%0 Journal Article %A Susan Tzotzos %A Bernhard Fischer %A Helmut Pietschmann %A Hendrik Fischer %A Rudolf Lucas %A Waheed Shabbir %A Rosa Lemmens-Gruber %T Characterisation of TNF-alpha lectin-like domain derived peptides associated with improved alveolar fluid clearance in pulmonary oedema %D 2011 %J European Respiratory Journal %P 4688 %V 38 %N Suppl 55 %X The beneficial effect of the lectin-like domain of TNF-alpha, including the TIP peptide which mimics this domain, on activation of oedema resorption, improved alveolar clearance and protection of lung function after transplantation, is well documented from several independent in vitro and in vivo studies using animal models. The effect is mediated by activation of sodium uptake through the amiloride-sensitive epithelial sodium ion channel (ENaC), which plays a major role in alveolar fluid clearance in normal and diseased lungs. Several peptides mimicking the lectin-like domain of human TNF-alpha, and differing from the human TIP peptide by mutation or substitution of amino acid residues with non-natural derivatives, were synthesised and tested for their ability to enhance sodium current through ENaC in A549 cells with the patch clamp technique.For all ENaC-activating TIP peptides a maximum effect was observed at 120 nM. Compared to TNF-alpha (EC50 8.2 nM) and the original human TIP peptide (EC50 54.3 nM), several of the newly-designed peptides were more effective at enhancing amiloride-sensitive current than the latter: the most active peptide had an EC50 of 19.9 nM. Our data suggest that TIP peptides with charge distribution and interatomic distances most closely resembling the 3D structure of the native lectin-like domain of TNF-alpha, are those with greater ability to enhance activation of sodium current through ENaC. No standard therapy exists for pulmonary oedema, thus these TIP peptides represent promising therapeutic agents for activating sodium uptake from the alveolar fluid through ENaC and improving clinical outcome in this condition. %U