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Am J Physiol Lung Cell Mol Physiol 293: L855-L858, 2007. First published August 10, 2007; doi:10.1152/ajplung.00305.2007
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EDITORIAL FOCUS

Modulation of alveolar fluid clearance by reactive oxygen-nitrogen intermediates

Weifeng Song1,4 and Sadis Matalon1,2,3,4

Departments of 1Anesthesiology, 2Physiology and Biophysics, 3Environmental Health Sciences, and 4Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama

IN THIS ISSUE of AJP-Lung, Kaestle et al. (28) report that an increase in left atrial pressure in isolated perfused lungs induces a Ca2+-dependent increase of endothelial nitric oxide (NO) production, which decreases reabsorption of fluid across the alveolar epithelium, resulting in pulmonary edema. Furthermore, they report that in chronic heart failure, NO production by endothelial cells is impaired, and alveolar reabsorption is maintained. This very interesting study further highlights the role of endogenous NO in the regulation of alveolar fluid clearance (AFC) in disease.

The classic work of Matthay and coworkers (35, 36) clearly established the presence of sodium (Na+)-driven fluid transport across the alveolar epithelium. While the contribution of this process in alveolar fluid balance in healthy lungs has not been established, it has been shown that active Na+ transport limits the degree of alveolar edema in acute and chronic lung injury. For example, intratracheal instillation of a Na+ channel blocker in rats exposed to hyperoxia increased the amount of extravascular lung water (54). Conversely, intratracheal instillation of adenoviral vectors expressing the Na+-K+-ATPase genes increased survival of rats exposed to hyperoxia (9). Moreover, patients with acute lung injury who are still able to concentrate alveolar protein (as a result of active Na+ reabsorption) have a better prognosis than those who cannot (37, 51).

Insight into the nature and regulation of transport pathways has come from electrophysiological studies of freshly isolated and cultured alveolar type II (ATII) cells. Na+ ions diffuse passively down their electrochemical gradient into alveolar epithelial cells through apically located amiloride-sensitive cation and sodium-selective channels (4, 23, 26, 55) or cGMP-sensitive pathways (38) and are extruded across the basolateral cell membranes by the ouabain-sensitive Na+-K+-ATPase (10, 42). Ion channels on the apical surface usually constitute the rate-limiting step in this process, offering more than 90% of the resistance to transcellular Na+ transport.

There has been considerable interest in understanding whether NO modulates ion transport across the lung. NO is generated from three enzymes (eNOS, nNOS, and iNOS) that catalyze the oxidative deamination of L-arginine. Potential sources of NO in the lung include both rat- and human-activated alveolar macrophages (19), neutrophils, ATII cells (40, 52), and airway cells (1). Increased iNOS levels have been found in airway cells and human lung tissue obtained from patients with acute respiratory distress syndrome (ARDS) (14, 31, 44) and numerous inflammatory lung diseases.

The biological effects of NO depend on its concentration, the biochemical composition of the target, and the presence of other radicals and reactive species. NO binds to the heme group of soluble guanylate cyclase (sGC) resulting in increased cellular cGMP levels (21); it reacts with superoxide (O2·–) at near diffusion-limited rates to produce ONOO– (2) or with oxygen to form nitrogen dioxide (NO2; although this reaction is very slow at physiological levels of NO). Both of these species will result in the formation of a variety of reactive oxygen-nitrogen intermediates (RONS). In the presence of an electron acceptor, it may react with thiols to form nitrosothiols (RS-NO) (45–47). It is generally accepted that nitrosothiols formation and activation of sGC are reversible signaling effects that affect a large number of very important homeostatic functions. Furthermore, NO may decrease lung injury by decreasing adhesion of inflammatory cells to endothelial cells. However, at higher concentrations, both NO and RONS may cause extensive cellular injury by initiating iron-independent lipid peroxidation, sulfhydryl oxidation, DNA strand scission, tyrosine nitration, apoptosis, and cellular necrosis, as well as inactivating mitochondrial aconitase (15). Kaestle et al. (28) report that small amounts of NO, produced by the Ca2+ activation of eNOS (considered to be a low-output system) during an acute increase of left atrial pressure in isolated perfused rat lungs, cross the blood gas barrier and decrease AFC via cGMP-dependent mechanisms.

Reactive intermediates decrease ion transport across the alveolar epithelium in vivo. Several studies have investigated the possible association between RONS and Na+ transport across the alveolar epithelium in both animals with acute lung injury and patients with cardiogenic edema, acute lung injury, or ARDS. Pittet et al. (39) showed that reabsorption of isotonic fluid was inhibited during prolonged hemorrhagic shock. Instillation of aminoguanidine, an inhibitor of iNOS, restored fluid reabsorption to normal levels. Hickman-Davis et al. (18) showed mycoplasma infection resulted in significant decrease of both Na+-dependent AFC in Balb/c mice and inhibition of amiloride-sensitive Na+ currents across ATII cells isolated from these mice. However, normal levels of AFC were seen when Balb/c mice pretreated with cyclophosphamide to suppress inflammatory cells and decrease NO production by alveolar macrophages were infected with mycoplasmas (18). Zhu et al. (56) showed that increased levels of nitrate and nitrite (the stable byproducts of NO and RONS) in edema fluid samples of patients with acute lung injury were associated with slower rates of AFC across the lungs of patients with acute lung injury. RONS have also been shown to decrease ATII cell Na-K-ATPase in thrombin and oleic acid injury by promoting endocytosis from the basolateral plasma membrane via a mechanism involving phosphorylation of PKC{zeta} (49, 50). On the other hand, iNOS(–/–) mice as well as alveolar epithelial cells treated with iNOS inhibitors lack amiloride-sensitive transport and have lower levels of {alpha}- and {gamma}ENaC proteins (16). Thus although increased levels of RONS damage ion transport, basal levels of NO are necessary for the proper function of the amiloride-sensitive channels.

More definitive conclusions concerning the effects of NO and RONS on ion channels on alveolar epithelial cells were drawn from studies measuring ion transport across alveolar epithelial cells. Hu et al. (20) showed that steady-state peroxynitrite concentrations of less than 10 µM decreased amiloride-inhabitable 22Na+ uptake across freshly isolated rabbit ATII cells by at least 40% without affecting Na-K-ATPase activity. Compeau et al. (7) reported that incubation of confluent monolayers of fetal lung epithelial cells with LPS-activated alveolar macrophages for 16 h resulted in a 60% reduction in amiloride-sensitive short-circuit current (Isc) and 60% decrease in the density of a 25-pS nonselective cation, Ca2+-activated channel present in the apical membrane of these cells. These effects were abrogated by blocking the ability of alveolar macrophages to generate NO and were associated with a decrease in ENaC mRNA levels. Guo et al. (13) also reported that NO, generated by a variety of NO donors, decreased Isc across confluent monolayers of rat ATII cells with an IC50 of 0.4 µM without affecting transepithelial resistance. NO also inhibited ~60% of the amiloride-sensitive Isc across ATII cell monolayers following permeabilization of the basolateral membranes. However, incubation of ATII monolayers with a cell-permeable form of cGMP (8-BrcGMP; 400 µM) did not decrease Isc. 3-Morpholinosydnonimine (SIN-1), a generator of ONOO–, profoundly inhibited the amiloride-sensitive whole cell conductance in Xenopus oocytes expressing the three cloned subunits of the wild-type rat epithelial Na+ channel {alpha}-, beta-, {gamma} rENaC (8). Importantly, like in the studies of Guo et al. (13) in confluent monolayers of ATII cells, this effect was observed at very low ONOO– concentrations (~10 µM) suggesting that ONOO– may produce similar effects in vivo where concentrations have been estimated to occur at higher levels during inflammation. On the other hand, even supraphysiological concentrations of NO, generated by a variety of NO donors, had no effect on the amiloride-sensitive current. Substitution of one of the tyrosines in the {alpha}rENaC extracellular loop with alanine (Y279A) abrogates the reactive oxygen-nitrogen species-mediated decrease of amiloride-sensitive Na+ currents across Xenopus oocytes expressing {alpha}Y279A, beta, {gamma} rENaC (5). These findings are in agreement with the original report of Goodman et al. (12) and also showed that BrcGMP did not alter dome formation (a parameter for active salt and water transport) by ATII cells and suggest that the effects of NO are mediated through cGMP-independent mechanisms, such as posttranslational modifications of either ENaC per se, or structural proteins (such as actin and fondrin), which are necessary for proper action of ENaC (27).

Regulation of lung epithelial Na+ channels by cGMP. In contrast to the results cited above, other studies clearly show that NO modulates cation channel activity in both renal and alveolar epithelial cells by increasing cGMP levels. Light et al. (33) demonstrated the presence of a 28-pS cation channel in rat renal inner-medullary collecting duct cells, the activity of which was decreased both by cGMP per se and via cGMP kinase-induced phosphorylation. NO released from bradykinin-stimulated endothelial cells or spermine NONOate decreased net 22Na+ flux across isolated perfused cortical collecting ducts (48) and decreased Na+ Isc across a cortical collecting duct cell line while increasing their cGMP content (48). More recently, Helms et al. (17) reported that NO released from PAPANONOate decreased amiloride-sensitive Na+ current across confluent monolayers of Xenopus kidney distal nephron A6 and M1 cortical collecting duct cells mounted in Ussing chambers; furthermore, when these cells were patched in the cell-attached mode, PAPANOate decreased the open probability of the 4-pS ENaC channels without altering their unitary conductance.

In vitro studies on the regulation of Na+ transport by cGMP across confluent monolayers of cultured rat type II alveolar cells have led to contradictory results. As mentioned above, cGMP did not alter Isc across rat ATII monolayers (13). In contrast, cGMP, as well as NO, increased Isc and 22Na+ influx in tracheal and distal lung epithelial cells (41, 43). Jain et al. (22) reported that cGMP and GSNO significantly decreased single channel activity in rat ATII cells. However, Kemp et al. (30) showed that BrcGMP increased cation conductance in rat ATII cells, which was totally abolished by Zn2+. Furthermore, different responses of whole cell Na+ conductance to cGMP and GSNO in A549 cells were published by three independent groups (29, 32, 53). The most likely explanation for these contradictory responses is the existence of multiple families of Na+ channels in ATII cells (most likely with different ENaC subunit composition than the 4-pS ENaCs), the properties of which may be modified by culture conditions (34). For example, cell-permeable forms of cGMP activated a sodium conductance in Xenopus oocytes following heterologous expression of {alpha}-, beta-, {gamma}-, and {delta}ENaC but not {alpha}-, beta-, {gamma}ENaC alone (24). Expression of {delta}ENaC has been documented by both indirect immunofluorescence and RT-PCR in a variety of human lung epithelial cell lines (25). In addition to amiloride-sensitive channels, lung epithelial cells contain cyclic nucleotide-gated cation channels on their apical membranes (38). The biochemical composition of the cGMP-activated, non-{alpha}ENaC Na+ channels in lung epithelial cells is not known.

Kaestle et al. (28) report that endogenous NO, generated by eNOS following a transient increase of left atrial pressure, decreased sodium reabsorption by epithelial cells. This effect was mimicked by intratracheal instillation of BrcGMP and ameliorated by agents that inhibited either eNOS or sGC. Furthermore, eNOS(–/–) mice were protected from this effect. Since eNOS is a low-output NO-producing enzyme and some of the NO will be scavenged by red blood cell hemoglobin, as well as react with other cellular targets while crossing the extracellular space, alveolar epithelial cells must contain significant amounts of sGC and PKGs to transduce very small changes of NO to cGMP. One would have expected that similar effects would be seen by considerably lower levels of BrcGMP than used in this study (1 mM). In any event, these data clearly support the hypothesis that cGMP decreases alveolar reabsorption. It must be stressed that in this study, the authors measured bidirectional fluxes across the alveolar epithelium, so their results cannot be attributed to an increase of Cl– secretion (6).

Based on these data, one may conclude that increased levels of NO will increase the amount of fluid in the lungs of patients with cardiogenic edema. Indeed, at least one study has suggested that this is the case (3). Thus use of inhaled NO or agents that activate cGMP production (in an effort to reduce pulmonary vasoconstriction) may have to be carefully considered since inhibition of alveolar fluid transport has been correlated with worsening clinical outcome in patients with acute lung injury (37, 51). However, it is important to remember that the experiments of Kaestle et al. (28) were conducted in isolated perfused rats (which lack lymph flow), and these results apply only to an acute increase of left atrial pressure. As mentioned in the paper, chronic congestive heart failure damages the endothelium, which by decreasing levels of NO, preserves AFC. Also, a recent report indicates that cardiogenic edema fluid (but not plasma) increases amiloride-sensitive Na+ transport in both adult ATII cells and across the alveolar epithelium (11). Thus additional factors may come into play to prevent the NO decrease of AFC and prevent fluid accumulation into the alveolar spaces.


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This work was funded by the National Institutes of Health CounterACT Program through the National Institute of Environmental Health Sciences (U01-ES-015676) and also National Institutes of Health Grants R37-HL31197 and R01-HL-75540. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the federal government.


   ACKNOWLEDGMENTS
 
We thank Dr. Hugh O'Brodovich for numerous helpful suggestions and for reading and editing this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. Matalon, Dept. of Anesthesiology, Univ. of Alabama at Birmingham, BMR II Rm. 224, 901 19th St. South, Birmingham, AL 35205-3703 (e-mail: sadis{at}uab.edu)


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