WEEK 11 - Airway defensive function and pulmonary vascular function

Airway Defensive Function and Pulmonary Vascular Function

Defensive Functions of Respiratory Epithelia

• Respiratory epithelia serve as interfaces between the respiratory system and the external environment.

• Non-sterile air continuously flows through the airways and alveoli.

• Respiratory epithelia perform defensive functions against injury and infection:

  • Airway epithelia:

    • Mucociliary escalator: clears inhaled particles.

    • Secretion of antibodies into the fluid lining the lumen:

      • IgA in larger airways.

      • IgG in smaller bronchioles and alveoli.

  • Alveolar epithelia:

    • Alveolar macrophages are located in the alveoli and phagocytose inhaled foreign material.

The Cough Reflex

• The cough reflex is a protective airway reflex triggered by stimulation of cough receptors in the airways.

• Irritant receptors predominate as cough receptors.

• Cough receptors in the airway wall are mechanically sensitive (especially in the larynx and tracheal carina, stimulated by foreign objects or excessive mucous) and chemically sensitive (especially in the smaller bronchioles).

• When stimulated, these receptors transmit afferent neural signals up the vagi to the cough center in the medulla and evoke the cough reflex, which includes:

  • A deep inspiration.

  • Closure of the glottis, followed by strong contraction of the expiratory muscles, causing high air pressures within the lungs.

  • The glottis then opens suddenly, and air rushes out of the lungs via the mouth (nasopharynx is closed) at high velocity, carrying mucous and aspirated foreign matter.

• Irritant receptors in the nose can evoke the sneeze reflex, similar to the cough mechanism, but the expiratory airflow goes out via the nose.

The Mucociliary Escalator

• Most of the airways are lined internally with ciliated pseudo-stratified epithelium containing mucous-producing goblet cells.

• Ciliated pseudo-stratified epithelial cells are the most common cells of the respiratory epithelium, each having approximately 300 contractile cilia on its apical (luminal) surface.

• The next most common cells are goblet cells, which produce sticky mucous.

• The ciliated cells and goblet cells (and the multicellular glands, which secrete a less viscous serous liquid and are located below the epithelium) collectively make up the mucociliary escalator.

• Inhaled particles (including pathogens) stick to the mucous and are swept up from the tracheobronchial tree by the beating cilia towards the pharynx to be swallowed (cilia in the nasal passages and nasopharynx sweep mucous downwards to be swallowed).

• The mucous and serous fluid also help keep the airway epithelium moist.

• Chronic exposure to cigarette smoke results in an increase in goblet cell numbers and a reduction in the number of ciliated pseudo-stratified columnar cells in the respiratory epithelium; frequent productive coughing (mucous is brought up) may be required to clear the excessive mucous from the airways.

Functions of Pulmonary Circulation

• To bring venous blood in contact with alveolar air for gas exchange.

• To trap thrombi and emboli from systemic circulation.

• Metabolic functions:

  • Converts AT1 to AT2.

  • Inactivates locally acting mediators: noradrenaline, serotonin, bradykinin, prostaglandins (but no effect on adrenaline, histamine, AVP).

• Blood amount makes 40% of the weight of lungs.

• Total blood volume in pulmonary circulation is approximately 500 ml (veins 270 ml, arteries 150 ml, capillaries 80 ml).

• Branching of pulmonary vessels follows branching of airways. Dense capillary beds surround alveoli.

• Pulmonary arteries carry venous blood; pulmonary veins carry arterial blood.

• Pulmonary circulation does not provide blood supply to the conducting zone of airways.

Pulmonary and Bronchial Circulation

Pulmonary Vascular Pressures

• The entire cardiac output travels through both the right and left sides of the heart, but the right ventricular output only needs to travel to the adjacent lungs and therefore requires much less driving pressure than for the left ventricle and systemic circulation.

• Right ventricular pressures:

  • Systolic pressure is much lower than systolic left ventricular and aortic pressures (normally equals approximately 25 mm Hg compared to about 120 mm Hg).

  • Diastolic pressure normally equals approximately 0 mm Hg in both LV and RV.

• Pulmonary arterial pressures:

  • Systolic pulmonary arterial pressure = systolic right ventricular pressure.

  • Diastolic pulmonary arterial pressure = approximately 8 mm Hg, compared to around 80 mm Hg in the aorta (pulmonary arteries have some elastic recoil).

• Pulmonary capillary pressure:

  • Normally equals approximately 7 mm Hg (indirect estimate).

Systemic and Pulmonary Vascular Resistance

• The shorter length (and somewhat wider internal diameter) of the pulmonary vessels means that resistance to blood flow is much lower than in the systemic circulation (Poiseuille’s equation).

• This means that the right ventricle can pump the same amount of blood as the left ventricle but with much less driving pressure.

• Total Peripheral Resistance (TPR) is the total resistance to blood flow in the systemic circulation and is calculated as the pressure gradient along the entire systemic circulation (mean arterial pressure minus venal caval pressure) divided by the total blood flow in the systemic circulation (cardiac output).

• Using typical normal values this comes to: TPR = 93
  ewline mm
  ewline Hg ÷ 5
  ewline L/min = approx.
  ewline 19
  ewline mm
  ewline Hg.min.L^{-1}

• Similarly, Pulmonary Vascular Resistance (PVR) is the total resistance to blood flow within the pulmonary circulation and is calculated as: (mean pulmonary artery pressure - left atrial pressure) ÷ cardiac output.

• Using typical normal values this comes to: PVR = (16
  ewline mm
  ewline Hg – 2
  ewline mm
  ewline Hg) ÷ 5
  ewline L/min = approx.
  ewline 3
  ewline mm
  ewline Hg.min.L^{-1}

Relationships Between Flow, Pressure, and Resistance

• Mean blood pressure (BP) = Blood flow x Vascular resistance (For the systemic circulation this translates to: Mean systemic arterial blood pressure = Cardiac output x Total peripheral resistance).

• Vascular resistance = BP ÷ Blood flow

• Flow = Pressure/Resistance, or Blood
  ewline flow = Blood
  ewline pressure/Vascular
  ewline resistance

• Ohm’s law

Relationships between Vascular Diameter, Length, and Resistance

• (P1 - P2) = F. (Poiseuille's equation)

• n – blood viscosity

• F – blood flow

• F = (P1 - P2) * π * r^4 / (8 * n * l)

• Pressure = Flow * Resistance (Ohm’s law)

• Resistance = (8 * n * l) / (π * r^4)

• Small changes in diameter (or radius) produce large changes in resistance.

Hypoxic Pulmonary Vasoconstriction

• A reduction in alveolar P{O2} (especially if P{AO2} < 70 mm Hg) results in constriction of adjacent pulmonary blood vessels over the ensuing 3-10 minutes (hypoxic pulmonary vasoconstriction).

• The opposite effect occurs (i.e., vasodilation) during hypoxia in the systemic vasculature (i.e., hypoxia causes systemic vasodilation – an important part of systemic microcirculation autoregulation).

• Hypoxia induces pulmonary vasoconstriction:

  • Induced by low O2 content in the alveoli

  • Potentiated by high CO_2

  • Could be regional (e.g., bronchus obstruction) or generalized (high altitude, asthma, COPD)

• Note: this vasoconstriction effect of hypoxia is opposite to systemic circulation.

• Generalized pulmonary vasoconstriction leads to pulmonary hypertension, RV hypertrophy, and heart failure.

Physiological Significance of Hypoxia-Induced Pulmonary Vasoconstriction

• Hypoxic pulmonary vasoconstriction is the major autoregulatory mechanism matching regional blood flow to regional ventilation.

• It prevents blood from perfusing poorly oxygenated areas of the lungs.

• Hypoxia-induced pulmonary vasoconstriction plays a physiological role before birth (in fetus, there is no O2 in alveoli, and only 12% of total cardiac output goes to the lungs).

• First breath > alveolar oxygenation > relaxation of pulmonary vessels > increase in pulmonary blood flow

Effective Oxygenation Requires Matching of Ventilation and Perfusion

• In order for the lungs to effectively oxygenate and decarbonate the blood, the alveoli need to be both adequately ventilated and perfused, so that matching of alveolar ventilation and perfusion is crucial for effective gas exchange.

• For example, in a lung that has collapsed in a pneumothorax or has filled with fluid in pneumonia:

  • Ventilation ceases, so that the pulmonary venous blood returning from that lung remains deoxygenated.

  • Mixing of this deoxygenated blood with the oxygenated blood from the non-affected lung will seriously reduce the systemic arterial P{O2}.

  • However, hypoxic pulmonary vasoconstriction serves a useful function by diverting pulmonary blood flow to where it is most useful - i.e., away from the poorly ventilated lung to the healthy lung.

  • This will minimize the drop in systemic arterial P{O2}, and instead most of the entire cardiac output can pass through the healthy lung where it can be fully oxygenated.

Reflexes That Affect Ventilation

• Chemoreflex stimulates respiratory drive (increased tidal volume and respiratory rate), mediated by:

  • Central chemoreceptors – located in the medulla, sensitive to CO2 and H+ (requires CO2 to diffuse across the blood-brain barrier and form carbonic acid, which dissociates to release H+).

  • Peripheral chemoreceptors – located in the carotid and aortic bodies, stimulated by decreasing P{O2} (weakly sensitive to CO_2 and H+).

• Reflexes mediated by lung and airway receptors – e.g., irritant receptors in the airways which cause reflex coughing and sneezing. Also includes the Hering-Bruer inflation reflex where lung inflation stimulates airway stretch receptors, which inhibits inspiration, but this reflex is weak in adult conscious humans.

• Neural afferent signals from somatic muscle and tendon proprioceptors (e.g., immediate increase in ventilation at the onset of exercise).

Initial vs. Steady State Ventilatory Responses to Exercise

• Neurally mediated changes in respiratory drive are important in regulating ventilation during exercise and produce rapid and potent effects.

• Chemical factors are important in bringing final adjustments to ventilation during exercise to keep P{O2}, P{CO2}, and pH levels as normal as possible.

• Centrally-mediated changes in respiratory drive are important in regulating ventilation during the onset of exercise. This is an example of feed-forward control.

• Chemoreflex-mediated changes are important in maintaining adequate pulmonary ventilation during ongoing exercise to keep P{O2}, P{CO2}, and pH levels as normal as possible.

Regulation of Ventilation During Steady State Exercise

• V{O2} and V{CO2} (rate of O2 consumption and CO2 production) can increase up to 20-fold during strenuous exercise in the healthy individual; ventilation increases almost exactly in step with increased metabolic rate during “steady state” exercise.

• Therefore, during steady state exercise, minute ventilation and alveolar ventilation increase linearly with respect to increasing V{O2}.

• The close matching between increased metabolic rate and increased ventilation in healthy individuals ensures that systemic arterial P{O2}, P{CO2}, and pH change very little during “steady state” exercise.

• Although minute ventilation increases linearly with respect to V{O2} and exercise workload, respiratory frequency contributes more than tidal volume at higher levels of minute ventilation.

• However, minute ventilation increases disproportionately to V{O2} at exercise workloads above the lactate inflection point (at around 60% of V{O2} max in unfit individuals) because at this workload, blood lactate levels begin to increase, and the lactic acid’s H+ stimulates the respiratory center.

Initial Ventilatory Responses to Exercise

• When the brain transmits motor impulses to contracting skeletal muscles during exercise, collateral nerve impulses are transmitted to the brain stem to excite the respiratory center (“anticipatory” stimulation of ventilation). This appears to be at least partly a learned response.

• In addition, joint and muscle proprioreceptors in the arms and legs are stimulated by body movements and send excitatory signals to the respiratory center. These proprioceptive reflexes can be evoked by passive movement.

• These neurally mediated effects produce immediate changes in minute ventilation and alveolar ventilation before increased metabolic rate by the exercising muscles has had sufficient time to increase blood P{CO2} and lower the blood P{O2} and pH.

• Therefore, at the onset of exercise, arterial P{CO2} often falls initially, and arterial pH rises initially (P{O2} can rise initially, but this is not important because ventilation is little affected by an increase in P{O2} when P{O2} > 100 mm Hg).

How Exercise Affects Pulmonary Hemodynamics

Airway Defensive Function and Pulmonary Vascular Function

Defensive Functions of Respiratory Epithelia

• Respiratory epithelia serve as interfaces between the respiratory system and the external environment.

• Non-sterile air continuously flows through the airways and alveoli.

• Respiratory epithelia perform defensive functions against injury and infection:

  • 
    Airway epithelia:

  • Mucociliary escalator: clears inhaled particles efficiently by the coordinated beating of cilia moving mucus up the respiratory tract.

  • Secretion of antibodies into the fluid lining the lumen:

    • IgA in larger airways to neutralize pathogens.

    • IgG in smaller bronchioles and alveoli for opsonization and complement activation.

  • 
    Alveolar epithelia:

  • Alveolar macrophages are located in the alveoli and actively phagocytose inhaled foreign material, including bacteria and dust particles. These macrophages play a crucial role in preventing infections and maintaining a clean alveolar environment.

The Cough Reflex

• The cough reflex is a protective airway reflex triggered by stimulation of cough receptors in the airways, helping to clear irritants and secretions.

• Irritant receptors predominate as cough receptors.

• Cough receptors in the airway wall are mechanically sensitive (especially in the larynx and tracheal carina, stimulated by foreign objects or excessive mucous) and chemically sensitive (especially in the smaller bronchioles).

• When stimulated, these receptors transmit afferent neural signals up the vagi to the cough center in the medulla and evoke the cough reflex, which includes:

  • A deep inspiration to maximize air intake.

  • Closure of the glottis, followed by strong contraction of the expiratory muscles, causing high air pressures within the lungs.

  • The glottis then opens suddenly, and air rushes out of the lungs via the mouth (nasopharynx is closed) at high velocity, carrying mucous and aspirated foreign matter.

• Irritant receptors in the nose can evoke the sneeze reflex, similar to the cough mechanism, but the expiratory airflow goes out via the nose, clearing nasal passages.

The Mucociliary Escalator

• Most of the airways are lined internally with ciliated pseudo-stratified epithelium containing mucous-producing goblet cells.

• Ciliated pseudo-stratified epithelial cells are the most common cells of the respiratory epithelium, each having approximately 300 contractile cilia on its apical (luminal) surface.

• These cilia beat in a coordinated manner to propel mucus and trapped particles upwards.

• The next most common cells are goblet cells, which produce sticky mucous to trap inhaled particles and pathogens.

• The ciliated cells and goblet cells (and the multicellular glands, which secrete a less viscous serous liquid and are located below the epithelium) collectively make up the mucociliary escalator.

• Inhaled particles (including pathogens) stick to the mucous and are swept up from the tracheobronchial tree by the beating cilia towards the pharynx to be swallowed (cilia in the nasal passages and nasopharynx sweep mucous downwards to be swallowed).

• The mucous and serous fluid also help keep the airway epithelium moist, preventing the epithelium from drying out and maintaining its integrity.

• Chronic exposure to cigarette smoke results in an increase in goblet cell numbers and a reduction in the number of ciliated pseudo-stratified columnar cells in the respiratory epithelium; frequent productive coughing (mucous is brought up) may be required to clear the excessive mucous from the airways.

Functions of Pulmonary Circulation

• To bring venous blood in contact with alveolar air for gas exchange, ensuring efficient oxygenation and carbon dioxide removal.

• To trap thrombi and emboli from systemic circulation, preventing them from reaching vital organs.

• Metabolic functions:

  • Converts AT1 to AT2 by angiotensin-converting enzyme (ACE) located on the endothelial cells of pulmonary capillaries.

  • Inactivates locally acting mediators: noradrenaline, serotonin, bradykinin, prostaglandins (but no effect on adrenaline, histamine, AVP).

• Blood amount makes 40% of the weight of lungs.

• Total blood volume in pulmonary circulation is approximately 500 ml (veins 270 ml, arteries 150 ml, capillaries 80 ml).

• Branching of pulmonary vessels follows branching of airways. Dense capillary beds surround alveoli, optimizing gas exchange efficiency.

• Pulmonary arteries carry venous blood; pulmonary veins carry arterial blood.

• Pulmonary circulation does not provide blood supply to the conducting zone of airways.

Pulmonary and Bronchial Circulation

Pulmonary Vascular Pressures

• The entire cardiac output travels through both the right and left sides of the heart, but the right ventricular output only needs to travel to the adjacent lungs and therefore requires much less driving pressure than for the left ventricle and systemic circulation.

• Right ventricular pressures:

  • Systolic pressure is much lower than systolic left ventricular and aortic pressures (normally equals approximately 25 mm Hg compared to about 120 mm Hg).

  • Diastolic pressure normally equals approximately 0 mm Hg in both LV and RV.

• Pulmonary arterial pressures:

  • Systolic pulmonary arterial pressure = systolic right ventricular pressure.

  • Diastolic pulmonary arterial pressure = approximately 8 mm Hg, compared to around 80 mm Hg in the aorta (pulmonary arteries have some elastic recoil).

• Pulmonary capillary pressure:

  • Normally equals approximately 7 mm Hg (indirect estimate).

Systemic and Pulmonary Vascular Resistance

• The shorter length (and somewhat wider internal diameter) of the pulmonary vessels means that resistance to blood flow is much lower than in the systemic circulation (Poiseuille’s equation).

• This means that the right ventricle can pump the same amount of blood as the left ventricle but with much less driving pressure.

• Total Peripheral Resistance (TPR) is the total resistance to blood flow in the systemic circulation and is calculated as the pressure gradient along the entire systemic circulation (mean arterial pressure minus venal caval pressure) divided by the total blood flow in the systemic circulation (cardiac output).

• Using typical normal values this comes to: TPR = 93
  
  ewlinemm
  
  ewlineHg ÷ 5
  
  ewlineL/min = approx.
  
  ewline19
  
  ewlinemm
  
  ewlineHg.min.L^{-1}

• Similarly, Pulmonary Vascular Resistance (PVR) is the total resistance to blood flow within the pulmonary circulation and is calculated as: (mean pulmonary artery pressure - left atrial pressure) ÷ cardiac output.

• Using typical normal values this comes to: PVR = (16
  
  ewlinemm
  
  ewlineHg – 2
  
  ewlinemm
  
  ewlineHg) ÷ 5
  
  ewlineL/min = approx.
  
  ewline3
  
  ewlinemm
  
  ewlineHg.min.L^{-1}

Relationships Between Flow, Pressure, and Resistance

• Mean blood pressure (BP) = Blood flow x Vascular resistance (For the systemic circulation this translates to: Mean systemic arterial blood pressure = Cardiac output x Total peripheral resistance).

• Vascular resistance = BP ÷ Blood flow

• Flow = Pressure/Resistance, or Blood
  
  ewlineflow = Blood
  
  ewlinepressure/Vascular
  
  ewlineresistance

• Ohm’s law

Relationships between Vascular Diameter, Length, and Resistance

• (P1 - P2) = F. (Poiseuille's equation)

  • n – blood viscosity

  • F – blood flow

• F = (P1 - P2) * π * r^4 / (8 * n * l)

• Pressure = Flow * Resistance (Ohm’s law)

• Resistance = (8 * n * l) / (π * r^4)

• Small changes in diameter (or radius) produce large changes in resistance.

Hypoxic Pulmonary Vasoconstriction

• A reduction in alveolar P
  {O2} (especially if P {AO2} <!-- ### Physiological Significance of Hypoxia-Induced Pulmonary Vasoconstriction

• Hypoxic pulmonary vasoconstriction is the major autoregulatory mechanism matching regional blood flow to regional ventilation.

• It prevents blood from perfusing poorly oxygenated areas of the lungs, optimizing gas exchange efficiency.

• Hypoxia-induced pulmonary vasoconstriction plays a physiological role before birth (in fetus, there is no O2 in alveoli, and only 12% of total cardiac output goes to the lungs).

• First breath > alveolar oxygenation > relaxation of pulmonary vessels > increase in pulmonary blood flow

Effective Oxygenation Requires Matching of Ventilation and Perfusion

• In order for the lungs to effectively oxygenate and decarbonate the blood, the alveoli need to be both adequately ventilated and perfused, so that matching of alveolar ventilation and perfusion is crucial for effective gas exchange.

• For example, in a lung that has collapsed in a pneumothorax or has filled with fluid in pneumonia:

  • Ventilation ceases, so that the pulmonary venous blood returning from that lung remains deoxygenated.

  • Mixing of this deoxygenated blood with the oxygenated blood from the non-affected lung will seriously reduce the systemic arterial P{O2}.

• However, hypoxic pulmonary vasoconstriction serves a useful function by diverting pulmonary blood flow to where it is most useful - i.e., away from the poorly ventilated lung to the healthy lung.

• This will minimize the drop in systemic arterial P{O2}, and instead most of the entire cardiac output can pass through the healthy lung where it can be fully oxygenated.

Reflexes That Affect Ventilation

• Chemoreflex stimulates respiratory drive (increased tidal volume and respiratory rate), mediated by:

  • Central chemoreceptors – located in the medulla, sensitive to CO2 and H+ (requires CO2 to diffuse across the blood-brain barrier and form carbonic acid, which dissociates to release H+).

  • Peripheral chemoreceptors – located in the carotid and aortic bodies, stimulated by decreasing P{O2} (weakly sensitive to CO_2 and H+).

• Reflexes mediated by lung and airway receptors – e.g., irritant receptors in the airways which cause reflex coughing and sneezing. Also includes the Hering-Bruer inflation reflex where lung inflation stimulates airway stretch receptors, which inhibits inspiration, but this reflex is weak in adult conscious humans.

• Neural afferent signals from somatic muscle and tendon proprioceptors (e.g., immediate increase in ventilation at the onset of exercise).

Initial vs. Steady State Ventilatory Responses to Exercise

• Neurally mediated changes in respiratory drive are important in regulating ventilation during exercise and produce rapid and potent effects.

• Chemical factors are important in bringing final adjustments to ventilation during exercise to keep P{O2}, P{CO2}, and pH levels as normal as possible.

• Centrally-mediated changes in respiratory drive are important in regulating ventilation during the onset of exercise. This is an example of feed-forward control.

• Chemoreflex-mediated changes are important in maintaining adequate pulmonary ventilation during ongoing exercise to keep P{O2}, P{CO2}, and pH levels as normal as possible.

Regulation of Ventilation During Steady State Exercise

• V{O2} and V{CO2} (rate of O2 consumption and CO2 production) can increase up to 20-fold during strenuous exercise in the healthy individual; ventilation increases almost exactly in step with increased metabolic rate during “steady state” exercise.

• Therefore, during steady state exercise, minute ventilation and alveolar ventilation increase linearly with respect to increasing V{O2}.

• The close matching between increased metabolic rate and increased ventilation in healthy individuals ensures that systemic arterial P{O2}, P{CO2}, and pH change very little during “steady state” exercise.

• Although minute ventilation increases linearly with respect to V{O2} and exercise workload, respiratory frequency contributes more than tidal volume at higher levels of minute ventilation.

• However, minute ventilation increases disproportionately to V{O2} at exercise workloads above the lactate inflection point (at around 60% of V{O2} max in unfit individuals) because at this workload, blood lactate levels begin to increase, and the lactic acid’s H+ stimulates the respiratory center.

Initial Ventilatory Responses to Exercise

• When the brain transmits motor impulses to contracting skeletal muscles during exercise, collateral nerve impulses are transmitted to the brain stem to excite the respiratory center (“anticipatory” stimulation of ventilation). This appears to be at least partly a learned response.

• In addition, joint and muscle proprioreceptors in the arms and legs are stimulated by body movements and send excitatory signals to the respiratory center. These proprioceptive reflexes can be evoked by passive movement.

• These neurally mediated effects produce immediate changes in minute ventilation and alveolar ventilation before increased metabolic rate by the exercising muscles has had sufficient time to increase blood P{CO2} and lower the blood P{O2} and pH.

• Therefore, at the onset of exercise, arterial P{CO2} often falls initially, and arterial pH rises initially (P{O2} can rise initially, but this is not important because ventilation is little affected by an increase in P{O2} when P{O2} > 100$$ mm Hg).

How Exercise Affects Pulmonary Hemodynamics