Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a myeloid growth factor, which induces proliferation and differentiation of macrophages and dendritic cells. Recently, several publications highlighted GM-CSF as highly protective in different preclinical models of pneumonia-associated lung injury, including influenza virus, Klebsiella pneumoniae, and Streptococcus pneumoniae infection and others (1-4). Importantly, GM-CSF protects the host in both the early phase of acute lung infection and during the stage of regeneration of the injured lung epithelium. GM-CSF applied to or expressed in the distal airways promotes bacterial or viral clearance by expanding alveolar macrophages or CD103 1 migratory lung dendritic cells or by stimulating their host defense capacity (1-4). GM-CSF is considered an important factor for terminal differentiation and classical activation of alveolar macrophages via PU. 1-and IRF5-dependent transcriptional programs, which is discussed as an underlying mechanism of improved macrophage host defense capacity in response to GM-CSF (5, 6). Furthermore, GM-CSF exerts multiple beneficial effects on the epithelial lung barrier, as it protects alveolar epithelial cells against oxidative stress-induced mitochondrial injury (7), and it promotes type II alveolar epithelial cell proliferation after LPS challenge (8). Of note, mice overexpressing GM-CSF in type II alveolar epithelial cells to high local levels were strongly protected from infection and injury (1, 3, 4, 8), suggesting that high levels of GM-CSF in the alveoli or the alveolar lining fluid should be achieved for putative acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) treatment. Notably, GM-CSF levels in bronchoalveolar lavage (BAL) fluid were correlated with improved outcome of patients with ARDS (9), and early clinical studies suggested that it might improve respiratory function in patients with sepsis (10). Together, these data provide strong evidence that GM-CSF improves host defense, attenuates epithelial cell injury, promotes repair of the epithelium, and improves barrier function and gas exchange in ALI/ARDS (11). We report on six patients with pneumonia-associated ARDS who received GM-CSF as compassionate treatment. Given that systemic GM-CSF delivery in patients with sepsis-induced lung injury failed to improve outcome (12), and considering that high local concentrations of GM-CSF in the alveolar lining fluid are a prerequisite for its beneficial effect in preclinical ARDS models, we applied GM-CSF per inhalation. The University Ethics Committee was informed about the compassionate treatment (informed consent was obtained from the legal representative of each patient) and had approved use of BAL biobank material and data derived from patients subjected to sequential bronchoscopy for diagnostic purposes. Compassionate GM-CSF treatment was provided to patients who were diagnosed with moderate to severe community-acquired pneumonia-or ventilator-associated pneumonia-associated ARDS according to the Berlin definition criteria (mean 6 SEM baseline PaO2/FIO2= 91.5 6 13.3), received antibiotic treatment according to guidelines, and did not improve with respect to oxygenation after> 6 days of mechanical ventilation, with or without additional extracorporeal membrane oxygenation support. One hundred twenty-five micrograms of recombinant GM-CSF (Sargramostim, Leukine, Bayer HealthCare Pharmaceuticals, Seattle, WA) were applied by Aeroneb Solo device (Covidien, Neustadt, Germany) at an interval of 48 hours (Figure 1A). To exclude any influence of the nebulization procedure on efficacy of the drug, we …