Department of Physiology: Respiratory System Physiology-Review & Illustrations

Pulmonary ventilation: This includes inspiration and expiration.

[A] Inspiration: It is an active process due to increase in the chest cage volume causing the lungs to be expanded. Chest cage volume is increased by:

Downward movement of the diaphragm which accounts for 75% of the change in intrathoracic volume during quiet inspiration. In inspiration, contraction of the diaphragm pulls the lower surfaces of the lungs downward.
Contraction of external intercostal muscles raises the rib cage with consequentmovement of sternum forward away from the spine, making the anterioposterior thickness of the chest greater (by 25%) during maximum inspiration.

When extra drive for respiration is needed or in restrictive airway diseases, the other accessory inspiratory muscles for raising the rib cage came into action such as sternocleidomastoid, anterior serrati, and scalenis.

[B] Expiration: Normal expiration is a passive process. The lungs can be shrink or contracted by two ways:

Relaxation of diaphragm and the inspiratory muscles which cause compression on the lungs.
Elastic recoil tendency of the lung. The lungs have a continual elastic tendency to collapse and therefore to pull away from the chest wall. It is caused by two different factors: [A] The presence of elastic fibers (elastin) throughout the lungs which are stretched by lung inflation and therefore attempt to shorten. They account for about one third of the recoil tendency
[B] The surface tension of the fluid lining the alveoli which is more important, accounts for about two thirds of the recoil tendency, and causes a continual elastic tendency for the alveoli to collapse. The surface tension is caused by intermolecular attraction between the surface molecules of the alveolar fluid that is each molecule pulls on the next one.

When extra drive for respiration is needed or in obstructive airway diseases, the other accessory expiratory muscles are contracted and added to the force needed for rapid expiration such as abdominal recti and internal intercostal muscles.

The Pleura

It consists of parietal and visceral plurae and plural fluid in between them.
The parietal pleura is highly sensitive to pain; the visceral pleura is not, due to its lack of sensory innervation.
Intrapleural pressure (or intrathoracic pressure) (figure) is always slightly below atmospheric pressure (– 4 mm Hg, i.e. about 756 mmHg), at the end of expiration and – 6 mm Hg at the end of inspiration.
The difference between pleural pressure and alveolar pressure is the transpulmonary pressure (figure) which is the driving pressure for lung expansion.
The difference between the alveolar pressure and the body surface pressure is called transthoracic pressure (figure).
The difference between the mouth pressure and the alveolar pressure is called transairway pressure.
The functions of pleura:

Lubrication, allows the pleurae to slide effortlessly against each other during ventilation.
Holding the lungs and rib cage together, due to surface tension of the pleural fluid and the negative intrapleural pressure.
Prevents lung collapse (creation of pressure gradient)
Compartmentalization, The pleurae, mediastinum, and pericardium compartmentalize the thoracic organs and prevent infections of one organ from spreading easily to neighboring organs.

General classification of lung disorders: Lung disease is any disease or disorder where lung function is impaired. There are three major physiologic categories of lung diseases:

Obstructive lung diseases: Difficulty to exhale all the air in the lungs, such as asthma , emphysema , and chronic bronchitis.
Restrictive lung diseases: Difficult to get air in to the lungs, such as: [1] Lack of surfactant. [2] Pulmonary fibrosis, pulmonary edema. [3] Pleural fibrosis. [4] Decrease in the amount of ventilated lung tissue, such as removal of one lung (pneumonectomy). [5] Diseases of the thoracic cage muscles such as paralyzed and fibrotic muscles. [6] Diseases that reduces the expansibility of the thoracic cage such as deformities of the chest cage (as kyphosis, sever scoliosis).
Gas diffusion diseases: A defect in the ability of the tissue of the alveoli to move oxygen into a person's blood through the respiratory membrane, such as pulmonary edema, respiratory distress syndrom, pulmonary odema.

The role of surfactant: It has many important functions:

It reduces the surface tension of the fluid lining the alveoli (figure) and therefore, allowing the lungs to expand.
It stabilizes the sizes of the alveoli: Surfactant plays an important role in stabilizing the sizes of the alveoli (figure) ensure that the alveoli in any one area of the lung all remain approximately the same size.
It prevents accumulation of edema fluid in the alveoli: By decreasing the surface tension of the fluid in the alveoli which tends to pull fluid into the alveoli from the alveolar wall.

Expansibility of the lungs and thorax: Compliance: It is a measure of the ease with which the lung inflates. This is expressed as the volume increase in the lungs for each unit increase in alveolar pressure or for each unit decrease in pleural pressure. Compliance = [V2-V1] / [P2-P1]. The Compliance of the normal lungs and thorax combined (total pulmonary Compliance) is 200 ml / cm H₂O. Any conditions that restrict expansion of the lungs (restrictive lung diseases) cause abnormal low compliance. Increased compliance is produced by the pathological processes that occur in emphysema (due to decrease of elastic fibers) and also result of the aging process.

The work of breathing: 2-3% of the total body energy expended by the body is required to energize the pulmonary ventilatory process. During normal quiet breathing most of the work performed by the respiratory muscles is used to expand the lungs against its elastic forces (compliance work). A small amount of only few per cent of the total work is used to overcome tissue resistance (tissue resistance work) which is due to the viscosity of the lungs and chest wall structures and somewhat more is used to overcome airway resistance (airway resistance work). Compliance work and tissue resistance works are especially increased by diseases that cause fibrosis of the lungs. On the other hand, airway resistance work is increased in heavy breathing and in obstructive airway diseases.

The pulmonary volumes and capacities: Pulmonary ventilation can be recorded by using the spirometer.

[1] The tidal volume (TV): Is the volume of air inspired or expired with each normal breath and it is about 500 ml in average young adult man.
[2] The inspiratory reserve volume (IRV): Is the extra volume of air that can be inspired over and beyond tidal volume and it is about 3000 ml.
[3] The expiratory reserve volume (ERV): Is the extra volume of air that can be expired after the normal tidal expiration, which is about 1100 ml.
[4] The residual volume (RV): Is the volume of air still remaining in the lungs after the most forceful expiration, which is about 1200 ml. This is important because it provides air in the alveoli to aerate the blood even between breaths which otherwise the concentration of oxygen and carbon dioxide in the blood would rise and fall markedly with each respiration, which would certainly be disadvantageous to the respiratory process. This volume cannot be measured directly by spirometer. Therefore, indirect methods must be used.
[5] The inspiratory capacity (IC) = TV +IRV = 500 +3000 = 3500 ml. This is the amount of air that a person can breathe beginning at the normal expiratory level and distending the lungs to the maximum amount.
[6] The functional residual capacity (FRC) = ERV + RV = 1100 + 1200 = 2300 ml. This is the amount of air remaining in the lungs at the end of normal expiration
[7]. The vital capacity (VC) = IRV + TV + ERV = 3000 + 500 + 1100 = 4600 ml. This is the maximum amount of air that a person can expel from the lungs after filling the lungs first to their maximum extent, and then expiring to the maximum extent.
[8] The total lung capacity (TLC) = VC + RV = 4600 + 1200 = 5800 ml. This is the maximum volume to which the lungs can be expanded with the greatest possible inspiratory effort.

All pulmonary volumes and capacities are about 20-25% less in women than men, and they are greater in large athletic persons that in small and asthenic persons. Pulmonary volumes and capacities change with the position of the body, most of them decreasing when the person lies down and increasing on standing, this change with position is caused by two factors: [A]. A tendency for the abdominal contents to press upward against the diaphragm in the lying position. [B]. An increase in the pulmonary blood volume in the lying position, which correspondingly decreases the space available for pulmonary air.

The figure (must be reviewed) shows the changes in respiratory volumes and capacities in restrictive and in obstructive lung diseases. In restrictive lung diseases, TLC is reduced mainly due to reduction in VC. While in obstructive lung diseases, TLC is increased mainly to increase in RV.

Peak expiratory flow (PEF): It is the maximum airflow obtained during maximum expiratory effort after maximum inspiration (400-600 liters/min). The maximum expiratory flow is much greater when the lungs are filled with a large volume of air than when they are almost empty. Consequently, PEF is affected by age, gender, and by height of the subject. Maximum expiratory flow is reduced in cases of restrictive lung diseases and in obstructive lung diseases.

Forced vital capacity (FVC): It is the maximum volume of air expired forcefully following maximum inspiration. In normal subject, the FVC is the person’s vital capacity (VC). However, in obstructive lung diseases, FVC is lower than VC because of small airway collapse and air trapping.

Timed forced vital capacity (or timed forced expiratory volume per first sec, FEV₁): It is the volume of air expired during the first second of forced vital capacity. Normally it is about 80% of the total FVC.

Percent vital capacity (FEV₁%): It is equal to [FEV₁/VC] x 100. In normal subject, the FEV1% is at least 80%. However, in obstructive lung diseases like asthma, FEV₁% is markedly reduced while normal in restrictive lung diseases.

Flow-Volume Curves: Flow-volume curves or loops are graphic representations of the relationship between maximal flow rates and volume of gas during a forced maneuver. The flow volume curves can be used to measure the following: 1. Flow rates during expiration. 2. Peak expiratory flow rate (PEFR). 3. Forced vital capacity (FVC). 4. Forced Expiratory Flow 25%–75% (FEF 25%–75%). The FEF 25%–75% measurement reﬂects the condition of medium- to small-sized airways. Although the FEF 25%–75% has no value in distinguishing between obstructive and restrictive disease, it is helpful in further conﬁrming—or ruling out—an obstructive pulmonary disease in patients with borderline low FEV₁%.

The minute respiratory volume (the minute pulmonary ventilation): The minute respiratory volume is the total amount of new air moved into the respiratory passages each minute and this is equal to TV (500 ml) x respiratory rate (about 12 breaths / min) = 6000 ml.

The dead space: It is the space in which the gas exchange is not taking place. The respiratory passages where no gas exchange takes place are called the anatomical dead spaces (which consist of nose, pharynx, larynx, trachea, bronchi, and bronchioles). The normal anatomical dead space air in the young adult is about 150 ml. This increases slightly with age. It also increases during a maximal inspiration because the trachea and bronchi expand as the lungs expand. There is another type of dead space and is called physiological dead space. This is due to some alveoli are not functional or are only partially functional because of absent or poor blood flow through adjacent pulmonary capillaries.

The minute alveolar ventilation is the volume of new air that reaches the alveoli and is available for gas exchange with the blood equals to = respiratory rate x (tidal volume-dead space), 12 x (500 – 150) = 4200 ml/min.

The factors that affect resistance to air ﬂow:

1. Air way diameter: Is the main component of airway resistance. Resistance to air flow is inversely proportional to air way diameter (or cross sectional area of the air way passages). According to airway diameter, resistance to air ﬂow is of three types: [A] Fixed resistance (cannot change the diameter as in nose, pharynx, larynx, and trachea). [B] Variable resistance (can change the diameter due to the presence of smooth muscles as in bronchi and bronchioles). [C] Dynamic resistance (change in diameter in airway passages that are not supported by cartilages in response to transpulmonary pressures as in bronchioles and distal to them). → → → →The air way resistance can be calculated by the following formula: R = 8*ɳ*L / π*P*r⁴ (where P is the pressure difference [P2-P1], r is the radius of the tube, ɳ is viscosity of the media, L is the length of the tube).
2. Lung volume: At low lung volume, the cross-sectional area is reduced and airway resistance increases, and vice versa.
3. Turbulent gas ﬂow: As the turbulent of the gas flow is increased the resistance to air flow is increased. Turbulent ﬂow occurs where gas ﬂow velocity is high as in: [A] In the larger central airways (small total cross sectional area), [B] At branch points along the conducting airways. Reduction in air way diameter as in bronchoconstriction as a result of reduction in the airway diameter and increases the velocity of ﬂow.

Respiratory passageways resistance :Approximately one-half of the resistance to airflow (Fixed resistance) occurs in the upper respiratory tract (nose and pharynx, fixed resistance) when breathing through the nose (small cross sectional area). This is significantly reduced when mouth breathing. The other one-half of the resistance lies within the lower respiratory tract (variable resistance). This includes bronchi, bronchioles, and terminal bronchioles. This is because they contain smooth muscle in their walls. The chief site of airway resistance in the airway passages is at the medium-sized bronchi, where the radius of the individual bronchi is decreased (i.e. small cross sectional area). The least resistance to air flow is in the very small bronchioles and terminal bronchioles (dynamic airway resistance) because of their large cross-sectional area. However, they are liable to dynamic airway compression because they are not prevented from collapsing by any rigidity (cartilage rings) of their walls.

The smooth muscles of the bronchioles are under nervous and humoral control:

Nervous and humoral control of bronchiole smooth muscle contractions.
Factor	Effect
Parasympathetic stimulation	Bronchoconstriction
Histamine, leukotrienes and Slow Reactive Substance of Anaphylaxis (SRA)	Bronchoconstriction
Low blood PCO₂	Bronchoconstriction
High blood PCO₂	Bronchodilatation
Sympathetic stimulation to the adrenal glands (epinephrine and norepinephrine)	Bronchodilatation, by activation of b₂ receptors

COUGH REFLEX: Stimulated by irritation of lower respiratory mucosa (protective) → Afferent (vagus) → Medulla oblongata → Set of responses.

SNEEZE REFLEX: Stimulated by irritation of upper respiratory mucosa → 5th cranial nerve (trigeminal nerves) → Medulla oblongata → Set of responses.

The set of responses: They are automatic sequence of events triggered by the neuronal circuits of the medulla causing the following effects:

[1] About 2.5 liters of air is inspired .
[2] The epiglottis closes, and the vocal cords shut tightly to entrap the air within the lungs.
[3] The abdominal muscles contract forcefully, pushing against the diaphragm while other expiratory muscles also contract forcefully. Consequently the pressure in the lungs raises to as high as 100 mm Hg or more.
[4] The vocal cords and the epiglottis suddenly open widely (in case of cough reflex and the uvula, in addition, is depressed in case of sneeze reflex) so that air under pressure in the lungs explodes outward. The rapidly moving air (75-100 miles / hour) usually carries with it any foreign matter that is present in the bronchi or trachea or the nasal passages.

The respiratory unit (respiratory membrane): The part of the respiratory system at which gas exchange between the pulmonary blood and the alveolar air is taking place through its membrane. It is estimated to be about 100 square meters, with an average thickness of about 0,6 micron. It consists of the following layers:

[1] A layer of fluid lining the alveolus and containing surfactant.
[2] The alveolar epithelium.
[3] The epithelial basement membrane.
[4] A very thin interstitial space.
[5] A capillary basement membrane that in many places fuses with the epithelial basement membrane and obliterating the interstitial space.
[6] The capillary endothelial membrane.

Factors that affect rate of gas diffusion through the respiratory membrane:

[1] The thickness of the membrane: Any factor that increases the thickness can decrease the rate of gases diffusion (as occurs in in edema of the lung and in some fibrotic diseases of the lung).
[2] The surface area of respiratory membrane: When the total surface area is decreased the exchange of gases through the membrane is decreased (as occurs in emphysema of the lung).
[3] The diffusion coefficient of the gas in the substance of the membrane, which is the water of the membrane: This depends proportionally on the solubility of the gas in the membrane and inversely on the square root of its molecular weight. Therefore, for a given pressure difference, CO₂ diffuse through the membrane about 20 times as rapidly as O₂. Oxygenin turn diffuses about two times as rapidly as nitrogen.
[4] The pressure difference between the two sides of the membrane, which tends to move the gas from area of higher partial pressure to an area of low partial pressure.

Lung diffusing capacity: It is the volume of a gas that diffuses through the membrane each minute for a pressure difference of 1 mm Hg. In average young male adult, the diffusing capacity for oxygen under resting conditions average 21-25 ml/min/mm H, and for CO₂ of about 400-450 ml/min/mm Hg. This is because the diffusion coefficient of CO₂ is 20 times that of O₂.

Ventilation – perfusion ratio (V/Q): It is the ratio of ventilation of a given alveolus to its blood perfusion which is 0.93 (range 0.8-1) and at which proper gas exchange between the blood of alveolar capillaries and alveolar blood is taking place.

At the top of the lung, V/Q is higher (>1.0) (i.e. normal ventilation and low perfusion) than the ideal value, which causes a moderate degree of physiologic dead space → wasted ventilation → severe muscular fatigue and high alveolar PO₂ and low alveolar PCO2(as occurs in pulmonary embolism, a fall in arterial pressure following hemorrhage or breathing against a high pressure as occurs when a person is blowing on a musical instrument).
At the base of the lung, V/Q is low (<0.8) (i.e. low ventilation and normal perfusion) than ideal value as in the base of the lung, which causes a moderate degree of physiological shunted blood → wasted perfusion → low blood PO₂ (hypoxemia) and high blood PCO₂ (hypercapnia). Also, some additional blood flows through the bronchial vessels rather than through the alveolar capillaries, normally about 2% of the cardiac output, this too is unoxygenated, i.e. anatomical shunted blood. The total quantitative amount of shunted blood is called the physiological-anatomical shunt.

Compensatory mechanisms (autoregulation) for matching the ventilation and blood flow (perfusion) in alveoli:

[1] Local blood PO₂: Low alveolar ventilation → Low delivering of O₂ to the blood → Low blood O₂ in the pulmonary vessel → vasoconstriction of pulmonary vessels supplied that alveolus and vice versa.
[2] Local blood PCO₂: High alveolar ventilation → High washing out CO2 from blood → Low blood CO₂ in the pulmonary vessel → bronchoconstriction of the airways supplied that alveolus and vice versa.

Transport of oxygen and carbon dioxide in the blood and body fluids:

	Alveolar air	Arterial blood	Cellular gases		Venous blood
PO₂ (mm Hg)	104	95	<40	40
PCO₂ (mm Hg)	40	40	>46	46

Transport of O₂ in the blood:

97% of O₂ transported in by the blood in chemical combination with Hb in RBC.
3% of O₂ transported in by the blood in a dissolved state in the water of the plasma and blood cells.

O2-Hb dissociation curve: Is a graph that shows the relationship between the percent saturation of hemoglobin and partial pressures of oxygen. It is an S – shaped curve.

A change (whether an increase or a decrease) in PO₂between 10 and 60 mm Hg is associated with similar steep proportional change in the percent saturation of hemoglobin with O₂. At a PO₂ of 60 mm Hg, 90% of the total Hb is combined with O₂.
From 60 mm Hg PO₂ and above, a further increase in PO₂ produces only a much small increase in O₂ binding.
Arteries blood has a PO₂ of about 95 mm Hg → Hb saturation with O₂ is 97% (from O2-Hb dissociation curve) → 19.4 ml of O₂ / 100 ml of blood.
Venous blood has a PO₂ of about 40 mm Hg → Hb saturation with O₂ is 75% (from O2-Hb dissociation curve) → 14.4 ml of O₂ / 100 ml of blood.

Therefore, under normal conditions about 5 ml of O₂ is transported to the tissues by each 100 ml of blood.

P₅₀, is PO₂ at which the Hb is half saturated with O₂.

The O2-Hb dissociation curve is not fixed in position; but it can be shift to the left or right.

The factors that displace the curve to the right, which means that at any given PO₂, Hb has less affinity for O₂ (higher P₅₀), are:

[1] Increased [H⁺] with pH decreasing from 7.4 to 7.2.
[2] Increased CO₂ concentration.
[3] Increased 2,3-diphosphoglycerate (2,3-DPG).
[4] Increased blood temperature.

The factors that shift the curve to the left, which means that at any given PO₂, Hb has more affinity for O₂, are:

[1] Decrease in [H⁺] with an increase in pH from 7.4 to 7.6.
[2] Decreased CO₂ concentration.
[3] Decreased 2,3-diphosphoglycerate (2,3-DPG) as in stored blood under blood bank conditions.
[4] Decreased blood temperature.
[5] The presence of large amount of Hb-F.

Bohr Effect is the effect of CO₂ concentration and [H⁺] on the affinity of Hb to O₂.

[1] In pulmonary circulation → Excess washout of CO₂ from blood to alveoli → Decrease in [CO₂] and [H⁺] in the blood of pulmonary circulation → Hb has more affinity for O₂ (lower P₅₀) → Blood pick up more O₂ from alveoli (loading with O₂).
[2] In tissue circulation → Excess picking up of CO₂ from cells to the blood → Increase in [CO₂] and [H⁺] in the blood of tissue circulation → Hb has less affinity for O₂ (higher P₅₀) → Blood release more O₂ from blood to cells (unloading with O₂).

Transport of CO₂ in the blood: Under normal resting conditions an average of 4 ml of CO₂ is transported from the tissues to the lungs in each 100 ml of blood. The CO₂ in the venous blood is carried to the lung in the following ways:

[1] About 7% of all CO₂ transported to the lungs is in a dissolved state in the blood (plasma and blood cells).
[2] About 70% of CO₂ react with water inside the RBC to form carbonic acid, a reaction catalyzed by the enzyme in RBC called carbonic anhydrase.
[3] The remaining 23% of CO₂ are transported to the lungs by combination with plasma proteins and with Hb in form of carbaminohaemoglobin (HbCO2).

Haldane effect: Is the effect of O₂ concentration on the affinity of Hb to CO₂(HbCO₂).

The smaller the amount of oxygen bound to hemoglobin, the greater the amount of carbon dioxide that can bind to it, and vice versa.

The control of respiration:

This is achieved by respiratory center located in the brain which is composed of three major groups of neurons located bilaterally within the reticular formation of the medulla oblongata and pons.

[1] The dorsal respiratory group (DRG) of neurons: DRG is responsible for the basic rhythm of respiration by autonomous repetitive bursts of inspiratory action potentials. The nerve signal from DRG is transmitted to:

The diaphragmatic muscles (through contralateral phrenic).
To external intercostal muscles through spinal motoneurons.
To the ventral respiratory group.

[2] The ventral respiratory group (VRG): These neurons are located in the medulla and innervate mainly inspiratory and expiratory accessory muscles. VRG is inactive during during normal quiet respiration. When the respiratory drive for increased pulmonary ventilation becomes greater than normal (such as during exercise), respiratory signals from DRG spell over into the VRG. As a consequence, the VRG contributes to the respiratory drive as well.

[3] The pneumotaxic group: This group of neurons is located within the upper pons and they transmit impulses continuously to the dorsal respiratory group of neurons. The primary effect of these is to control the the duration of the filling phase of the lung cycle (duration of inspiration).

Regulation of respiratory center activity:

1. Chemical regulation of respiration:

[A] PCO₂ and [H⁺]: An increase in blood [CO₂] → causes an increase in brain interstitial fluid [H+] → Stimulate central chemoreceptors → Stimulate respiratory center → causing greatly increased strength of both the inspiratory and expiratory signals to the respiratory muscles. 80% of the drive for ventilation is a result of stimulation of the central chemoreceptors. Central chemoreceptors are adaptable type of receptors (within 1-2 days). They have a very potent acute effect on controlling respiration but only a weak chronic effect after a few days’ adaptation.
[B]. PO₂: A decrease in blood PO2 → stimulates peripheral chemoreceptors (in the carotid and aortic bodies, none adaptable type of receptors ) → send signals through glossopharyngeal and vagus nerves → Stimulate respiratory center → causing increased strength of both the inspiratory and expiratory signals to the respiratory muscles.

Peripheral chemoreceptors are:
Sensitive to PCO₂, pH, blood flow, and to temperature.
Sympathetic discharge → vasoconstriction → increasing the sensitivity to hypoxia.
Parasympathetic discharge → vasodilation → decreasing sensitivity to hypoxia.
Arterio-venous oxygen difference in peripheral chemoreceptors is very small.
Under normal conditions, the PO₂ mechanism in regulation of respiration through peripheral chemoreceptors plays only small role.

NOTE: In patient with chronic hypoxia, O₂ lack becomes a far more powerful stimulus to respiration than usual, sometimes increasing the ventilation as much 5-7 times. Therefore, during O₂ therapy, relief of the hypoxia occasionally causes the level of pulmonary ventilation to decrease so low that lethal levels of hypercapnia develop. For this reason, O₂ therapy in hypoxia is sometimes contraindicated, particularly in conditions that otherwise tend to cause hypercapnia, such as depressed respiratory center activity or airway obstruction.

2. Peripheral receptors for regulation of respiration:

[A] Stretch receptors:

Bronchial stretch receptors are located in the wall of the bronchi and bronchiole that transmit inhibitory signals through the vagi into the dorsal respiratory group of neurons when the lungs become overstretched (Hering-Breuer inflation reflex).
j (juxtacapillary) receptors are located in the alveolar walls, close to the capillaries and are stimulated by distension of the pulmonary vessels.
Chest wall receptors are located within the respiratory muscles. This can detect the force generated by the respiratory muscle during breathing. If the force required distending the lungs becomes excessive (either as a result of high airway resistance or low compliance), the information from these receptors gives rise to the sensation of dyspnea (difficulty in breathing).

[B] Irritant receptors: Those are located between the epithelial cells of the large airways and are stimulated by smoke, noxious gases, and particulates in the inspired air. These receptors initiate reflexes that cause coughing, bronchoconstriction, mucus secretion, and breathe holding (i.e., apnea).

[C] Joint proprioceptors: Those are located in the joint capsules and transmit excitatory impulses to the respiratory center.

[D] Touch, thermal, and pain receptors: Can also stimulate the respiratory center. For example, irritants in the nasal cavity can initiate a sneeze reflex. In addition, through these receptors one can observe the respiratory response when cold water is splashed onto a person, and also the common practice of spanked a newborn baby on the buttocks.

3. Brain centers for regulation of respiration:

Reticular Activating System (RAS): Located in the reticular system of the brain stem; its activity is associated with the "awake" or "conscious" state. When active, it simulates respiratory ventilation. When RAS activity is reduced, as during sleep, ventilation is reduced and PCO₂ increases by a few mm Hg.
Limbic System: Respiratory changes in emotion.
Motor cortex: Respiration can be controlled voluntarily. Respiration can be controlled voluntarily, and that one can hyperventilate or hypoventilate to such an extent that serious derangements in PCO₂, pH and PO₂ can occur in the blood.
Muscle exercise: The brain, upon transmitting motor impulses to the contracting muscles, is believed to transmit collateral impulses to the brainstem to excite the respiratory center. Also, the movement of body parts during exercise is believed to excite joint and muscle proprioceptors that then transmit excitatory impulses to the respiratory center.
Vasomotor center: Almost any factor that increases the activity of the vasomotor center also has at least a moderate effect on increasing respiration.
Body temperature. An increase in body temperature increases the rate of respiration directly by increasing respiratory center activity and indirectly by increasing the cellular metabolism and eventually enhances the chemical stimuli for increased respiration.

The response of the respiratory system to exercise and stress :

[A] An increase in the diffusing capacity of the respiratory membrane for O₂, due to opening up a number of previously dormant pulmonary capillaries, and dilatation of already functioning pulmonary capillaries thereby increases the surface area of blood into which the oxygen can diffuse.
[B] Increased alveolar ventilation, this is due to Reflexes originating from body movements (proprioceptors). Increase in body temperature.Epinephrine release (during exercise).Impulses from the cerebral cortex to the contracting muscles, is believed to transmit collateral impulses into the brain stem to excite the respiratory center.
[C] More ideal ventilation-perfusion ratio in the upper part of the lungs.
[D] During exercise, there is a considerable shift of the Hb-O₂ dissociation curve to the right (i.e. decrease in the affinity of Hb to combine with O₂) in the muscle capillary blood due to the release of large amounts of CO₂, acids, and phosphate compounds, in addition to high temperature of the muscles. Then in the lungs, the events are reversed, thus, the shift occurs in the opposite direction (i.e. to the left, which means an increase in the affinity of Hb to combine with O₂), thus allowing pickup of extra amounts of O₂ from the alveoli.
[E] The pulmonary blood flow can increase severalfold without causing an excessive increase in pulmonary artery pressure for the following two reasons: previously closed vessels open up (recruitment), and the vessels enlarge (distension). Recruitment and distension of the pulmonary blood vessels both serve to lower the pulmonary vascular resistance (and thus to maintain low pulmonary blood pressures) when the cardiac output has increased. See the Summary of respiratory responses to exercise.

Pulmonary blood flow:

Low-pressure (25/8 mm Hg, a mean of about 14 mm Hg), low-resistance (1.8 mm Hg/L/min, about 10% of the systemic vascular resistance, which is about 18 mm Hg/L/min), highly compliant system (at a normal pressure, approximately half the pulmonary capillaries are closed, and with increasing pulmonary arterial pressures (for example as a consequence of increase of left atrial pressure), these previously closed capillaries open (recruitment) and distended, and consequently the pulmonary vascular resistance declines).
Interstitial fluid pressure is more negative in the pulmonary circulation than in the systemic circulation.
The pulmonary capillaries are more permeable to proteins than the skeletal muscle capillaries, and, therefore, the interstitial concentration of protein is greater in the pulmonary circulation.
The pulmonary circulation is composed principally of two types of vessels: extra alveolar (larger arteries and veins) which are located outside the alveoli and are tethered to the elastic tissue of the lung and are exposed to the intrapleural pressure. The intra alveolar vessels (pulmonary capillaries) those are located between the alveoli.
At lower lung volumes, the intra alveolar vessels are near maximally open (because the alveolar air pressure is minimum and no compression over these blood vessels) while the caliber of the extra alveolar vessels is small (because the transmural pressure gradient across the walls of these vessels is reduced due to the lesser subatmospheric pressure in the intrapleural space).
Pulmonary vascular resistance is mainly determined by intra alveolar vessels because the greatest cross-sectional area exists in the millions of intra alveolar vessels.
Sympathetic stimulation constricts the pulmonary blood vessels. There are a varity of vasoactive vasoconstricting agents such as arachidonic acid, leukotrienes, thromboxane A₂, prostaglandin F₂, angiotensin-II, serotonin, epinephrine, and norepinephrine.
Parasympathetic stimulation causes vasodilation. There are a varity of vasoactive vasodilating compounds such as Ach, bradykinin, and prostacyclin.
Pulmonary blood flow and pressure decreases from the bottom to the top of the lung in upright individuals. This occurs because gravity.
The gradient in pulmonary blood flow from the top to the bottom of the lung is also caused by the higher lung (alveolar) volumes at the top of the lung (which tend to compress the capillaries and increase resistance in the apical region) relative to the base (less compression on the capillaries and decrease resistance).

Effects of aging on the respiratory system

↓VC ↓IRV, ↓ERV, ↓alveolar ventilation, ↑TV, ↑RV, ↑Dead space,
↓Respiratory muscle power,
↓Compliance of the thoracic cage while ↑lung compliance,
↓Gas exchange across the respiratory membrane,
↓The mucus–cilia escalator to move the mucus.

Hypoxia (cellular deficiency of O₂): Brain is the most sensitive tissue to hypoxia; complete lack of oxygen can cause unconsciousness in 15 sec and irreversible damage within 2 minute. Traditionally; hypoxia has been divided into 4 types (see also table):

[1] Hypoxic hypoxia: In which the PO₂ of the arterial blood is reduced due to insufficient O₂ gets to the alveoli or inadequate ventilation of the alveoli or insufficient diffusion of O₂through the respiratory membrane.
[2] Anaemic hypoxia: In which the arterial PO₂ is normal but the amount of Hb available to carry O₂ is reduced.
[3] Stagnant or ischaemic hypoxia: In which the blood flow to a tissue is so low that adequate O₂ is not delivered to it despite a normal PO₂ and Hb concentration.
[4] Histotoxic hypoxia: In which the amount of O₂delivered to a tissue is adequate because of the action of a toxic agent, the tissue cells cannot make use of the O₂ supplied to them such as in cyanide poisoning, in which the action of cytochrome oxidase is completely blocked and therefore, the tissues cannot utilize the O₂. Also, deficiency of oxidative enzymes or other elements in the tissue oxidative system can lead to this type of hypoxia such as vitamin B deficiency (Beriberi).

Consequences of severe hypoxia :

A. leads to accumulation of lactate ions in tissues
B. stimulates the sympathetic nervous system
C. decreases cerebral vascular resistance
D. induces erythropoietin secretion
E. increases synthesis of 2,3-BPG
F. increases P50 of Hb

Cyanosis: It is a darkness or blueness of the skin and mucous membrane and appears when the reduced Hb concentration of the blood in the capillaries is more than 5 gm/dl. Cyanosis is divided into 2 types:

[1] Central cyanosis: In which there is arterial blood undersaturation or an abnormal Hb derivative, and the mucous membranes and skin are both affected.
[2] Peripheral cyanosis: This is due to a slowing of blood flow to an area and abnormally great extraction of O₂ from normally saturated arterial blood. Often, in these conditions, the mucous membranes of the oral cavity may be spared.

Hypercapnia: It means excess CO₂ in the body fluids. Hypercapnia does not necessarily occur in association with hypoxia except only when hypoxia is caused by hypoventilation or by circulatory deficiency.

O₂ toxicity: Prolong administration (16–24 hours or more) of more than 50% concentration of O₂ at atmospheric pressure (100 kPa or 760 mm Hg) has been demonstrated to exert toxic effects. These are:

The production of the superoxide anion (O^2-) and H₂O₂ and lipid peroxidation.
Respiratory passages become irritated, and lung damage,
Inhibition the ability of lung macrophages to kill bacteria,
Surfactant production is reduced,
Decreases GABA content of the brain,
Decrease in ATP content of the liver and kidney,
Severe arteriolar constriction and the local tissues blood flow sometimes decreases to less than 50% of the normal.