Non-Respiratory Functions of Lungs

Non-respiratory functions of lungs/These nonrespiratory functions of the lung include its own defense against inspired particulate matter, the storage and filtration of blood for the systemic circulation, the handling of vasoactive substances in the blood, and the formation and release of substances used in the alveoli or circulation.

Non-respiratory functions of lungs

•  In addition to their functions in gas exchange, the lungs have a no. Of metabolic functions: 1.Defence mechanism 2.Maintenance of water balance 3.Regulation of body temperature 4.Regulation of acid-base balance 5.Metabolism of biologically active substances
• Like the skin, the lung is exposed to the external environment, the membranes are delicate and need to be kept moist. Every day the lungs are exposed to >7000lit. Of air and its fine tissues req. Protection from the daily bombardment of particles incl. Dust, pollen, pollutants, viruses, bacteria The respiratory tract is protected by different mechanisms at its various levels. Physical mechs. Incl. COUGH is imp. In the upper airways.
• The lower airways are served by the mucociliary clearance mechanism The gas exchange units are protected by surfactant& cellular defenders including the patrolling alveolar macrophages
• The nose is the 1st imp. contributor to the physical defences of the upper airway It comprises a stack of fine aerodynamic filters of respiratory epithelium covering the turbinate bones that remove most large particles from the inspired air. The filtering effect is greatly enhanced by fine hairs in the entire. nares &by mucociliary action which apart from a small area anterior to the info. turbinates is directed mostly such that trapped particles are swallowed or expectorated.
• During cough & expectoration, the larynx acts as a sphincter, which is an essential protective mechanism for the lower airways during swallowing & vomiting. Larger particles that penetrate the nose and are deposited by impaction or sedimentation in the main airways are trapped by the lining fluids of the trachea & bronchi and cleared by the mucociliary clearance mechanism. (mucociliary escalator)Those smaller particles, down to a few nm in size, deposited in the acinar part of the lung are dealt with by the alveolar macrophages
• Cough is generated in 4distinctphases 1.Inspiration 2.Compression of intrathoracic gas against a closed glottis 3.Explosive expulsion as the glottis opens 4.relaxation of the airways
• Its entirely responsible for tracheobronchial cleanliness The mucus forms a raft on the top of the cilia, which sweep in a cephalic direction Each epithelium lining the bronchi possess about 200cilia on its surface The cilia beat 12-14 times/sec
• Saccharin is placed in the entire. Nares The time taken to observe sweet taste is calculated Normally its <30sec Its a simple & practical clinical test to assess ciliary function
• 1.direct cine bronchographic measurement of the movement of the Teflon discs 2.assessment of the rate of clearance of radio aerosols by external imaging techniques
• The main functions of mucus are to trap & clear particles, Dilute noxious influences Lubricate the airways Humidy the inspired air
• Complex surface-active material lining the alveolar surface that reduces the surface tension And prevents the lung from collapsing at resting transpulmonary pressures Surfactant also provides a simple but elegant mechanism for alveolar clearance, since at end-expiration surface tension decreases and the surface film moves from the alveolus towards the bronchioles thus carrying small particles towards the mucociliary transport system
• Surfactant is synthesised by alveolar type2 pneumocytes Comprises at least 4 different specific proteins Sp –A, B, C, D These proteins have important roles in host defence Many studies show that surfactant exerts a variety of influences on alveolar macrophages,incl., chemotaxis & enhancement of phagocytosis & killing of microbes
• Normal surfactant also enhances local pulmonary non-specific immune defence mechanism by suppressing the development of specific T lymphocyte-mediated immune responses to inhaled antigens and T cell proliferation Its also likely that surfactant exerts influences on neutrophil functions incl., neutrophil adherence
• ANTI bacterial ANTI Proteinases Surfactant proteins Alpha1 proteinase inhibitor Igs display IgA Alpha1 antichymotrypsin defensins alpha2macroglobulin Lactoferrins, lysozyme Secretory mucoproteinase inhibitor Complement display c3 ELAFFIN, Tissue inhibitors of metalloproteinases
• These are derived from blood-borne monocytes that originate in the bone marrow Possess marked phagocytic ability, being able to ingest and destroy pathogenic bacteria & particles Able to generate mediators in the initiation of inflammation and to present Ags in the initiation of immune responses
• Primary host defence phagocytosis & killing of microorganisms by oxygen radicals and Nitric oxide-dependent mechanisms and enzymes Inflammatory response. Initiation generation of neutrophil chemokines eg.IL8 generation of monocyte chemokines eg. MIP-1 alpha Generation of agents that activate endothelial cells eg.IL1, TNFalpha Generation of acute-phase response.IL1,TNFalpha,IL6
• Local intracellular generation of NO is an imp., a defence mechanism against microorganisms Activated macrophages also form nitrate & nitrite which contribute to antifungal & antiparasitic, activities of macrophages
• Unlike RBCs, up to 12 of neutrophils remain in the vascular compartment at any given time are not circulating but form the marginated pool which is in dynamic equilibrium with the circulating pool of vascular neutrophils The marginated pool can be released into the circulating pool by exercise or epinephrine The vascular bed of the lung &spleen make the most important contributions to the marginated pool and therefore serve as a source of rapidly releasable neutrophils in time of stress or injury
• The presence of a large no. Of neutrophils loitering in the pulmonary microvascular bed may be of local advantage in host defence Their mobilisation and effectiveness is likely to be augmented in local lung responses to inhaled microbes or toxins and in the generation of the local inflammatory response to lung invasion by streptococci there may be a downside to the presence of this marginated pool of neutrophils in pulmonary microvessels they may put the lung particularly at risk of developing injury in multiorgan failure
• The respiratory tract plays a role in the water loss mechanism. During expiration, water evaporates through the expired air and some amount of body water is lost by this process In COPD patients Expiration is prolonged…..so more water is lost l/t dehydration.
• During expiration, along with water, heat is also lost from the body. Thus respiratory tract plays a role in the heat loss mechanism
• Lungs play a role in the maintenance of the acid-base balance of the body by regulating the CO2 content in blood CO2 is produced during various metabolic reactions in tissues of the body When it enters the blood, CO2 combines with water to form carbonic acid Since carbonic acid is unstable, it splits into hydrogen and bicarbonate ions CO2 +H2OH2CO3H+ +HCO3-
• The entire reaction is reversed in the lungs when CO2 is removed from the blood into the alveoli of lungs H+ +HCO3–H2CO3CO2 +H2O As CO2 is a volatile gas, it is practically blown out by ventilation.
• When metabolic activities are accelerated, more amount of CO2 is produced in the tissues Concentration of H+ is also increased This leads to a reduction in pH. Increased H+ ion conc., causes increased pulmonary ventilation(hyperventilation) By acting through various mechanisms like chemoreceptors in aortic & carotid bodies and in the medulla of the brain Due to hyperventilation, excess CO2 is removed from body fluids and the pH. is brought back to normal
•  Lungs contain a fibrinolytic system that lyses clots in the pulmonary vessels i.e why breathing exercises (alternate nose breathing) are advised to DVT (deep vein thrombosis), Thromboembolic cases
• By renin-angiotensin metabolism angiotensin, II causes the release of aldosterone from the adrenal cortex, which in turn causes Na+ retention, + angiotensin II causes vasoconstriction= increased BP
• Lungs release a variety of substances that enter the systemic arterial blood They remove other substances from the systemic venous blood that reach via the pulmonary artery Prostaglandins are removed from the circulation, but PGs are also synthesised in the lungs and released into the blood when lung tissue is stretched
• Prostaglandins are powerful locally acting vasodilators and inhibit the aggregation of blood platelets. Through their role in vasodilation, prostaglandins are also involved in inflammation
• Substances are synthesised and used in the lungs surfactant Substances which are synthesised or stored and released into the blood PGs, histamine, kallikrein Substances which are partially removed from the lungs PGs ,bradykinin, adenine nucleotides, serotonin, norepinephrine, acetylcholine Substances which are activated in the lungs Angiotensin 1 angiotensin2
• Large amounts of the angiotensin-converting enzyme responsible for this activation are located on the surface of the endothelial cells of the pulmonary capillaries. The converting enzyme also inactivates bradykinin Circulation time through the pulmonary capillaries is <1sec Yet 70% of the angiotensin1 reaching the lungs is converted to angiotensin2 in a single trip through the capillaries
• Four other peptidases have been identified on the surface of the pulmonary endothelial cells, but their physiological role is unsettled. Removal of serotonin and norepinephrine reduces the amounts of these vasoactive substances reaching the systemic circulation so that the effect of these stress hormones is decreased
• Many other vasoactive substances pass through the lung without being metabolised Epinephrine Dopamine Oxytocin Vasopressin Angiotensin2

Lung Capacity and Volume

Lung volumes and capacities refer to phases of the respiratory cycle; lung volumes are directly measured while capacities are inferred.

Lung Capacity

Lung capacity generally refers to the total amount of air inside the lungs at certain phases of the respiratory cycle. It is usually measured as the amount of air that is exhaled after inhalation; this is measured with a device called a spirometer.

There are many different types and terms for the different components of lung capacity that all have different characteristics. In general, measuring lung capacity is important because it serves as the best indicator of lung health by quantifying the functional ability of the lungs to cycle air.

Vital Capacity

Vital capacity (VC) is the maximum amount of air that a person can exhale after inhaling as much air as possible. It is also the sum of tidal volume and the inspiratory and expiratory reserve volumes, which capture the differences between normal breathing and maximal breathing.

The inspiratory reserve volume is the extra space for air after a normal inspiration, and the expiratory reserve volume is the extra air that can be exhalaed after a normal expiration. VC tends to be decreased in those with restrictive lung diseases, such as pulmonary fibrosis, making VC a good diagnostic indicator of restrictive lung diseases.

Other important lung volumes related to lung capacity are residual volume (RV) and total lung capacity (TLC).

• RV: The amount of air left in the lungs after a maximal expiration.
• TLC: The volume of the lungs at maximal inflation, which is the sum of VC and RV.

FEV1/FVC Ratio

The most widely used diagnostic application for lung capacities is the ratio between forced expiratory volume (FEV1) and forced vital capacity (FVC).

• FEV1: The volume of air exhaled in one second of forced expiration.
• FVC: The total volume of exhaled air during forced expiration.

The FEV1/FVC ratio is an important indicator of lung health and is the standard approach for diagnosing COPD (chronic pulmonary obstructive disease), which includes emphysema and bronchitis, which are both caused by smoking. An FEV1/FVC ratio that is greater than .8 indicates a normal lung with generally healthy function, however, a ratio below .8 indicates a significant degree of airway obstruction and suggests COPD.

The obstruction becomes worse the lower the ratio becomes, which increases the likelihood of respiratory failure and death. The FEV1/FVC ratio naturally falls as humans age, however, smoking (the cause of COPD) will cause much larger decreases in FEV1/FVC ratio than what is normal.

Smoking causes this damage by initiating an inflammatory response in the lungs. Those who quit smoking will not experience a regain the FEV1/FVC ratio lost from smoking, however, their rate of FEV1/FVC ratio decline will slow to normal, and their life expectancy will be less impacted.

Those with asthma, an acute form obstructive lung disease, will show a low FEV1/FVC ratio during an asthma attack, which returns to normal after the attack is over. Therefore, to diagnose asthma, many clinicians expose patients to methacholine or histamine to trigger mild asthma attacks to measure FEV1/FVC ratios.

Nonrespiratory Air Movements

The lungs have a number of metabolic functions in addition to their functions in gas exchange.

While the primary function of the lungs is gas exchange, they have several other functions, which are both metabolic and mechanical. These include the secretion of many enzymes and proteins involved in other body systems and nonrespiratory air movements.

Metabolic Functions

The lungs secrete many enzymes and proteins that serve non-respiratory metabolic functions.

ACE (angiotensin-converting enzyme) is an enzyme secreted by the endothelial cells of the capillaries in the lungs. ACE converts angiotensin I into angiotensin II, which are two important hormones in the renin-angiotensin feedback loop of the renal system.

This system works to regulate blood pressure and blood volume by changing the amount of water retained by the kidneys. In general, more ACE leads to more angiotensin II, which leads to more aldosterone, which leads to more retained water through sodium reabsorption in the kidney, which leads to increased blood volume and blood pressure.

ACE inhibitors are a common treatment for those with hypertension, as it will reduce the amount of ACE, which will cause the kidney to excrete more water, which lowers blood volume and blood pressure.

The epithelial cells and macrophages of the lungs secrete many molecules that have immune system functions. In general these molecules have anti-microbial functions.

• Immunoglobin A (IgA): An antibody that can attack pathogens and mark them for phagocytosis from macrophages and neutrophils.
• Protease: Secreted from lung macrophages and neutrophils during inflammatory response to damage pathogens. A fibrinolytic that can break up thrombosis (blood clots) in the lungs.
• Reactive oxygen species (ROS): Free radicals, which are any substance with an unpaired electron in the valence shell, can cause oxidative stress (damage) in cells. They are used to kill pathogens after being engulfed (phagocytized) by immune cells.
• Anti-microbial peptides: Various chemokines and proteins that are secreted by the mucus membranes of the airways. They can damage and inhibit pathogens and are considered a barrier component of the immune system.

Mechanical Functions

There are several types of non-respiratory air movements that have important functions that are not primarily related to gas exchange. One example is voice production for speaking and singing, which involves fine control over the direction and flow of the air as it passes into the upper respiratory tract.

Other mechanical functions include sneezing and coughing, which protect the lungs and airways from irritants that could potentially cause damage. Coughing is a result of constriction from nervous stimulation in the trachea and larynx and also serves to dislodge mucus trapped inside the lungs.

Postural and ventilatory changes

A change in posture from supine to erect in normal individuals results in ∼400 ml of pulmonary blood volume being redistributed to the systemic circulation. During forced expiration against a closed glottis (e.g. valsalva manoeuvre), the pulmonary blood volume decreases by 50%. On the other hand, the pulmonary blood volume doubles with forced inspiration. Changes in pulmonary vascular volume are also influenced by the activity of the sympathetic nervous system.¹

Filter for blood borne substances

The lung is ideally positioned to filter out particulate matter such as clots, fibrin clumps, and other endogenous and exogenous materials from entering the systemic circulation. This plays an important role in preventing ischaemia or even infarction to vital organs.

Physical filtration

The lung acts as a physical barrier to various blood-borne substances but is not completely efficient in protecting systemic circulation. Pulmonary capillaries have a diameter of 7 µm. But it has been shown in animal studies that glass beads of up to 500 µm can pass through a perfused lung.³ Post-mortem studies have shown that almost 25% (15–40%) of the population have a probe patent foramen ovale. Increased pressure in the right atrium secondary to events such as coughing or Valsalva manoeuvre produces demonstrable blood flow between the right and left atria. Therefore, emboli, particularly fat and gas emboli, can still pass through the pulmonary capillary filter, or bypass the lung entirely via the foramen ovale. The pulmonary microcirculation is designed to maintain alveolar perfusion in the face of substantial embolization. However, emboli blocking major vessels or extensive micro-embolization can result in a life-threatening ventilation-perfusion mismatch. Pulmonary micro-embolism also initiates neutrophil activation leading to increased permeability and alveolar oedema in the affected area and has been implicated in the aetiology of acute lung injury.

Chemical filtration

Pulmonary capillaries also produce substances that break down blood clots. Pulmonary endothelium is a rich source of fibrinolysin activator, which converts plasminogen present in plasma to fibrinolysin, which subsequently breaks down fibrin-to-fibrin degradation products. The lung thus has an efficient fibrinolytic system, which lyses clots in the pulmonary circulation.² In addition, the lung is the richest source of heparin (which inhibits coagulation) and thromboplastin (which by converting prothrombin to thrombin, promotes coagulation).¹ Hence the lung may play a role in the overall coagulability of blood to promote or delay coagulation and fibrinolysis.

Defence against inhaled substances

Every day, about 10 000 litres of air comes into contact with 50–100 m² of the alveolar epithelium. There are various mechanisms along the respiratory tract that are involved in providing protection against inhaled physical and chemical substances.

Defence against inhaled particles

A pseudo-stratified ciliated columnar epithelium lines the upper airway from the posterior two-thirds of the nose to the respiratory bronchioles. This is covered with a ‘mucous blanket’ that is composed of a highly viscous mucopolysaccharide gel secreted by goblet cells in the epithelium and mucous cells of the submucosal glands, floating on a low-viscosity serous fluid layer secreted by the bronchial glands. This ‘mucous blanket’ forms the first line of defence against inhaled physical substances.

Mucociliary escalator

The cilia beat within the serous layer of the airway lining fluid in a coordinated fashion at a frequency of 10–15 Hz. In healthy individuals, this action moves the overlying mucus towards the pharynx at a rate of about 1 mm min⁻¹ in the small peripheral airways but can be as quick as 20 mm min⁻¹ in the trachea. This is known as the ‘mucociliary escalator’. Inspired particles >5 µm are deposited by impaction on the mucus covering the nose and larger airways. Particles between 2 and 5 µm in diameter are deposited by sedimentation in smaller airways, where the airflow rates are extremely low. The cilia propel this outer ‘blanket’ of mucus with the entrapped particles and microorganisms over the serous layer. They act together to move the mucus from peripheral airways to central airways, from which the mucus is expectorated or swallowed. Smaller particles (<2 µm) reach the alveoli as aerosols and about 80% is exhaled.⁴ The rest may be deposited in the alveoli as a result of Brownian motion. The random movement of microscopic particles suspended in a liquid or gas is caused by collisions with molecules of the surrounding medium is termed Brownian motion after its identifier, Scottish botanist Robert Brown (1773–1858).

Factors affecting the mucociliary function

The impaired mucociliary function may be because of abnormal mucus production or defective ciliary motility. The secretions of goblet cells are stimulated by inhaled irritant gases and inflammatory mediators. Neural control of bronchial gland secretions is mediated by the parasympathetic nervous system via the vagus nerve, increasing secretions with vagal stimulation, and vice versa. Secretions are also reduced by the administration of opioids. Ciliary motility is impaired by dehydration, smoking, anaesthesia, dry inspired gases, extremes of temperature, and ciliary dysmotility syndromes,  for example, Kartagener syndrome. Drugs that depress ciliary motility include inhaled anaesthetic agents, local anaesthetics, opioids, atropine, and alcohol. In Vitro studies have shown that midazolam, propofol, thiopental, and dexmedetomidine do not directly impair ciliary motility, whereas high doses of ketamine and fentanyl stimulate ciliary motility.

Effects of impaired mucociliary function

A defective mucociliary escalator can lead to chronic sinusitis, recurrent chest infections, and bronchiectasis. When mucociliary clearance is decreased, the cough becomes increasingly important for the removal of secretions from the airways. In intensive care, the disruption of this function by critical illness, intubation, ventilation, and prolonged high-inspired oxygen concentrations predisposes the patient to atelectasis, hypoxia, and infection.

Immune function

Optimal lung defences require the coordinated action of multiple cell types. Immune function within the lung is mediated by pulmonary alveolar macrophages (PAMs) and a variety of immune mediators.

Pulmonary alveolar macrophages

Amoeboid PAMs engulf the particles that reach the alveoli and deposit them on the mucociliary escalator or remove them via blood or lymph. The macrophages are particularly effective against bacteria and ensure that the alveolar region of the lung is effectively sterile. Pam also have a role in antigen presentation, T-cell activation, and immunomodulation. When PAMs ingest large amounts of inhaled particles, especially cigarette smoke, silica, and asbestos, they release lysosomal products into the extracellular space causing inflammation and eventually fibrosis. Neutrophil activation within the lung also leads to the release of proteases such as trypsin and elastase. These chemicals, while very effective at destroying pathogens, can also damage normal lung tissue. This is prevented by the proteases being swept away by the mucus coating the respiratory tree, and by conjugation with alpha₁-antitrypsin, which renders them inactive.⁴ Hence, in alpha₁-antitrypsin deficiency, surplus trypsin and elastase lead to tissue destruction that in turn leads to pulmonary emphysema.

Immune mediators in the lung

The airway epithelial cells secrete a variety of substances such as mucins, defensins, lysozyme, lactoferrin, and nitric oxide, which non-specifically shield the lung from microbial attack.⁷ They also produce a number of mediators of inflammation such as reactive oxygen species, cytokines [tumour necrosis factor (TNFα), interleukins (IL-1β), granulocyte/macrophage colony-stimulating factor (GM-CSF)], and platelet-activating factor to recruit inflammatory cells to the site of inflammation. Immunoglobulins, mainly IgA, present in the bronchial secretions resist infections and help maintain the integrity of the respiratory mucosa.⁸

Immunomodulation therapies in lung disease

New therapies using immunomodulating agents to prevent or minimize non-specific inflammation within the lungs are being developed. Broncho-Vaxom® (OM-85 BV; OM Laboratories, Geneva, Switzerland), a lyophilized bacterial extract from eight species of bacteria (Haemophilus influenzae, Neisseria catarrhalis, Klebsiella pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Staphylococcus aureus, Klebsiella ozaenae, Diplococcus pneumoniae), has been found to enhance antibody synthesis together with better resistance to bacterial infection resulting in a well-balanced, non-inflammatory immune response against invading pathogens. This results in a reduction in the number and duration of chest infections in chronic obstructive pulmonary disease (COPD) patients.⁹ Recombinant interferon-γ1b administered as an adjuvant along with anti-tuberculosis therapy has been shown to reduce the inflammatory response in the lung, improve clearance of pathogenic tuberculosis bacteria, and improve constitutional symptoms in patients suffering from pulmonary tuberculosis.¹⁰

Defence against inhaled chemicals

The large surface area of the alveoli is perfectly suited for gas exchange, but can also serve as a portal of entry for inhaled toxic agents. The fate of these inhaled chemical substances depends on their size, water-solubility, inspired concentration, and their metabolism within the lung.⁴ Akin to hepatic metabolism, both phase I and II metabolism takes place within the lungs. The metabolism of inhaled chemicals is detailed in a separate section of this article.

Endocrine and metabolic functions

Isolated pulmonary neuroendocrine cells (PNECs) and innervated cell clusters called neuroepithelial bodies (NEBs) are widely distributed in the airway mucosa and are together referred to as the ‘pulmonary neuroendocrine system’. The role played by these cells in health and disease is becoming clearer.¹¹ They secrete a wide variety of amines (e.g. serotonin) and peptides (e.g. bombesin). PNEC play a significant role in cell growth, differentiation, and branching morphogenesis in the developing lung. NEBs are located at airway bifurcations and degranulate in the presence of hypoxia. It is postulated that they act as hypoxia-sensitive chemoreceptors linked to the central nervous system by their vagal afferent sensory fibres.

While some of the endocrine and metabolic functions of the lung are ill-defined and poorly understood, others are well established and summarized in Table 1.

Amines

The pulmonary endothelium selectively takes up norepinephrine and serotonin (5HT) from the blood while sparing histamine, dopamine, and epinephrine. This results in the removal of 30% of norepinephrine and 98% of 5HT in a single pass through the lungs.⁴ Norepinephrine is metabolized by intracellular monoamine oxidase (MAO) and catechol-O-methyl transferase, while MAO breaks down 5HT. There are no effects on histamine, dopamine, or epinephrine because these compounds cannot be transported into the pulmonary endothelial cells due to the lack of an active transport mechanism.

Peptides

Angiotensin-converting enzyme (ACE) is found in plasma and systemic vascular endothelium, but is present in much larger quantities on the endothelium of pulmonary vessels. On passage through the lung, the inert decapeptide angiotensin I is converted into the vasoactive octapeptide angiotensin II by ACE. Although the circulation time within the pulmonary capillaries is <1 s, 70% of the angiotensin I reaching the lung is converted to angiotensin II.² The latter is 50 times more active than its precursor and is unaffected on passing through the lung. Similarly, the vasoactive nonapeptide bradykinin is also broken down by ACE in the lung. Atrial natriuretic peptides and endothelins are also removed by the lung.

Arachidonic acid derivatives

Arachidonic acid metabolites PGE, PGE₂, PGF_2α, and leukotrienes are metabolized extensively in the lung by specific enzymes, while PGA₂ and PGI₂ pass through unchanged. As with catecholamines, the selectivity for specific prostaglandins is attributed to selectivity in uptake pathways and not to intracellular enzymes.

Purine derivatives

The purines adenosine monophosphate (AMP), adenosine diphosphate, and adenosine triphosphate are metabolized to adenosine by specific enzymes on the surface of the pulmonary endothelial cells. Adenosine is taken up rapidly into the endothelial cells where it is phosphorylated to AMP or deaminated to inosine and ultimately to uric acid.

This selectivity of the lung seems to imply that it acts as a metabolic filter removing certain locally important vasoactive substances, while substances important to systemic regulation pass unaffected. It also implies that vasoactive substances normally removed by the lung may have profound systemic effects if they were to bypass the lung.

Pulmonary drug metabolism

The lung is an important extra-hepatic site for mixed-function oxidation by the cytochrome P450 system but unlike hepatocytes, their activity cannot be induced. Their metabolic capacity is small and easily saturated. An important role of lungs may therefore be to act as a buffer by binding i.v. drugs, preventing an acute increase in systemic concentrations. The same metabolic systems also play a role in the biotransformation and detoxification of inhaled substances.

Pulmonary extraction

Pulmonary extraction refers to the transfer of a drug from the blood into the lung. The drug may then be metabolized or released unchanged back into the blood. Several drugs, including some used during anaesthesia, are taken up, metabolized, or released slowly from the lungs.¹² Pulmonary endothelial cells are the primary site for binding or metabolism of i.v. drugs. They have high metabolic activity and an important role in breaking down endogenous substrates, but their metabolic capacity is low and easily saturated.

Effects of pulmonary drug extraction

In most patients, i.v. drugs are retained in the lungs by binding to specific sites on the pulmonary endothelium. Pulmonary extraction buffers the rate of rising in drug concentration within the systemic circulation. Pulmonary extraction may also help maintain a steady-state concentration by releasing ‘excess’ bound drug as the plasma concentration decreases. In the presence of moderate-to-severe right-to-left shunts, loss of buffering from lungs could result in a dangerous rise in the plasma concentration for certain drugs, for example, lidocaine. Co-administration of drugs such as antidepressants and beta-blockers, which compete for similar binding sites, or the presence of significant lung disease has also been shown to decrease pulmonary uptake of drugs resulting in potentially toxic systemic concentrations. Conversely, some drugs tend to accumulate within the lung causing dangerous local toxicity, for example, paraquat, nitrofurantoin, bleomycin, and amiodarone.

Pulmonary extraction of anaesthetic drugs

While most drugs used in anaesthesia are taken up by the lung to some extent, only prilocaine is metabolized within the lung.¹² Drugs with a significant pulmonary uptake are basic amines with a pKa of >8. Other factors known to influence the pulmonary uptake are molecular weight, lipophilicity, protein binding, ventilation, perfusion, oxygenation, co-administration of other drugs, cardio-pulmonary bypass, ageing, lung pathology, and anaesthesia.¹⁰ None of the drugs with high pulmonary extraction undergo significant metabolism within the lung. As the systemic levels decrease, drug is released from the lung. The extent of pulmonary extraction for anaesthetic agents is shown in Table 2.

Pulmonary metabolism of inhaled drugs

There are three major benefits that may be attained by delivering medication to the lungs via the inhaled route: rapid onset of action, high local concentration by delivery directly to the airways (and hence high therapeutic ratio and increased selectivity), and needle-free systemic delivery of drugs with poor oral bioavailability.¹³ As a consequence of rapid absorption and low metabolic activity, many inhaled drugs have near-complete bioavailability via the lung. However, some isoforms of the cytochrome P450 enzymes are present in higher quantities in the lung in comparison with the liver. This may explain why some inhaled drugs such as theophylline, salmeterol, isoprenaline, budesonide, and ciclesonide undergo significant metabolism in the lung, while others do not. Metabolism of inhaled chemicals is not always beneficial. For example, some innocuous chemicals in cigarette smoke are metabolized into potential carcinogens by the lung. In an attempt to improve airway selectivity and minimize systemic side-effects; several drugs particularly inhaled steroids, have been designed to take advantage of biotransformation within the lungs as prodrugs or soft drugs.

Prodrugs

An inactive drug that is metabolized to its active form before or at its biological target within the lung is called a ‘prodrug’. The prodrug beclomethasone dipropionate is metabolized to the more potent 17-beclomethasone monopropionate by esterases in the lungs. This reduces the risks of side effects within the oropharyngeal tract from this steroid.¹³ Another steroid, ciclesonide, is metabolized into its active form by esterases in the lungs and further reversibly conjugated to fatty acids. Similarly, reversible conjugation of budesonide with fatty acids within the lung helps to retain it within the larger airways. Budesonide conjugates are gradually hydrolyzed and free budesonide is regenerated. This results in prolonged lung retention, increased duration of action, and a lower elimination time.

Soft drugs

An active drug molecule that is readily inactivated by hydrolysis at its target site within the lung or blood is called a ‘soft drug’. Several soft drug steroids (itrocinonide, γ-butyrolactone steroids, fluocortin butyl-ester, and butixocort propionate) have been in clinical development as inhaled drugs with the purpose of maintaining a high local intrinsic activity, but are readily inactivated in the lung or blood avoiding systemic spillover and side-effects.

Conclusion

• Trap for airborne particles:  generally, nothing larger than 2.5μm gets to the alveoli

• Reservoir of blood: the lungs contain about 10% of the circulating blood volume

• Route of drug administration (eg. nebulised steroids and bronchodilators)

• Route of drug elimination  (eg. volatile anaesthetics)

• Metabolism (eg. conversion of of angiotensin-I, and degradation of neutrophil elastase by α1-antitrypsin)

• Modulator of acid-base balance by virtue of CO₂ elimination

• Modulator of the clotting cascade: the lungs contain thromboplastin, heparin and tissue plasminogen activator

• Filter for the bloodstream: particles larger than an RBC are trapped (~8  μm size barrier), which includes clots, tumour cells and other emboli

• Antimicrobial and immune functions: Alveolar macrophages and sequestered neutrophils, mast cells in the lung and bronchi, immunoglobulin in the respiratory mucus (IgA)

• Modulation of body temperature: heat loss can occur by respiration

• Organ of speech: the lungs form a part of the system which permits communication by sound and language

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