REVIEW. Observations on the ability of the nose to warm and humidify inspired air* Robert M. Naclerio, Jayant Pinto, Paraya Assanasen, Fuad M.

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71069_Naclerio:71069_Naclerio :11 Pagina 1 REVIEW Rhinology, 45, , 2007 Observations on the ability of the nose to warm and humidify inspired air* Robert M. Naclerio, Jayant Pinto,
71069_Naclerio:71069_Naclerio :11 Pagina 1 REVIEW Rhinology, 45, , 2007 Observations on the ability of the nose to warm and humidify inspired air* Robert M. Naclerio, Jayant Pinto, Paraya Assanasen, Fuad M. Baroody Department of Surgery, Section of Otolaryngology-Head and Neck Surgery, The University of Chicago, Chicago, IL, USA SUMMARY The major function of the nose is to warm and humidify air before it reaches to the lungs for gas exchange. Conditioning of inspired air is achieved through evaporation of water from the epithelial surface. The continuous need to condition air leads to a hyperosmolar environment on the surface of the epithelium. As ventilation increases, the hyperosmolar surface moves more distally, covering a larger surface area of the airway, and stimulates epithelial cells to release mediators that lead to inflammation. This inflammation is not identical to allergic inflammation, but causes both short-term and long-term changes in the epithelium. In the short term, it increases paracellular water transport in an attempt to enhance conditioning, and it stimulates sensory nerves to initiate neural reflexes. It also disrupts channels in the cellular membrane, which might permit greater penetration of foreign proteins, such as allergens, leading to further inflammatory cascades, and stimulates sensory nerves to initiate neural reflexes. The long-term inflammation induced over time by the hyperosmolar milieu could worsen the ability of the nose to condition air, requiring more of the conditioning to occur in the lower airway and leading to adverse consequences for the respiratory system. Key words: humidity, nose, allergic rhinitis, temperature, water transport Adults condition more than 14,000 liters of air per day; this requires more than 680 grams of water, approximately 1/5 of our adult daily water intake (1). The mechanisms, by which the nose conditions inspired air and how this ability is altered in patients with allergic rhinitis and asthma, are the subject of this review. Water transport: a fundamental biological process The regulation of the transport of water across biological membranes is fundamental to the maintenance of homeostasis between bodily fluid compartments, to the preservation of organisms under adverse conditions, and, indeed, to life itself (2). Higher organisms could not exist without epithelial barriers that separate the internal and external milieus. To separate these compartments, cell membranes are composed of lipid bilayers that are relatively impermeable to ions. Therefore, to facilitate biological processes, ions must cross these membranes or pass between cells to exert their effects. Membrane proteins known as ion channels, pumps, and transporters mediate water transport. Ion channels enable rapid passive movement of selected ions across cell membranes. More than 100 families of channel-forming proteins/peptides exist in prokaryotes and eukaryotes (3). Transcellular transport through specific membrane pumps and channels actively generates electro-osmotic gradients that are critical for a variety of cellular functions (4). Tight junctions, located between cells, are the main routes for passive ion permeation. Inflammatory mediators, such as histamine, can alter tight junctions, allowing macromolecules to pass from the external to the internal environment (5, 6). Aquaporins and channelopathies Besides the classic Na + and Cl - ion transporters, other proteins can be involved in water transport, such as the glucose transporter, the c-amp-activated cystic fibrosis transmembrane conductance regulator, the urea transporter UT3, and multiple Na + -solute cotransporters. Aquaporins (AQs), a family of small membrane-spanning proteins, are expressed in plasma membranes of many cell types involved in fluid transport (7). The expression of many AQs is functionally significant for movement of water across cell membranes. Interestingly, they respond to osmotic gradients, and their activity is generally measured by an osmotic swelling assay (8). Mutation in the AQP2 water channel causes the rare non-x-linked form of hereditary nephrogenic diabetes insipidus (9) and shows the requirement of the human renal water channel aquaporin-2 for vasopressin-dependent concentration of urine (9). Aquaporins have been implicated in respiratory disease. For example, AQP1, -4, and -5 are expressed in lung tissue. Transgenic aqua- *Received for publication: March 29, 2007; accepted: April 16, 2007 71069_Naclerio:71069_Naclerio :11 Pagina 2 2 Naclerio et al. porin knockout mice with targeted gene disruption in AQP1 and AQP5 have very low lung water permeability (2). Additionally, AQP-5-deficient mice have been shown to show bronchial hyperreactivity (10). These data implicate water transport in related respiratory disease in the lower airway, which may also characterize the upper airway. Channelopathies, diseases that result from defects in ion channel function, are being discovered with increasing frequency. Channelopathies arise through a number of mechanisms, such as mutations in the promoter and coding region of ion channel genes, defects in genes encoding molecules that regulate channel function, or the development of autoantibodies to channel proteins that inhibit their function. Additionally, many drugs and mediators such as phosphodiesterase inhibitors, nitric oxide, VIP, and leukotrienes have effects on ion channels, affording another mechanism by which they can develop acquired or secondary dysfunctions that can cause disease (11). Many diseases also have secondary effects on ion channel activity, for example, maturity-onset diabetes. Hence, the role of water transport proteins and ion channels is relevant to a number of diseases through a wide variety of mechanisms. The epithelial barrier function and beyond There is growing evidence that the respiratory epithelium has a number of functions in addition to its role as a barrier between the internal and external environments. It produces multiple cytokines that participate in airway inflammation, such as granulocyte macrophage colony-stimulating factor, for which the epithelium is the principal source (12). The epithelium also makes metalloproteases that may be involved in airway remodeling (13). Holgate hypothesized that a primary defect in the epithelium, which causes abnormal responses to various stimuli and cannot undergo the normal repair process, is responsible for asthma (14). The epithelium is also now recognized as a critical component of the innate immune system. Epithelial defects may be secondary to chronic inflammation. To illustrate this point, an analogy can be drawn to inflammatory bowel disease. In the gut of patients with this disorder, inflammation affects water transport and leads to diarrhea (15). For years, the mechanism postulated to underlie the diarrhea was an inflammation-induced increase in secretions. We now know that the diarrhea is actually caused by increased production of interferon, which diminishes absorption of Na +. This is an example of the interaction between inflammation and epithelial water/ion transport that can cause disease. Another component of epithelial function is nasal mucociliary transport, an important factor in heat and water exchange and protection of the mucosal interface. This process requires an aqueous periciliary fluid layer of a height that allows cilia to move the viscoelastic mucus on its surface. Too much or too little periciliary fluid leads to ineffective mucociliary transport, which can lead to disease. For example, dryness leads to increased bacterial adherence and is believed to play a role in the development of sinusitis. How might these processes be affected to cause disease in the upper and lower airway? A number of studies have suggested that decreased water transport in the upper airway causes conditioning to occur lower in the airway. McFadden and colleagues showed that air not fully conditioned by the nose will have to be conditioned further by the lower airway (16). Annensi et al. showed that subjects reporting nasal sensitivity to cold dry air (CDA) had a more rapid decline in FEV 1 over five years compared to those without such sensitivity (17). Inhalation of the same volume of dry air through the mouth, in contrast to the oronasal route, causes a greater reduction in FEV 1 in asthmatic subjects (18, 19). Moreover, prolonged repeated exposure of the airways to inadequately conditioned air can induce inflammation in the lower airways (20), the penultimate example being the changes that occur in the trachea after a total laryngectomy. Dehydration injury of the epithelium includes epithelial desquamation, leukocyte infiltration, vascular leakage, and mast cell degranulation, all of which can worsen inflammation. Furthermore, a change of the epithelium from ciliated to squamous nonciliated leads to a further decrease in its ability to transport water. Hence, the study of nasal conditioning has both a fundamental basis in the critical function of water transport, an important relationship to inflammation, and direct clinical relevance to a variety of diseases, including those of the upper and lower airway. Models of nasal conditioning We have been interested in understanding nasal function in health and disease. Toward this goal, we have developed several in vivo, human models of nasal function. We have consistently used the relevant organ in the relevant species to address questions about the mechanisms that underlie nasal air conditioning. Nasal provocation with cold, dry air We were interested in studying the mechanism by which the inhalation of cold, dry air induces rhinorrhea. We reasoned that the inhalation of dry air caused drying of the nasal mucosa and creation of a hyperosmolar milieu, which can activate mast cells in vitro, leading to mediator release and subsequent symptoms (21). We thus allowed subjects to breathe CDA and monitored the subsequent response by scoring symptoms and measuring the levels of mediators in nasal lavage. CDA resulted in an increase in symptoms compared to baseline and in the release of inflammatory mediators. The pattern of these recovered mediators suggests that mast cells participate in this nasal reac- 71069_Naclerio:71069_Naclerio :11 Pagina 3 Nasal air conditioning 3 tion. Because the early response to CDA produces the same pattern of mediator release, as does the early response to antigen, we asked whether a late-phase reaction follows the response to CDA. In fact, significantly more symptoms and higher histamine and TAME levels (a marker of vascular permeability) than in control exposures were recovered in the first ten hours after CDA, showing a late inflammatory response (22). Additionally, epithelial cells in the lavage fluid were found in increased numbers compared to those in appropriate controls, suggesting that tight junctions are disrupted (23). We then undertook several studies to establish a mechanism for mast cell activation. To address the hypothesis that the hyperosmolar milieu generated by the drying of the nasal mucosa stimulated the release of mast cell mediator, we followed two directions: we evaluated the effect of nasal mucosal provocation with a hyperosmolar stimulus, and we attempted to determine changes in the osmolality of surface secretions after CDA challenge. Healthy human volunteers underwent nasal challenge with isosmolar and hyperosmolar mannitol solutions. We found that hyperosmolar challenge caused histamine and leukotriene C4 release (24). Dose-response curves between increasing osmotic loads and histamine recovery in lavage fluids were obtained. We concluded that hyperosmolar stimuli cause histamine release in vivo, possibly from mast cells. Although a spectrum of responsiveness to CDA probably exists in the general population, we were able to select both individuals who respond and those who do not respond to the CDA challenge, based on the presence or absence of a typical history of nasal symptoms upon exposure to a cold and windy environment. This criterion has a specificity of 94% in selecting a CDA responder. To assess whether the reactivity to hypertonic loads of the two extreme groups differs, we challenged 11 CDA responders and 19 non-responders with isosmolar and hyperosmolar mannitol solutions (24). The results indicated that CDA responders released more histamine in their nasal secretions after hyperosmolar provocation than did CDA nonresponders, possibly because of impairment of water transportation across the mucosa. The second approach to linking hyperosmolarity to the CDAinduced response involved measurement of the osmolarity of nasal secretions after CDA challenges. We initially measured the osmolality of returned lavage fluids (25). In each of 9 CDA responders, this index was increased after CDA challenge, compared to baseline, from 288 ± 3 to 306 ± 5 mosm/kg H 2 O (p 0.01). In contrast, the returned-fluid osmolality of six CDA non-responders did not differ from baseline. Significant correlations were found between mediator concentrations and the osmolality of recovered lavages (rs = 0.617, p 0.02; r s = 0.679, p 0.01 for histamine and TAME, respectively). As a control, we measured the osmolarity of nasal secretions obtained after allergen challenge of atopic individuals and found no significant changes. These studies provided the first evidence in human subjects that inhalation of CDA increased the osmolality of respiratory secretions. Although the changes were statistically significant and different from those in appropriate controls, the increments in osmolality were small, most likely secondary to the dilutional effect of the isosmolar saline lavage used for collecting secretions. We sought, therefore, to measure the osmolality of surface secretions directly. We collected secretions directly from the mucosas of CDAsensitive individuals with filter paper discs before and after challenge. The limitation of this method was that, except on rare occasions, we could not obtain a sufficient volume of nasal secretions at baseline to perform osmolality measurements. We therefore chose to compare the osmolality of CDAinduced secretions to that of methacholine- and histamineinduced secretions. Because CDA non-responders have little or no secretion on their mucosal surface after CDA challenge, only CDA responders were evaluated with these protocols (25). The osmolality of nasal secretions (mosm/kg H 2 O) (mean ± SEM; n = 8) after provocation with CDA was 381 ± 5.6; with methacholine, 337 ± 3.5; and with histamine, 315 ± 3.1. Histamine, which, in addition to glandular stimulation, induces vascular permeability, resulted in the lowest osmolality. In contrast, methacholine, a glandular secretagogue, produced slightly hyperosmolar secretions. Cold, dry air led to significantly higher osmolality compared to either methacholine or histamine (p 0.05), confirming our hypothesis that the osmolality of nasal secretions is increased after inhalation of CDA. These data also suggest that nasal glandular secretions are hyperosmolar. This finding is in agreement with the data of Mann and colleagues in dogs (26). More importantly, these combined observations were consistent with our overall hypothesis that individuals vary in their ability to condition air, and those with the least ability to condition air develop hyperosmolar secretions and a clinical response to CDA inhalation. The model used in the above experiments involves the inhalation of air through the nose and exhalation through the mouth. Strohl and colleagues showed that the inhalation of air through the nose and exhalation through the mouth induced an increase in nasal airway resistance, but when the same subjects inhaled and exhaled air through the nose, their airway resistance did not increase (27). They interpreted their experiment to imply that the pattern of breathing influences the response, and that the recovery of heat during expiration prevents the response. This work appeared to negate our studies. To address this concern, we performed experiments in which we assessed the response of subjects to CDA when it was both inhaled and exhaled through the nasal cavity (28).Incontrastto Strohl, we performed our experiments in 10 subjects who gave 71069_Naclerio:71069_Naclerio :11 Pagina 4 4 Naclerio et al. a history of clinical sensitivity to cold, windy environments and who had previously responded to our standard CDA challenge. The subjects were randomized to breathe either CDA or warm moist air (WMA) in and out through the nose for 45 minutes during two separate visits. The total change in secretion weight from baseline after the CDA exposure was 30 ±10 mg compared to 0 ± 1 mg for WMA, the difference being highly significant (p 0.009). During the WMA challenge, the levels of histamine and TAME esterase did not change significantly from baseline. In contrast, after breathing of CDA, there was a significant increase (p 0.01) from baseline in the levels of both histamine (3.9 ± 1.2 to 10.6 ± 2.7 ng/ml) and TAME (3.8 ± 1.4 to 4.6 ± 1.6 cpm). Although significantly increased, these levels did not change to the extent of those reported previously when the subjects inhaled the CDA through the nose and exhaled it through the mouth. This difference was anticipated based on the reduction of the stimulus, the amount of air to be conditioned. The fact that there was a significant change implies that the nasal mucosa does respond to conditioning CDA even though there is an estimated 30% recovery during exhalation. We believe that our protocol of breathing in through the nose and out through the mouth represents a means to augment the stimulus so that it is easier to study it. An analogy is that the inhalation of air with 5% CO 2 at 140 liters through the mouth while seated wearing nose clips serves as a model of exerciseinduced asthma. We then switched our focus from studying the mechanism of the CDA response to measuring the mechanics of the ability of the nose to condition air by using a nasal probe as our model. Development of a nasal probe The nose functions to warm and humidify air from ambient conditions that range from temperatures of -42 to 48 C and relative humidities from 0 to 100% (29). Nasal conditioning occurs from a resting ventilation of approximately 5 liters per minute (l/min) to sustained flow rates of 20 to 30 l/min before nasal breathing is supplemented with oral breathing. We reasoned that, if we could measure the temperature and relative humidity of inhaled air at the nasal inlet and then in the nasopharynx, we would be able to calculate the water content of the air at these two locations. The posterior (nasopharynx) measurements sample the airstream immediately after it exits the nose, thus providing information regarding the end results of nasal function. The difference between these contents (nasal inlet and nasopharynx) represents the amount of water invested by the nose into inhaled air, a good reflection of the conditioning capacity of the nose. Furthermore, because there is strong evidence that exhaled air is fully saturated, it would be necessary only to measure conditioning after inhalation (29-32). We therefore developed a probe for measuring the temperature and humidity of inhaled air within the nasopharynx and a similar one for measuring the same parameters at the nasal inlet. In a typical experiment, one of the patient s nostrils was decongested and anesthetized with oxymetazoline and lidocaine, and the probe was inserted through that nostril and positioned such that the tip of the probe bearing the temperature and humidity sensors was suspended in the nasopharynx, sampling air exiting the nasal cavities. This was confirmed by nasal endoscopy. That nostril was then occluded with a wax plug, and the other nasal cavity was exposed to air of different temperatures and humidities via a mask ap
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