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Response of the lungs to aspiration
Response of the Lungs to Aspiration Richard M. Effros, MD, Elizabeth R. Jacobs, MD, R. M. Schapira, Julie Biller, MD
Aspiration of acid from the stomach and water from the mouth can cause significant lung injury. Animal experiments suggest that acid entering the lungs is normally neutralized by bicarbonate derived from the plasma. It is hypothesized that this process may be impaired in patients with cystic fibrosis and that some of the airway injury that they experience may be related to this defect. This disease is characterized by abnormalities in the cystic fibrosis transmembrane conductance regulator, which normally conducts bicarbonate and chloride exchange. Evidence is discussed regarding the role of water channels (aquaporins) in transporting water from the airspaces into the vasculature. Am J Med. 2000;108(4A): 15S–19S. © 2000 by Excerpta Medica, Inc.
T
he intimate relationship of the upper gastrointestinal and respiratory tracts can be traced to the development of the lung as a derivative of the foregut in early terrestrial animals. Although there may have been some temporary advantage to this arrangement, the close proximity of the upper respiratory and gastrointestinal tracts has been associated with a number of unfortunate consequences. Unless a very complex series of voluntary and involuntary mechanisms works properly, fluid may be aspirated during drinking or vomiting. Aspirated fluids may be extremely acid if derived from the stomach or alkaline if they contain pancreatic or biliary secretions (retrograde aspiration). Alternatively, hypotonic or hypertonic fluids may be aspirated when patients with swallowing disorders attempt to drink (anterograde aspiration). A variety of mechanisms have evolved within the lungs, which act to reduce injuries caused by these solutions.
NEUTRALIZATION OF ACID IN THE LUNGS
From the Medical College of Wisconsin and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, USA. Requests for reprints should be addressed to Richard M. Effros, MD, Medical College of Wisconsin, Froedert Memorial Lutheran Hospital, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. © 2000 by Excerpta Medica, Inc. All rights reserved.
Although the early studies of Mendelson1 showed that acid is rapidly neutralized within the lungs, relatively little is known about the mechanisms responsible for this process. Recent studies suggest that the exchange of bicarbonate in the serum with chloride in the airspaces is responsible for much of the buffering observed in lungs exposed to acid.2 Several transporters and channels in pulmonary epithelial cells, which may play a role in neutralizing airspace acid, are shown in Figure 1. Evidence has been obtained that the cystic fibrosis transmembrane conductance regulator (CFTR) conducts both HCO3⫺ and Cl⫺,3,4 and abnormalities in this protein could slow acid neutralization. Abnormalities of CFTR also may have indirect effects on buffering: anion transport through outwardly rectifying, depolarization-activated Cl⫺ channels (ORCC) is abnormally reduced in isolated CF respiratory cells.5 It is conceivable that some of the lung injury observed in cystic fibrosis (CF) is related to inefficient buffering of aspirated acid. Reflux of acid is common among patients with CF. Malfoot and Dab6 found that when pH was measured in the esophagus of children with CF, 80% had significant reflux. In a recent French study,7 76% of 25 children with CF (mean age 219 days) without evidence of bronchopulmonary infection had abnormal gastroesophageal reflux by esophageal pHmetry. The percentage of time that the pH in the esophagus was ⬍4 was 12.8%. Reflux was particularly prolonged during the time 0002-9343/00/$20.00 15S PII S0002-9343(99)00290-9
A Symposium: Response of the Lungs to Aspiration/Effros et al
Figure 1. Schematic diagram of transport processes that could influence neutralization of acid in the airspaces. Three apical anion channels that may play a role in transporting HCO3⫺ into the airspaces and Cl⫺ out are shown. Some of the transport processes across the basolateral surface are also shown. AE-2 ⫽ anion exchange channel-2; CaRCC ⫽ calcium regulated chloride channel; CFTR ⫽ cystic fibrosis transmembrane conductance regulator; NB Symport ⫽ sodium bicarbonate symport: NHE-1 ⫽ sodiumhydrogen exchanger-1; ORCC ⫽ outwardly rectified chloride channel.
that patients were sleeping. These children had mild to moderate evidence for lung disease. Cucchiara et al8 reported that 12 of 14 children with CF (mean age 7.9 years) who had reflux symptoms had abnormally acidic esophageal pH. Inappropriate lower esophageal sphincter relaxation was the most common mechanism of reflux in these children. It is likely that abnormal reflux would be demonstrable in even more of these children if repeat pHmetry studies were conducted. For example, Vie et al7 found that if they did a second pH study, they were able to document acid reflux in 92% of the children with CF. There is additional evidence that reflux is a significant problem in children with CF: coughing is apparently reduced when they receive agents that reduce reflux.6 Furthermore, the frequency of esophagitis and Barrett’s esophagus (metaplasia related to prolonged acid exposure) is increased among patients with CF.9,10 Many children with CF do not complain of symptoms, and the high incidence of reflux might never have been detected if pHmetry had not been performed. However, a significant number of children with CF do have symptoms: 26.5% of children with CF complained of heartburn or regurgitation in one study, compared with only 5.6% of their normal siblings.10 Cough can be stimulated reflexly by exposure of the lower esophagus to acid solutions and need not indicate that acid actually has entered the lungs. However, evidence recently has been obtained that shows that microaspiration reduces the pH of the trachea in 16S
March 6, 2000 THE AMERICAN JOURNAL OF MEDICINE威
patients with CF.11 Various agents are administered in many children with CF to reduce gastric acid secretion. This reduces inactivation of pancreatic enzymes by acid, but the effect of these medications upon the progression of lung disease remains unknown. Expression of CFTR on apical epithelium of large airways appears to be significantly less than that on the smaller airways.12 High concentrations of CFTR are also found in the submucosal glands, which may secrete bicarbonate through these channels. Although CFTR expression is somewhat less prominent in the alveoli, exchange of Cl⫺ and HCO3⫺ through alveolar CFTR may play an important role in neutralization, because the alveolar surface area is more than 50 times as great as that of the airways. As indicated in Figure 2, bicarbonate transport at various sites in the gastrointestinal tract may normally buffer the pH of fluid aspirated from the stomach. For example, bicarbonate secretion by the esophagus,13,14 mouth,15 stomach (nonparietal cells),16 and duodenum17 have been documented in response to instillation of acid into the esophagus. Impairment of bicarbonate secretion by exocrine glands associated with these epithelial membranes may contribute to the high incidence of esophagitis and lung injury among patients with CF.18
WATER TRANSPORT IN THE LUNGS It has been known for many years that freshwater drowning is followed by the movement of water into the vascu-
Volume 108 (4A)
A Symposium: Response of the Lungs to Aspiration/Effros et al
Figure 2. Some exchange processes that could influence the pH of the upper gastrointestinal tract (right) and the respiratory surfaces (left). Postulated defects in bicarbonate-chloride exchange that may contribute to respiratory and gastrointestinal disease in cystic fibrosis are shown as bars across arrows. Dotted arrows indicate the direction of flow during aspiration. * ⫽ Principal sites of CFTR in the lungs.
Figure 3. Distribution of aquaporins in the respiratory tract. Aqp ⫽ aquporin; B⫽ basal cell; M ⫽ mucosal cell; S ⫽ serosal cell.
lature, whereas saltwater drowning results in the movement of water from the circulation to the airspaces. The direction in which water flows in these circumstances is related to the relative osmolality of these solutions, or more precisely, to the chemical potential of water in the two compartments. Until recently, there has been considerable uncertainty concerning the manner in which water molecules cross the barriers that separate the vascular and
airspace compartments. Early studies indicated that perfusion of air-filled lungs with hypertonic solutions results in the extraction of water from the pulmonary tissues without associated solutes.19 Subsequent studies showed that when fluid-filled lungs are perfused with hypertonic solutions, the fluid lost from the airspaces is also virtually solute free.20 It was concluded that osmotic gradients probably induce water transport across cellular mem-
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
17S
A Symposium: Response of the Lungs to Aspiration/Effros et al
branes, which resist the movement of small hydrophilic solutes, rather than through the junctions between cells, which would have presumably permitted the passage of these molecules with water. More than 40 years ago, Paganelli and Solomon21 and Sidel and Solomon22 demonstrated that filtration of water across red cell membranes in response to osmotic gradients occurs at a much more rapid rate than would be expected from experiments in which the diffusion of water across these same membranes was studied. They hypothesized the presence of small channels in the red cell membranes that efficiently conducted water in these osmotic experiments. The nature of these channels has been recently elucidated by Agre et al,23 who isolated and characterized the first of a family of water channels, now referred to as aquaporins. Recent studies have indicated that at least four of these channels are present in the lungs and are associated with both the endothelium and epithelium of the lungs (see Figure 3).23–30 Of importance was the observation, that, as in red cells, some of these channels can be inhibited by mercurial compounds. The exact function of the aquaporins remains uncertain. They may facilitate removal of water from the airspaces after accidental or incidental aspiration while drinking. Rapid absorption of water is essential to avoid impairment of gas exchange. This might be a useful property during freshwater drowning as well but, obviously, would be of no benefit during saltwater drowning, in which the aquaporins would conduct water into the airspaces. It is also possible that these channels allow water to follow Na⫹ out of the lungs when Na⫹ is actively transported by the epithelial cells out of the airspaces. A third function of the aquaporins in the lungs may be the maintenance of moisture on the respiratory surfaces, which require the presence of small amounts of water and water vapor to avoid drying, an effect that would compromise gas transport. A role in CO2 transport has been postulated.31
REFERENCES 1. Mendelson CL. The aspiration of stomach contents in the lungs during obstetric anesthesia. Am J Obstet Gynecol. 1946;52:191. 2. Effros RM, Darin C. Efficient anion transport is essential for prompt neutralization of inspired acid: a possible model of lung injury in cystic fibrosis. Am J Respir Crit Care Med. 1995;151:A741. (Abstract.) 3. Poulson JH, Fischer JH, Illek B, Machen TE. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA. 1994;91:5340 –5344. 4. Smith JJ, Welsh MJ. cAMP stimulates bicarbonate secretion across normal, but not cystic fibrosis airway epithelia. J Clin Invest. 1992;89:1148 –1153. 5. Schwiebert EM, Flotte T, Cutting GC, Guggino WB. Both CFTR and outwardly rectilying chloride channels contribute to cAMP-stimulated whole cell chloride currents. Am J Physiol. 1994;267:C1464 –C1477. 18S
March 6, 2000 THE AMERICAN JOURNAL OF MEDICINE威
6. Malfroot A, Dab I. New insights on gastro-esophageal reflux in cystic fibrosis by longitudinal follow up. Arch Dis Child. 1991;66:1339 –1345. 7. Vic P, Tassin E, Turck D, Gottrand F, Launay V, Farriaux JP. Frequency of gastroesophageal reflux in infants and in young children with cystic fibrosis. Arch Pediatr. 1995;2: 742–746. 8. Cucchiara S, Santamaria F, Andreotti MR, et al. Mechanisms of gastro-esophageal reflux in cystic fibrosis. Arch Dis Childhood. 1991;66:617– 622. 9. Hassall E, Israel A, Davidson AGF, Wong LT. Barrett’s esophagus in children with cystic fibrosis: not a coincidental association. Am J Gastroenterol. 1993;88:1934 –1938. 10. Scott RB, O’Laughlin EV, Gall G. Gastroesophageal reflux in patients with cystic fibrosis. J. Pediatr. 1985;106:223–227. 11. Ledson MJ, Wilson GE, Tran J, Walshaw MJ. Tracheal microaspiration in adult cystic fibrosis. J R Soc Med. 1998; 91:10 –12. 12. Engelhardt JF, Zepeda M, Cohn JA, Yankaskas JR, Wilson JM. Expression of the cystic fibrosis gene in adult human lung. J Clin Invest. 1993;93:737–749. 13. Brown CM, Rees WD. Human oesophageal bicarbonate secretion: a phenomenon waiting for a role. Gut. 1997;40: 693– 694. 14. Mertz-Nielsen A, Hillingso J, Buldiave K, Rask-Madsen J. Reappraisal of bicarbonate secretion by the human oesophagus. Gut. 1997;40:582–586. 15. Helm JF, Dodds WJ, Hogan WJ. Salivary responses to esophageal acid in normal subjects and patients with reflux esophagitis. Gastroenterology. 1987;92:1393–1397. 16. Crampton JR, Gibbons LC, Rees WDW. Effect of luminal pH on the output of bicarbonate and P2 by the normal human stomach. Gut. 1987;28:1291–1295. 17. Isenberg JI, Hogan DL, Koss MA, Selling JA. Human duodenal mucosal bicarbonate secretion. Evidence for basal secretion and stimulation by hydrochloric acid and a synthetic prostaglandin E sub I analogue. Gastroenterology. 1986;91:370 –378. 18. Feigelson J, Girault F, Pecau Y. Gastro-oesophageal reflux and esophagitis in cystic fibrosis. Acta Paediatr Scand. 1987;76:989 –990. 19. Effros RM. Osmotic extraction of hypotonic fluid from the lungs. J Clin Invest. 1974;54:935–947. 20. Effros RM, Mason GR, Sietsema K, et al. Pulmonary epithelial sieving of small solutes in rat lungs. J Appl Physiol. 1988;65:640 – 648. 21. Paganelli CV, Solomon AK. The rate of exchange of tritiated water across the human red cell membrane. J Gen Physiol. 1957;41:259 –277. 22. Sidel VW, Solomon AK. Entrance of water into human red cells under an osmotic pressure gradient. J Gen Physiol. 1957;41:243–257. 23. Agre P, Preston GM, Smith BL, Jung JS, Raina S, Monon S, Guggino WB, Nielsen S. Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol. 1993:265:F463–F476. 24. Folkesson H, Matthay MA, Hasegawa H, Kheradmand F, Verkman AS. Transcellular water transport in lung alveolar epithelium through mercurial-sensitive water channels. Proc Natl Acad Sci USA. 1994;91:4970 – 4974. 25. Effros RM, Darin C, Krenz CS. Evidence for asymmetrical distribution of CHIP28 aquaporins in alveolar-capillary barrier. FASEB J. 1995;9:A279. (Abstr.) 26. Hasegawa H, Lian SC, Finkbeiner WE, Verkman AS. Extra-
Volume 108 (4A)
A Symposium: Response of the Lungs to Aspiration/Effros et al renal tissue distribution of CHIP28 water channels by in situ hybridization and antibody staining. Am J Physiol. 1994: 266:C893–C903. 27. Macey RI. Transport of water and urea in red blood cells. Am J Physiol. 1984;246:C195–C203. 28. Raina S, Preston GM, Guggino WB, Agre P. Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. J Biol Chem. 1995;270:1908 –1912. 29. King LS, Nielsen S, Agre P. Aquaporin-1 water channel
protein in lung: ontogeny, steroid-induced expression, and distribution in rat. J Clin Invest. 1996;97:2183–2191. 30. Schnitzer J, Oh P. Aquaporin-1 in plasma membrane and caveolae provides mercury-sensitive water channels across lung endothelium. Am J Physiol (Heart Circ Physiol). 1996;270:H416 –H422. 31. Nakhoul NL, Davis BA, Romero MF, Boron WF. Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes. Am J Physiol. 1998;274: C543–C548.
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
19S
Aspiration of acid from the stomach and water from the mouth can cause significant lung injury. Animal experiments suggest that acid entering the lungs is normally neutralized by bicarbonate derived from the plasma. It is hypothesized that this process may be impaired in patients with cystic fibrosis and that some of the airway injury that they experience may be related to this defect. This disease is characterized by abnormalities in the cystic fibrosis transmembrane conductance regulator, which normally conducts bicarbonate and chloride exchange. Evidence is discussed regarding the role of water channels (aquaporins) in transporting water from the airspaces into the vasculature. Am J Med. 2000;108(4A): 15S–19S. © 2000 by Excerpta Medica, Inc.
T
he intimate relationship of the upper gastrointestinal and respiratory tracts can be traced to the development of the lung as a derivative of the foregut in early terrestrial animals. Although there may have been some temporary advantage to this arrangement, the close proximity of the upper respiratory and gastrointestinal tracts has been associated with a number of unfortunate consequences. Unless a very complex series of voluntary and involuntary mechanisms works properly, fluid may be aspirated during drinking or vomiting. Aspirated fluids may be extremely acid if derived from the stomach or alkaline if they contain pancreatic or biliary secretions (retrograde aspiration). Alternatively, hypotonic or hypertonic fluids may be aspirated when patients with swallowing disorders attempt to drink (anterograde aspiration). A variety of mechanisms have evolved within the lungs, which act to reduce injuries caused by these solutions.
NEUTRALIZATION OF ACID IN THE LUNGS
From the Medical College of Wisconsin and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, USA. Requests for reprints should be addressed to Richard M. Effros, MD, Medical College of Wisconsin, Froedert Memorial Lutheran Hospital, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226. © 2000 by Excerpta Medica, Inc. All rights reserved.
Although the early studies of Mendelson1 showed that acid is rapidly neutralized within the lungs, relatively little is known about the mechanisms responsible for this process. Recent studies suggest that the exchange of bicarbonate in the serum with chloride in the airspaces is responsible for much of the buffering observed in lungs exposed to acid.2 Several transporters and channels in pulmonary epithelial cells, which may play a role in neutralizing airspace acid, are shown in Figure 1. Evidence has been obtained that the cystic fibrosis transmembrane conductance regulator (CFTR) conducts both HCO3⫺ and Cl⫺,3,4 and abnormalities in this protein could slow acid neutralization. Abnormalities of CFTR also may have indirect effects on buffering: anion transport through outwardly rectifying, depolarization-activated Cl⫺ channels (ORCC) is abnormally reduced in isolated CF respiratory cells.5 It is conceivable that some of the lung injury observed in cystic fibrosis (CF) is related to inefficient buffering of aspirated acid. Reflux of acid is common among patients with CF. Malfoot and Dab6 found that when pH was measured in the esophagus of children with CF, 80% had significant reflux. In a recent French study,7 76% of 25 children with CF (mean age 219 days) without evidence of bronchopulmonary infection had abnormal gastroesophageal reflux by esophageal pHmetry. The percentage of time that the pH in the esophagus was ⬍4 was 12.8%. Reflux was particularly prolonged during the time 0002-9343/00/$20.00 15S PII S0002-9343(99)00290-9
A Symposium: Response of the Lungs to Aspiration/Effros et al
Figure 1. Schematic diagram of transport processes that could influence neutralization of acid in the airspaces. Three apical anion channels that may play a role in transporting HCO3⫺ into the airspaces and Cl⫺ out are shown. Some of the transport processes across the basolateral surface are also shown. AE-2 ⫽ anion exchange channel-2; CaRCC ⫽ calcium regulated chloride channel; CFTR ⫽ cystic fibrosis transmembrane conductance regulator; NB Symport ⫽ sodium bicarbonate symport: NHE-1 ⫽ sodiumhydrogen exchanger-1; ORCC ⫽ outwardly rectified chloride channel.
that patients were sleeping. These children had mild to moderate evidence for lung disease. Cucchiara et al8 reported that 12 of 14 children with CF (mean age 7.9 years) who had reflux symptoms had abnormally acidic esophageal pH. Inappropriate lower esophageal sphincter relaxation was the most common mechanism of reflux in these children. It is likely that abnormal reflux would be demonstrable in even more of these children if repeat pHmetry studies were conducted. For example, Vie et al7 found that if they did a second pH study, they were able to document acid reflux in 92% of the children with CF. There is additional evidence that reflux is a significant problem in children with CF: coughing is apparently reduced when they receive agents that reduce reflux.6 Furthermore, the frequency of esophagitis and Barrett’s esophagus (metaplasia related to prolonged acid exposure) is increased among patients with CF.9,10 Many children with CF do not complain of symptoms, and the high incidence of reflux might never have been detected if pHmetry had not been performed. However, a significant number of children with CF do have symptoms: 26.5% of children with CF complained of heartburn or regurgitation in one study, compared with only 5.6% of their normal siblings.10 Cough can be stimulated reflexly by exposure of the lower esophagus to acid solutions and need not indicate that acid actually has entered the lungs. However, evidence recently has been obtained that shows that microaspiration reduces the pH of the trachea in 16S
March 6, 2000 THE AMERICAN JOURNAL OF MEDICINE威
patients with CF.11 Various agents are administered in many children with CF to reduce gastric acid secretion. This reduces inactivation of pancreatic enzymes by acid, but the effect of these medications upon the progression of lung disease remains unknown. Expression of CFTR on apical epithelium of large airways appears to be significantly less than that on the smaller airways.12 High concentrations of CFTR are also found in the submucosal glands, which may secrete bicarbonate through these channels. Although CFTR expression is somewhat less prominent in the alveoli, exchange of Cl⫺ and HCO3⫺ through alveolar CFTR may play an important role in neutralization, because the alveolar surface area is more than 50 times as great as that of the airways. As indicated in Figure 2, bicarbonate transport at various sites in the gastrointestinal tract may normally buffer the pH of fluid aspirated from the stomach. For example, bicarbonate secretion by the esophagus,13,14 mouth,15 stomach (nonparietal cells),16 and duodenum17 have been documented in response to instillation of acid into the esophagus. Impairment of bicarbonate secretion by exocrine glands associated with these epithelial membranes may contribute to the high incidence of esophagitis and lung injury among patients with CF.18
WATER TRANSPORT IN THE LUNGS It has been known for many years that freshwater drowning is followed by the movement of water into the vascu-
Volume 108 (4A)
A Symposium: Response of the Lungs to Aspiration/Effros et al
Figure 2. Some exchange processes that could influence the pH of the upper gastrointestinal tract (right) and the respiratory surfaces (left). Postulated defects in bicarbonate-chloride exchange that may contribute to respiratory and gastrointestinal disease in cystic fibrosis are shown as bars across arrows. Dotted arrows indicate the direction of flow during aspiration. * ⫽ Principal sites of CFTR in the lungs.
Figure 3. Distribution of aquaporins in the respiratory tract. Aqp ⫽ aquporin; B⫽ basal cell; M ⫽ mucosal cell; S ⫽ serosal cell.
lature, whereas saltwater drowning results in the movement of water from the circulation to the airspaces. The direction in which water flows in these circumstances is related to the relative osmolality of these solutions, or more precisely, to the chemical potential of water in the two compartments. Until recently, there has been considerable uncertainty concerning the manner in which water molecules cross the barriers that separate the vascular and
airspace compartments. Early studies indicated that perfusion of air-filled lungs with hypertonic solutions results in the extraction of water from the pulmonary tissues without associated solutes.19 Subsequent studies showed that when fluid-filled lungs are perfused with hypertonic solutions, the fluid lost from the airspaces is also virtually solute free.20 It was concluded that osmotic gradients probably induce water transport across cellular mem-
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
17S
A Symposium: Response of the Lungs to Aspiration/Effros et al
branes, which resist the movement of small hydrophilic solutes, rather than through the junctions between cells, which would have presumably permitted the passage of these molecules with water. More than 40 years ago, Paganelli and Solomon21 and Sidel and Solomon22 demonstrated that filtration of water across red cell membranes in response to osmotic gradients occurs at a much more rapid rate than would be expected from experiments in which the diffusion of water across these same membranes was studied. They hypothesized the presence of small channels in the red cell membranes that efficiently conducted water in these osmotic experiments. The nature of these channels has been recently elucidated by Agre et al,23 who isolated and characterized the first of a family of water channels, now referred to as aquaporins. Recent studies have indicated that at least four of these channels are present in the lungs and are associated with both the endothelium and epithelium of the lungs (see Figure 3).23–30 Of importance was the observation, that, as in red cells, some of these channels can be inhibited by mercurial compounds. The exact function of the aquaporins remains uncertain. They may facilitate removal of water from the airspaces after accidental or incidental aspiration while drinking. Rapid absorption of water is essential to avoid impairment of gas exchange. This might be a useful property during freshwater drowning as well but, obviously, would be of no benefit during saltwater drowning, in which the aquaporins would conduct water into the airspaces. It is also possible that these channels allow water to follow Na⫹ out of the lungs when Na⫹ is actively transported by the epithelial cells out of the airspaces. A third function of the aquaporins in the lungs may be the maintenance of moisture on the respiratory surfaces, which require the presence of small amounts of water and water vapor to avoid drying, an effect that would compromise gas transport. A role in CO2 transport has been postulated.31
REFERENCES 1. Mendelson CL. The aspiration of stomach contents in the lungs during obstetric anesthesia. Am J Obstet Gynecol. 1946;52:191. 2. Effros RM, Darin C. Efficient anion transport is essential for prompt neutralization of inspired acid: a possible model of lung injury in cystic fibrosis. Am J Respir Crit Care Med. 1995;151:A741. (Abstract.) 3. Poulson JH, Fischer JH, Illek B, Machen TE. Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA. 1994;91:5340 –5344. 4. Smith JJ, Welsh MJ. cAMP stimulates bicarbonate secretion across normal, but not cystic fibrosis airway epithelia. J Clin Invest. 1992;89:1148 –1153. 5. Schwiebert EM, Flotte T, Cutting GC, Guggino WB. Both CFTR and outwardly rectilying chloride channels contribute to cAMP-stimulated whole cell chloride currents. Am J Physiol. 1994;267:C1464 –C1477. 18S
March 6, 2000 THE AMERICAN JOURNAL OF MEDICINE威
6. Malfroot A, Dab I. New insights on gastro-esophageal reflux in cystic fibrosis by longitudinal follow up. Arch Dis Child. 1991;66:1339 –1345. 7. Vic P, Tassin E, Turck D, Gottrand F, Launay V, Farriaux JP. Frequency of gastroesophageal reflux in infants and in young children with cystic fibrosis. Arch Pediatr. 1995;2: 742–746. 8. Cucchiara S, Santamaria F, Andreotti MR, et al. Mechanisms of gastro-esophageal reflux in cystic fibrosis. Arch Dis Childhood. 1991;66:617– 622. 9. Hassall E, Israel A, Davidson AGF, Wong LT. Barrett’s esophagus in children with cystic fibrosis: not a coincidental association. Am J Gastroenterol. 1993;88:1934 –1938. 10. Scott RB, O’Laughlin EV, Gall G. Gastroesophageal reflux in patients with cystic fibrosis. J. Pediatr. 1985;106:223–227. 11. Ledson MJ, Wilson GE, Tran J, Walshaw MJ. Tracheal microaspiration in adult cystic fibrosis. J R Soc Med. 1998; 91:10 –12. 12. Engelhardt JF, Zepeda M, Cohn JA, Yankaskas JR, Wilson JM. Expression of the cystic fibrosis gene in adult human lung. J Clin Invest. 1993;93:737–749. 13. Brown CM, Rees WD. Human oesophageal bicarbonate secretion: a phenomenon waiting for a role. Gut. 1997;40: 693– 694. 14. Mertz-Nielsen A, Hillingso J, Buldiave K, Rask-Madsen J. Reappraisal of bicarbonate secretion by the human oesophagus. Gut. 1997;40:582–586. 15. Helm JF, Dodds WJ, Hogan WJ. Salivary responses to esophageal acid in normal subjects and patients with reflux esophagitis. Gastroenterology. 1987;92:1393–1397. 16. Crampton JR, Gibbons LC, Rees WDW. Effect of luminal pH on the output of bicarbonate and P2 by the normal human stomach. Gut. 1987;28:1291–1295. 17. Isenberg JI, Hogan DL, Koss MA, Selling JA. Human duodenal mucosal bicarbonate secretion. Evidence for basal secretion and stimulation by hydrochloric acid and a synthetic prostaglandin E sub I analogue. Gastroenterology. 1986;91:370 –378. 18. Feigelson J, Girault F, Pecau Y. Gastro-oesophageal reflux and esophagitis in cystic fibrosis. Acta Paediatr Scand. 1987;76:989 –990. 19. Effros RM. Osmotic extraction of hypotonic fluid from the lungs. J Clin Invest. 1974;54:935–947. 20. Effros RM, Mason GR, Sietsema K, et al. Pulmonary epithelial sieving of small solutes in rat lungs. J Appl Physiol. 1988;65:640 – 648. 21. Paganelli CV, Solomon AK. The rate of exchange of tritiated water across the human red cell membrane. J Gen Physiol. 1957;41:259 –277. 22. Sidel VW, Solomon AK. Entrance of water into human red cells under an osmotic pressure gradient. J Gen Physiol. 1957;41:243–257. 23. Agre P, Preston GM, Smith BL, Jung JS, Raina S, Monon S, Guggino WB, Nielsen S. Aquaporin CHIP: the archetypal molecular water channel. Am J Physiol. 1993:265:F463–F476. 24. Folkesson H, Matthay MA, Hasegawa H, Kheradmand F, Verkman AS. Transcellular water transport in lung alveolar epithelium through mercurial-sensitive water channels. Proc Natl Acad Sci USA. 1994;91:4970 – 4974. 25. Effros RM, Darin C, Krenz CS. Evidence for asymmetrical distribution of CHIP28 aquaporins in alveolar-capillary barrier. FASEB J. 1995;9:A279. (Abstr.) 26. Hasegawa H, Lian SC, Finkbeiner WE, Verkman AS. Extra-
Volume 108 (4A)
A Symposium: Response of the Lungs to Aspiration/Effros et al renal tissue distribution of CHIP28 water channels by in situ hybridization and antibody staining. Am J Physiol. 1994: 266:C893–C903. 27. Macey RI. Transport of water and urea in red blood cells. Am J Physiol. 1984;246:C195–C203. 28. Raina S, Preston GM, Guggino WB, Agre P. Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. J Biol Chem. 1995;270:1908 –1912. 29. King LS, Nielsen S, Agre P. Aquaporin-1 water channel
protein in lung: ontogeny, steroid-induced expression, and distribution in rat. J Clin Invest. 1996;97:2183–2191. 30. Schnitzer J, Oh P. Aquaporin-1 in plasma membrane and caveolae provides mercury-sensitive water channels across lung endothelium. Am J Physiol (Heart Circ Physiol). 1996;270:H416 –H422. 31. Nakhoul NL, Davis BA, Romero MF, Boron WF. Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes. Am J Physiol. 1998;274: C543–C548.
March 6, 2000
THE AMERICAN JOURNAL OF MEDICINE威
Volume 108 (4A)
19S