Several expert committees recommend a high fluid intake in patients with chronic bronchitis and asthma. Is there a relationship between fluid intake or hydration status and broncho-pulmonary disorders like bronchitis and asthma?
First, basic physiologic mechanisms like regulation of lung fluid balance and water transport at pulmonary surfaces were analyzed, in order to characterize the role of local hydration status in lung and airways. Second, making use of the computer-based literature searches (PubMed), evidence for a role of hydration status in complex physiological and pathophysiological conditions of lungs and airways like perinatal lung adaptation (PLA) (in prematures), mucociliary clearance(MC) and asthma was categorized.
The movement of fluid between the airspaces, interstitium, and vascular compartments in the lungs plays an important physiological role in the maintenance of hydration and protection of the lung epithelium and significantly contributes to a proper airway clearance.
PLA is characterized by a rapid change from fluid secretion to fluid absorption in the distal respiratory tract, with the literature data confirming a critical role of the epithelial sodium channel. Only few studies have investigated the effect of different fluid input regimens on PLA in prematures. MC relies on the interaction between epithelial water fluxes, mucus secretions, and ciliary activity. Whereas animal data show that drying of the airway epithelium decreases MC, few clinical studies investigating the effect of local or systemic hydration on MC have led to ambiguous results. Asthma (A) is characterized by chronic airway inflammation and episodic airway obstruction. Data in animals and humans indicate an association between exercise-induced-A and conditioning (humidity and heat exchange) of inspired air. However, epidemiological studies (children and adults), investigating the role of fluid (and salt) input in the etiology of the disease as well as studies analyzing different markers of hydration status during asthmatic attacks have so far led to conflicting results. Some expert groups recommend sufficient hydration as a complementary A-therapy.
Analysis of basic physiological mechanisms in lungs and airways clearly demonstrates a critical role for water transport and local hydration status. In broncho-pulmonary diseases, however, analysis of the complex pathophysiological mechanisms is difficult. Thus, we still need more studies to confirm or refute mild dehydration or hypohydration as a risk factor of broncho-pulmonary disorders.
Water is an essential nutrient; moreover, it is the most abundant compound in the human body. There is increasing evidence that fluid intake and renal and extrarenal fluid losses vary between individuals, and that hydration status is not uniform in the population as well. Recent research indicates that dehydration may impair metabolism on a cellular level (Häussinger et al, 1993; Lang et al, 1998; Kleiner, 1999).
The basic function of the lung is to enable an efficient gas exchange between a complex inner aqueous body system and a dry outside atmosphere. Thus, the hydration status of broncho–pulmonary structures and composition of the airway surface liquid may be assumed to contribute to the maintenance of an efficient function. However, is there any sound evidence confirming an effect of dehydration on lung function either under normal circumstances or in certain complex (patho)physiological situations?
The first part of the paper characterizes some basic physiologic mechanisms of water homeostasis in the lungs like fluid balance and aspects of water transport between broncho–pulmonary compartments. The second part analyses the experimental and clinical data supporting a role of hydration status in three more complex challenges of broncho-pulmonary function, namely, perinatal adaptation of ventilation, mucociliary clearance (MC), and asthma.
As there is no accepted gold standard for markers of hydration status, different parameters characterizing systemic hydration (Table 1) were used in the computer–based (PubMed) literature searches. Papers identified in this automatized literature searches were then classified according to accepted categories of evidence (Green & Britton, 1998).
Basic physiologic mechanisms in lungs and airways
Blood supply to the lungs
The lungs are served by two circulations. The pulmonary circulation conducts the entire cardiac output from the right to the left heart. The pulmonary arteries branch with the airways. Within the gas exchanging zone, their arterioles give rise to a network of pulmonary capillaries in the alveolar walls to optimize gas exchange. The second circulation, the so-called bronchial circulation, arises directly from the aorta or from the intercostal arteries. The bronchial arteries supply the walls of the trachea and bronchi and also nourish the major pulmonary vessels, nerves, interstitium, and pleura (Culver, 1999) (Figure 1). Extensive small vessel anastomoses occur between these vessels and both the pre- and postcapillary pulmonary vasculature. The bronchial veins from the larger airways and hilar region drain via the systemic veins (particularly, the azygos system) into the right atrium. The bronchial circulation has a role in the regulation of temperature and humidity in the airways, thus enabling the conditioning of inspired air. As it supplies the fluid for secretion through the airways mucosa, it is the main source preventing mucosal drying and airway desiccation (Wagner, 1997).
The fluid flux across the pulmonary vascular endothelium is influenced by the same pressure relationships as in the systemic capillaries, summarized in the modified Starling equation:
The microvessel filtration pressure (J) is determined by the differences between pulmonary capillaries and pulmonary interstitial fluid in either hydrostatic pressure (Ppc, pulmonary capillary pressure; Ppt, pulmonary interstitial fluid hydrostatic pressure) and protein osmotic pressure (πpp, plasma protein osmotic pressure, πpt, tissue protein osmotic pressure). Normally, the hydrostatic pressure difference favors filtration, whereas the net osmotic force is absorptive and inward (Taylor et al, 1997). Generally, several factors tend to keep the lung from becoming edematous. However, fluid flux is very sensitive to small intravascular or perivascular pressure changes.
Airway edema, as opposed to pulmonary edema, is a subject that has not been extensively investigated. Airway edema is mostly formed by transsudation or exsudation of liquid from the bronchial microvasculature. Edema accumulating in the airway wall will lead to a marked narrowing of the airways. This effect is accompanied by mechanical uncoupling between the airways and surrounding parenchyma, if edema forms in the loose peribronchial connective tissue. Furthermore, edema within the lumen of the airways will also cause an increase in the surface tension of the liquid lining the airways and may interfere with MC (Defebach et al, 1987; Yager et al, 1995; Paré et al, 1997).
Water transport at pulmonary surfaces
The epithelial cells lining bronchi and alveoli have an impressive ability to secrete and reabsorb fluid actively (against both hydrostatic and osmotic gradients). Thus, they maintain a thin layer of airway surface liquid, producing an environment for humidification of inspired air and for capture of foreign substances, viruses, and bacteria, furthermore facilitating an efficient MC to remove the entrapped substances (Gabriel & Boucher, 1997).
Experimental lung preparations have measured salt and water transport across alveolar and distal airway epithelia. It is generally accepted that the net balance between electrolyte absorption and secretion controls the movement of fluid by osmotic pressure (Boucher, 1994a; Matthay et al, 1996). A primary motion force for the transport of sodium seems to be the sodium/potassium-ATPase (sensitive to oubain), located on the basolateral membrane (Figure 2). In combination with the apical epithelial sodium channel (EnaC), which is sensitive to the potassium sparing diuretic amiloride, this results in a net transepithelial sodium absorption (Gabriel & Boucher, 1997; Widdicombe, 1997).
Recently, a family of molecular water channels, called aquaporins, has been identified. They are small (about 30 KDa) integral membrane proteins expressed widely in fluid-transporting epithelia and endothelia (King & Agre, 1996). Several aquaporin (AQP)-type water channels are expressed in mammalian airways and lungs (Figure 2): AQP1 in microvascular endothelia, AQP3 in the upper airway epithelia, AQP4 in the upper and lower airway epithelia, and AQP5 in the alveolar epithelia (King & Agre, 2000). One would expect a primary role for these channels in regulating the transport of salt and water between airspace, interstitial, and vascular compartments in the lung. Surprisingly, experiments in knockout mice deficient in these aquaporins did not favor an important role for the fluid transport in mouse airways (Verkman, 1998; van Os et al, 2000). Moreover, aquaporins seem to play at most a minor role in airway humidification, and in the regulation of volume or composition of airway surface liquid (Song et al, 2000, 2001).
Markers of hydration status and complex conditions of the lungs and airways
Perinatal lung adaptation
Most infants make the transition from intrauterine to postnatal life with no obvious respiratory difficulty. Thus, it is easy to forget that before birth the lungs are filled with an essentially protein-free salt–water solution. The secretion and presence of fetal lung liquid are essential for the normal development of the human lung. In the mammalian fetus, active epithelial chloride secretion provides the driving force for the flow of liquid from the lung microcirculation through the interstitium into potential airspaces. Thus, before birth, the balance between production and drainage of luminal liquid has an important effect on lung development (Burri, 1997).
During birth, it is critical that this fluid is effectively transported out of the airspaces, so that normal gas exchange can take place. The majority of fluid is cleared as a result of the lung epithelium's active transport of sodium from the luminal to its interstitial surface with subsequent absorption into the vasculature (some is squeezed out during a vaginal delivery, only little is cleared by the lungs' lymphatic vessels). So, in conclusion, the distal respiratory tract switches from a predominantly chloride-secreting membrane before birth to a predominantly sodium-absorbing membrane after birth (Bland, 1997; O'Brodovich, 1997).
The cloning of the amiloride-sensitive EnaC (Canessa et al, 1993), which is made of three homologous subunits (Canessa et al, 1994), enabled subsequent genetic experiments supporting a central role for the so-called alpha subunit of this channel in the clearance of fetal lung liquid at birth.
In mice, inactivation of the alpha subunit gene locus of the EnaC led to a respiratory distress syndrome and early neonatal death (Barker et al, 1998). Moreover, in preterm and term guinea–pigs, the messenger RNA expression of the alpha subunit of the EnaC reached a peak level at term, accompanied by an increase in the amiloride-blockable component of lung fluid clearance (Baines et al, 2000). These and other experimental data clearly demonstrate that the transport processes via the EnaC are indispensable for lung liquid clearance at birth (Hummler & Horiberger, 1999; Matalon & O'Brodovich, 1999; Smith et al, 2000).
A recent Cochrane analysis states that in prematures, restricted water intake is associated with a trend towards increased risk of dehydration and reduced risk of broncho-pulmonary dysplasia (not significant); possible effects on ventilation were not further specified (Bell & Acarregui, 2001). The results of our literature search combining perinatal ventilation and parameters of hydration status are shown in Table 2. We found only few studies (Bauer et al, 1996; Wlodek et al, 1998; Baines et al, 2000; Kavvadia et al, 1999), which in conclusion could not demonstrate an unequivocal effect of different fluid regimens on perinatal ventilation in prematures.
Figure 3 shows a schematic representation of the mucociliary apparatus, which in the lower airways of mammals, extends from the larynx to terminal bronchioles. It consists of ciliated surface epithelial cells, mucous epithelial cells and submucosal glands, and the surface liquid covering the epithelium. It is the interaction between epithelial water fluxes and mucus secretion on the one hand and ciliary activity on the other, which ensures a mechanical, biological, and chemical barrier in the airway (Wanner et al, 1996). Classically, the surface liquids have been divided into two layers: the periciliary watery layer (or sol phase) close to the cell surface and the mucous viscous layer (or gel phase) on top of the sol phase. It is evident that effective ciliary beating is dependent on the depth and consistency of these two layers (Yeates et al, 1997).
Extensive studies have suggested that airway epithelia regulate the composition and/or volume of airway surface fluid (Boucher, 1994a, 1994b). Further studies in human tracheobronchial epithelial cultures (Matsui et al, 1998) recently demonstrated that the entire periciliary fluid is transported at approximately the same rate as mucus (about 40 μm/s), and that the removal of the mucous layer reduced periciliary fluid transport by more than 80%. The cephalad movement of periciliary liquid along airway epithelial surfaces makes this mucus-driven transport an important component of salt and water physiology in the lungs.
There is ample information on regulation of MC in health and disease (Houtmeyers et al, 1999); moreover, new models describe the regulation of volume and composition of airway surface fluid more precisely (Wang et al, 2001). However, there is only spare information about a possible effect of local or systemic hydration on MC. Animal data showed that the inspiration of dry air decreased bronchial MV, while transiently decreasing tracheal ciliary beat frequency. Both functions recovered after prolonged exposure (Winters & Yeates, 1997). The authors postulated that the depth and tonicity of the periciliary airway lining fluid were first changed during inhalation, but were then restored by active transepithelial transport of water and ions. That means that the local compartment is defended against external perturbations of hydration status.
Table 2 shows that the PubMed search for ‘mucociliary clearance AND water intake’ only identified 14 items, mostly papers on animal experiments or review articles on secretions and transport processes in airways. Two observations in humans reported on the reduction of MC in diabetes (Sachdeva et al, 1993) and on impairment of nasal MC during breathing of dry air, respectively (Salah et al, 1988). However, scanning of relevant journals and cross-referencing helped to find an animal experiment and a clinical observation investigating the effects of systemic hydration. In 1985, Marchette described, that in dogs tracheal mucous velocity was not altered by intravenous infusion of 5% dextrose solution at volumes from 5 to 35 ml/kg (Marchette et al, 1985). Moreover, in 1987, Shim compared sputum volume in subjects with chronic bronchitis in different states of hydration (defined by more or less fluid intake). They found a lack of effect of hydration on the volume of sputum collected each morning (Shim et al, 1987).
Asthma is defined, in physiologic terms, as a generalized narrowing of the airways, which varies over short periods of time, either spontaneously, or as a result of treatment. Among others, characteristic pathologic features include airway inflammation with local edema and excess secretion. It is the most common disease encountered in children living in industrialized countries (Partridge, 1999; Postma et al, 1999). Is there any evidence for including ‘hydration status’ in recommendations for primary or secondary prevention of asthma?
Among others, asthmatics show airway hyper-reactivity. That means, patients with this illness develop bronchial narrowing to a greater extent in response to smaller quantities of physical, chemical, and pharmacologic stimuli than do healthy individuals (Van Schoor et al, 2000). For example, hyperventilation induced by exercise like walking, jogging, or running induces a bronchoconstriction, which may be characterized by a fall in the forced expiratory volume. However, this bronchoconstrictor reaction is blunted by breathing air already warmed to body temperature (McFadden and Gilbert, 1994; Bar-Or et al, 1997). Further experiments proposed, that exercise-induced bronchoconstriction is related to the consequences of incomplete heating (thermal hypothesis) and humidifying (osmotic, or airway drying hypothesis) large volumes of air during exercise (McFadden, 1997; Anderson & Daviskas, 2000).
In 1993, the McFadden group observed interesting possible relationships between intravenous infusion of isotonic fluid and reactivity to hyperpnea in normal and asthmatic subjects. In asthmatic subjects, saline infusion (about 30 ml/kg over 15–20 min) mirrored the obstruction seen with hyperventilation, whereas in normal subjects saline produced more bronchial narrowing than did hyperventilation. However, when the two stimuli were given together, the timing of the infusion altered the asthmatic subject's response. Giving fluid late amplified the obstruction, whereas giving it early in the hyperventilation challenge blunted the airway narrowing (Gilbert et al, 1993).
The PubMed-based search led to some papers (Table 2), most reporting studies of drug metabolism in asthmatic subjects (for a review see, eg, Taburet & Schmit, 1994). Epidemiological studies investigating the role of fluid and salt input in the etiology of asthma have led so far to conflicting results (for a review, see Ardern & Ram, 2001). Furosemide inhalation was shown in part to inhibit hyperpnea-induced airway obstruction (Freed et al, 1996). There are studies indicating impaired water excretion in asthma (Dawson et al, 1984; Singleton et al, 1986), whereas others note a trend towards hypertonicity during acute airway obstruction (Bahna & Kaushik, 1984), followed by weight gain and decrease of hematocrit during recovery (Gopalan et al, 1983). Several expert groups generally recommend hydration as a complementary therapy in asthma. Others suggest first assessing fluid status in children with acute asthma in order to decide if hydration as a complementary asthma therapy is necessary (NHL Guidelines, 1997).
The bronchopulmonary system is facilitating gas transport and exchange between the inner aqueous body systems and the dry atmosphere outside. Hydration status and water permeability are characteristic of different broncho-pulmonary structures. Water homeostasis is actively regulated and defended against desiccation or hyperhydration.
Experimental evidence points to an important role of hydration status and water transport in the broncho-pulmonary system in perinatal ventilation, MC, and asthma.
However, more clinical studies are needed to confirm or refute mild dehydration or hypohydration as a risk factor of broncho-pulmonary diseases.
Interpretation of human studies has to consider general methodological limitations and interindividual variability. Moreover, hydration status is not uniform in an individual, but seems to be regulated separately in various compartments of the body. Experiments with local (aerosol-inhalations) or systemic (infusion) water loading are likely to elicit homoeostatic compensatory effects, thus veiling the role of regional broncho-pulmonary hydration or general hydration status in health and disease.
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Environmental Health (2009)