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Reduction of Alveolar Epithelial Ion and Fluid Transport by Inflammatory Mediators

Institute of Child Health, University of Liverpool, Liverpool, United Kingdom

To the Editor:

Drs. Folkesson and Matthay discussed, in their review of progress in research on alveolar epithelial ion and fluid transport, the direct effects of bacteria and their lipopolysaccharides and exoenzymes as well as of influenza virus on respiratory epithelial ion transport and lung edema (1). An important issue not adequately covered in this review and previous reviews on the pathogenesis of pulmonary edema is the role of cytokines and their mediators generated in response to bacterial and viral pathogens in changes in alveolar epithelial ion transport and pulmonary fluid clearance. In children with pulmonary edema related to meningococcal septicemia, we recently found evidence for a reversible systemic reduction in epithelial sodium and chloride transport (2, 3). This change in ion transport was specific for sodium and chloride and did not extend to potassium transport. Nasal airway potential difference measurements showed that airway epithelial chloride channel function was reduced but sodium channel (ENaC) function appeared to be maintained. The data did not support a nonspecific breakdown of the epithelial barrier by bacteria as mechanism for pulmonary edema in septicemia. Our data supported the involvement of a specific abnormality of chloride and sodium transport in the acute phase of septicemia-induced pulmonary edema. In one ventilator-dependent patient with meningococcal septicemia reported previously, the transient abnormality of epithelial sodium and chloride transport was still very significant two weeks after admission and successful antibiotic therapy, suggesting that live bacteria or their exoenzymes and endotoxins could not be directly involved in the systemic ion transport reduction (4). An ongoing inflammatory response or its long-term effects was a more likely explanation for this phenomenon. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels are very high in the peripheral blood of patients with meningococcal septicemia and have been linked to poor outcome. Folkesson and Matthay mentioned the data showing that TNF is involved in up-regulation of alveolar fluid clearance (AFC) (1). A dichotomal role of TNF in regulation of AFC has, however, been established in a recent study. In a rat model TNF, when complexed with the soluble TNF receptor 1 construct (sTNFR1), increased alveolar fluid clearance via a lectin-binding structure, but without sTNFR1 it inhibited fluid clearance. STNFR1 seemed to modulate TNF function by diverting it from classical TNF receptors to an alternative receptor activating ENaC. Further, it was found that prolonged exposure of alveolar epithelial cells to TNF reduced ENaC mRNA expression (5). TNF is also an important stimulator of nitric oxide (NO) production in septicemia, as demonstrated in a mouse model of septic shock in which anti–TNF- antibodies reduced NO synthase activity and NO production significantly (6). NO is released by distal lung epithelial cells and alveolar macrophages in response to TNF, IL-1, and interferon- (7). NO reduced ENaC function and Na/K ATPase activity in alveolar epithelial cells significantly (8). NO repletion in a guinea pig model enhanced TNF-induced pulmonary edema significantly (9). IL-1 was found to antagonize the effects of prostaglandin E2 (PGE2), which stimulated chloride transport in canine tracheal epithelium and in Calu-3 bronchial epithelial cells by inducing excess production of PGE2. This led to a down-regulation of EP₄ prostanoid receptors and subsequently to a reduction of PGE2-induced cAMP production. Reduced intracellular cAMP levels then led to a reduction in cAMP-dependent cystic fibrosis transmembrane conductance regulator (CFTR) function (5). A more pronounced effect on CFTR function was noted for interferon (IFN-), which decreased CFTR-dependent chloride currents in bronchial epithelial cells by reduction of CFTR mRNA (5). Our study on meningococcal septicemia–related pulmonary edema demonstrated a closer relationship of pulmonary edema and its severity to indicators of reduced epithelial chloride transport (3). IL-1 was also found to reduce ENaC function in human bronchial epithelial cells and ENaC expression and sodium uptake in alveolar type II cells (5). IL-1 was hence able to reduce both respiratory epithelial sodium and chloride transport, and could thus contribute to a reduction in AFC. In summary, there is evidence that proinflammatory cytokines mediated partially by NO can decrease respiratory epithelial sodium and chloride and associated fluid transport. These cytokines are present in the systemic circulation in patients with septicemia and could be a major contributing factor, particularly in the early phase of septicemia-related pulmonary edema and ARDS by their effect on ion transport.

In pneumonia with intra-alveolar accumulation of bacteria, the local accumulation of cytokine-producing cells is associated with a high concentration of cytokines around respiratory epithelial cells, which may have profound local effects on ion transport and alveolar fluid accumulation. This may contribute to the formation of pneumonic lung consolidation. Future research into supportive therapies needs to address the important role of proinflammatory mediators in reduction of AFC. Manocha and coworkers (10), who reported on a retrospective study suggesting that use of inhaled salbutamol was associated with a shorter duration and lower severity of acute lung injury, summarized the data on the anti-inflammatory properties of -agonists. -agonists were found to decrease polymorphonuclear cell chemotaxis and accumulation in the lung, and decreased IL-1, TNF, and IL-6 production in macrophages. A first step in the direction of utilization of the beneficial effects of cytokines has been the development of a synthetic peptide (tip peptide) mimicking the lectin-like domain of TNF and using its ENaC activating activity. This peptide was found to increase alveolar edema reabsorption significantly (5).

Footnotes

Conflict of Interest Statement: M.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

1. Folkesson HG, Matthay MA. Alveolar epithelial ion and fluid transport: recent progress. Am J Respir Cell Mol Biol 2006;35:10–19.[Free Full Text]
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