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Therapeutic Options for Pulmonary Edema Associated with Nuclear Factor-B Activation in Septicemia

In their recent article, Arcaroli and colleagues found that increased nuclear translocation of nuclear factor (NF)-B associated with the IRAK-1 variant haplotype was accompanied by more severe septicemia-related lung injury manifesting itself in prolonged ventilation requirements (1). Underlying mechanisms have recently been explored in the mouse model of endotoxin-induced lung injury in which NF-B activation induced by knockout of heat shock protein expression was associated with more severe pulmonary disease (2), and in another study in which the inhibition of NF-B by an IB kinase inhibitor led to prevention of the endotoxin-induced increase in lung water accumulation (3). The pathogenetic mechanism by which NF-B activation leads to a reduction in pulmonary edema clearance has been clarified: NF-B activation is essential for tumor necrosis factor (TNF) and interleukin (IL)-1 production. Both cytokines reduced alveolar epithelial sodium and chloride and associated fluid transport (4).

We found that meningococcal septicemia-related pulmonary edema is strongly associated with a reduced epithelial sodium and chloride transport (5). TNF reduced epithelial sodium channel (ENaC) mRNA expression in alveolar epithelial cells, and IL-1 was noted to reduce cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function and ENaC expression in the same cell population. Nitric oxide (NO) is released by distal lung epithelial cells and alveolar macrophages in response to TNF and IL-1 and reduced sodium transport in alveolar epithelial cells through a reduction in ENaC and sodium potassium ATPase function (4).

Arcaroli and coworkers suggested in their discussion antiinflammatory therapies directed at NF-B activity or TNF expression. This approach, however, may be associated with adverse effects as NF-B activity is critically required for hematopoiesis and for the differentiation and maturation of both myeloid and lymphoid immune cells, including T lymphocytes, B lymphocytes, natural killer cells, and dendritic cells (6). TNF when bound to TNFR1 can activate ENaC via an alternative receptor and lead to an increase in pulmonary edema clearance, and its lectin binding tip peptide has been used successfully to increase pulmonary fluid clearance (4). Therapeutic approaches to increase in pulmonary fluid clearance should aim directly at an increase in alveolar ion transport. This was successful with the use of -agonists, which improve CFTR function via an increase in intracellular cAMP levels (4), in the -Agonist Lung Injury Trial. In our patients with meningococcal septicemia-related pulmonary edema, the reduced chloride channel function in the nasal airway was reversible by topical application of a -agonist (5).

Michael Eisenhut

Institute of Child Health, Liverpool, United Kingdom

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. Arcaroli J, Silva E, Maloney JP, He Q, Svetkauskaite D, Murphy JR, Abraham E. Variant IRAK-1 haplotype is associated with increased nuclear factor-B activation and worse outcomes in sepsis. Am J Respir Crit Care Med 2006;173:1335–1341.[Abstract/Free Full Text]
2. Singleton KD, Wischmeyer PE. Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis. Am J Physiol Lung Cell Mol Physiol 2006;290:L956– L961.[Abstract/Free Full Text]
3. Everhart MB, Han W, Sherrill TP, Arutiunov M, Polosukhin VV, Burke JR, Sadikot RT, Christman JW, Yull FE, Blackwell TS. Duration and intensity of NF-B activity determine the severity of endotoxin-induced acute lung injury. J Immunol 2006;176:4995–5005.[Abstract/Free Full Text]
4. Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm (Lond) 2006;3:5.
5. Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport. Pediatr Crit Care Med 2006;7:119–124.[CrossRef][Medline]
6. Liu SF, Malik AB. NF-kB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 2006;290:L622–L645.[Abstract/Free Full Text]

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