygen Transport
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
Myoglobin (Mb)
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
CO2 Transport
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
Basic structure: Alveoli and their epithelium
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).
PCO2 higher in
veins than alveolus and systemic arterial blood
PO2 almost same
in alveolus and pulmonary vein, but much higher than in systemic veins (and hence the pulmonary artery)
The high PO2in the lungs causes the blood to release CO2
O2 binding to Hb makes Hb more acidic
Less formation of Hb.CO2
Excess H+ binds bicarbonate to form carbonic acid
CO2 released
Hypoxaemia
(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
Hypercapnia
Increased CO2)
An area with ventilation but no perfusion is termed “dead space”.
Increased “dead space”
pulmonary embolus
Hypoventilation
Physiological response to low inspired O2
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
Altitude sickness
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!)
Genetic adaptations of high altitude populations
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
Key Points
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
