The diagnosis acute respiratory distress syndrome (ARDS) describes a type of acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, pulmonary edema, increased lung weight, and loss of aerated lung tissue.1,2 ARDS represents a worldwide public health problem with high mortality, and specific pharmacological interventions targeting key pathophysiological processes of ARDS are still lacking.3 AP301 (scientific name: human tumor necrosis factor α [TNF-α]-derived peptide) is a synthetic peptide composed of 17 natural amino acids (Cys–Gly–Gln–Arg–Glu–Thr–Pro–Glu–Gly–Ala–Glu–Ala–Lys–Pro–Trp–Tyr–Cys), with a molecular mass of ~2,000 Da. Basically, AP301 is a circularized presentation of the lectin-like domain (so-called TIP domain) of human TNF-α.4 Pulmonary administration of TIP peptide has been shown in a variety of small animal models of acute lung injury (ALI) to substantially alleviate pulmonary permeability edema of various pathophysiological conditions.5–10 It was suggested, that either enhancement of alveolar fluid clearance (AFC) or improvement of reduced pulmonary vascular permeability (or both), could be the primary mode(s) of action, thereby leading secondary to remarkable improvements of impaired gas exchange.10–13 Recently, these data were confirmed by a large-animal study, in which acute lung injury (ALI) was induced by bronchoalveolar lavage followed by injurious ventilation in anaesthetized domestic pigs.14 In this study, single administration of AP301 (i.e., nebulization of 1.0 mg/kg into the inspiratory branch of the ventilatory circuit), was associated with a significant, immediate and sustained decrease of lung fluid content, quantified by the extravascular lung water index (EVLWI). This effect was accompanied by a significant improvement of oxygenation (i.e., increase of PaO2/FiO2) and reduction of pulmonary shunt fraction (Qs/Qt). All these effects reflective of meaningful edema clearance, were maintained or gradually increased versus baseline and control group data over the entire observation period of 5 hours, thereby indicating a clinically useful effect duration of single oral AP301 inhalation.14 Recently, the primary pharmacology of AP301 was characterized by using chamber and whole cell patch clamp experiments in primary type II alveolar epithelial cells (AEC) isolated from rat, dog, and pig lungs.15 In the presence of AP301, amiloride-sensitive Na+ currents (via ENaC) in rat, dog, and pig AEC type II cells were increased by about 9-, 13-, and 16-fold, respectively, versus baseline conditions.15 These effects could be inhibited by the specific ENaC inhibitor amiloride. These results provide strong evidence that the pulmonary edema-clearing effect of AP301 is based on activation of the amiloride-sensitive Na+ current through ENaC in type II AECs across all tested species. This implies that AP301 mediates its favorable effects predominantly by upregulation of vectorial Na+ transport as driver of AFC. This is of importance, as available data suggest that ENaC function is reduced or down-regulated under the conditions of pulmonary permeability edema.16 As permeability edema is a frequent complication in a number of severe and life-threatening pulmonary conditions, such as ARDS, cardiogenic edema, high altitude pulmonary edema (HAPE), or ischemia-reperfusion injury, the latter of which can cause primary graft failure following lung transplantation, AP301 is a promising candidate with potential therapeutic value in all of these serious clinical pulmonary conditions.11,12 The aim of this paper is to present the overall translational concept and results of the first-in-man (FIM) study of AP301, which examined the local and systemic safety, and systemic exposure of ascending single doses of orally inhaled AP301 in healthy adult male subjects.