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BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive.MethodsSpectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 “gain-of-function” experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validateex vivoresults.ResultsWe provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead,ex vivoinfected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in “inflammatory alveolar macrophages”, comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection.ConclusionsCollectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment.

Human-based organ models can provide strong predictive value to investigate the tropism, virulence, and replication kinetics of viral pathogens. Currently, such models have received widespread attention in the study of SARS-CoV-2 causing the COVID-19 pandemic. Applicable to a large set of organoid models and viruses, we provide a step-by-step work instruction for the infection of human alveolar-like organoids with SARS-CoV-2 in this protocol collection. We also prepared a detailed description on state-of-the-art methodologies to assess the infection impact and the analysis of relevant host factors in organoids. This protocol collection consists of five different sets of protocols. Set 1 describes the protein extraction from human alveolar-like organoids and the determination of protein expression of angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and FURIN as exemplary host factors of SARS-CoV-2. Set 2 provides detailed guidance on the extraction of RNA from human alveolar-like organoids and the subsequent qPCR to quantify the expression level of ACE2, TMPRSS2, and FURIN as host factors of SARS-CoV-2 on the mRNA level. Protocol set 3 contains an in-depth explanation on how to infect human alveolar-like organoids with SARS-CoV-2 and how to quantify the viral replication by plaque assay and viral E gene-based RT-qPCR. Set 4 provides a step-by-step protocol for the isolation of single cells from infected human alveolar-like organoids for further processing in single-cell RNA sequencing or flow cytometry. Set 5 presents a detailed protocol on how to perform the fixation of human alveolar-like organoids and guides through all steps of immunohistochemistry and in situ hybridization to visualize SARS-CoV-2 and its host factors. The infection and all subsequent analytical methods have been successfully validated by biological replications with human alveolar-like organoids based on material from different donors.

Organ models have received widespread attention in the study of SARS-CoV-2, the pathogen causing the current COVID-19 pandemic. Human-based organ models can provide strong predictive value to investigate the tropism, virulence, and replication kinetics of viral pathogens. Applicable to a large set of organoid models and viruses, we provide a step-by-step work instruction for the infection of human lung organoids with SARS-CoV-2 in this protocol collection. We also prepared a detailed description on state-of-the-art methodologies to assess the infection impact and the analysis of relevant host factors in organoids. This protocol collection consists of five different sets of protocols. Set 1 describes the protein extraction from human lung organoids and the determination of protein expression of angiotensin-converting enzyme 2 (ACE2), as an exemplary host factor of SARS-CoV-2. Set 2 provides detailed guidance on the extraction of RNA from human lung organoids and the subsequent RT-qPCR to quantify the expression level of e.g., ACE2or other host factors of SARS-CoV-2 on RNA level. Protocol set 3 contains an in-depth explanation on how to infect human lung organoids with SARS-CoV-2 and how to quantify the viral replication by plaque assay and viral E gene-based RT-qPCR. Set 4 provides a step-by-step protocol for the isolation of single cells from infected human lung organoids for further processing in single-cell RNA sequencing or flow cytometry. Set 5 presents a detailed protocol on how to perform the fixation of human lung organoids and guides through all steps of immunohistochemistry and in situ hybridization to visualize SARS-CoV-2 and its host factors. The infection and all subsequent analytical methods have been successfully validated by biological replications with human lung organoids based on material from different donors.

This protocol describes the fixation of infected human lung organoids, as well as the sample preparation for immunohistochemistry and immunohistology of infected tissue from lung organoids.

SARS-CoV-2 utilizes the ACE2 transmembrane peptidase as essential cellular entry receptor. Several studies have suggested abundant ACE2 expression in the human lung, inferring strong permissiveness to SARS-CoV-2 infection with resultant alveolar damage and lung injury. Against this expectation, we provide evidence that ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation in the human alveolus. Instead, spectral imaging of ex vivo infected human lungs and COVID-19 autopsy samples depicted that alveolar macrophages were frequently positive for SARS-CoV-2, indicating viral phagocytosis. Single-cell transcriptomics of SARS-CoV-2 infected human lung tissue further revealed strong inflammatory and anti-viral activation responses in macrophages and monocytes, comparable to those induced by MERS-CoV, but with virus-specific gene expression profiles. Collectively, our findings indicate that severe lung injury in COVID-19 likely results from an overwhelming immune activation rather than direct viral damage of the alveolar compartment. Funding: ACH, LES, SH were supported by Berlin University Alliance GC2 Global Health (Corona Virus Pre-Exploration Project). ACH, SH, TW and CD were supported by BMBF (RAPID) and ACH, SH by BMBF (alvBarriereCOVID-19). KH, LB, SL, SH, CD, TW, ACH were funded by BMBF (NFN-COVID 19, Organo-Strat). KH, NS, LES, MW, SH, ADG, CD, TW and ACH were supported by DFG (SFB-TR 84). ACH was supported by BIH, Charite 3R, and Charite-Zeiss MultiDim. KH was supported by BMBF (Camo-COVID-19). MW, NS and SH was supported by BMBF (PROVID). MW and NS was supported by BIH and BMBF (SYMPATH, CAPSyS, NAPKON). BO and DB were funded through the BIH Clinical Single Cell Bioinformatics Pipeline. LB was supported by the BMBF (CoIMMUNE), the DFG (KFO 342) and the IZKF of the Medical Faculty of the WWU. Conflict of Interest: The authors declare no competing interests. Ethical Approval: The study was approved by the ethics committee at the Charite clinic (projects EA2/079/13) and Arztekammer Westfalen-Lippe and of the Westfalischen Wilhelms-Universitat (AZ: 2016-265-f-S). Written informed consent was obtained from all patients.

Zusammenfassung. Fragestellung: Die deskriptive Untersuchung von Anträgen auf Opferentschädigung für Kinder und Jugendliche sowie der soziodemografischen und traumaspezifischen Daten der Betroffenen. Methodik: Eine Analyse von 100 Akten der Opferentschädigung von Kindern und Jugendlichen mittels eines selbstentwickelten Kategoriensystems. Ergebnisse: Die Akten beinhalten ausschließlich interpersonelle Traumata, wovon 59 % Typ-II-Traumata sind. Die häufigste Gewaltform ist sexuelle Gewalt. Die Täter sind überwiegend Personen aus dem häuslichen Umfeld. Bei 79 % der Opfer wurden psychische Störungen diagnostiziert, am häufigsten die Posttraumatische Belastungsstörung. Schlussfolgerungen: Sexuell missbrauchte Kinder und Jugendliche machen einen Großteil der Zielgruppe von kinder- und jugendpsychotherapeutischen Traumaambulanzen nach dem Opferentschädigungsgesetz (OEG) aus. Solche Traumaambulanzen sollten demnach eine spezifische Expertise in der psychotherapeutischen Behandlung dieser Kinder und Jugendlichen anbieten.

Sharing instead of buying is regaining traction among today's consumers. This study aims at identifying segments of sharing consumers to unearth potentially viable clusters of a consumer behavior that is a market of growing economic relevance. By means of a qualitative study and a survey with a roughly representative sample of 1121 Swiss-German and German consumers, a set of trait-related, motivational, and perceived socioeconomic variables is identified that can be used to group individuals into segments that differ with regard to their approach to sharing. A cluster analysis based on these variables suggests four potential clusters of sharing consumers-sharing idealists, sharing opponents, sharing pragmatists, and sharing normatives. Two sets of testable propositions are derived that can guide further research in this domain and pave the way to a more targeted approach to the growing market of "sharing" businesses.

By means of an ethnographic approach, this research examines perceptions of fairness and consumer behavior in an emerging nonmonetary sharing system. In contrast to market exchanges, which are defined by clear rules and principles of reciprocity, the redistribution of goods in a “sharing” context is in many cases less institutionalized and thus open to contestation. We draw on concepts from institutional theory to map out the interplay of different and partly contradicting fairness perceptions in an emerging nonmonetary sharing system and explain how those are negotiated and synthesized. We explicitly highlight a nonrelational fairness principle, leading to the stabilization of the sharing system under study through processes of “goal sharing” and “hierarchical coupling.” We discuss our findings in terms of their implications on sharing theory and the role of fairness within this literature stream.

Defence mechanisms against intracellular bacterial pathogens are incompletely understood. Our study characterizes a type I IFN-dependent cell-autonomous defence pathway directed against Legionella pneumophila, an intracellular model organism and frequent cause of pneumonia. We show that macrophages infected with L. pneumophila produced IFNβ in a STING- and IRF3- dependent manner. Paracrine type I IFNs stimulated upregulation of IFN-stimulated genes and a cell-autonomous defence pathway acting on replicating and non-replicating Legionella within their specialized vacuole. Our infection experiments in mice lacking receptors for type I and/or II IFNs show that type I IFNs contribute to expression of IFN-stimulated genes and to bacterial clearance as well as resistance in L. pneumophila pneumonia in addition to type II IFN. Overall, our study shows that paracrine type I IFNs mediate defence against L. pneumophila, and demonstrates a protective role of type I IFNs in in vivo infections with intracellular bacteria.

Introduction Lung-protective ventilation reduced acute respiratory distress syndrome (ARDS) mortality. To minimize ventilator-induced lung injury (VILI), tidal volume is limited, high plateau pressures are avoided, and positive end-expiratory pressure (PEEP) is applied. However, the impact of specific ventilatory patterns on VILI is not well defined. Increasing inspiratory time and thereby the inspiratory/expiratory ratio (I:E ratio) may improve oxygenation, but may also be harmful as the absolute stress and strain over time increase. We thus hypothesized that increasing inspiratory time and I:E ratio aggravates VILI. Methods VILI was induced in mice by high tidal-volume ventilation (HVT 34 ml/kg). Low tidal-volume ventilation (LVT 9 ml/kg) was used in control groups. PEEP was set to 2 cm H2O, FiO2 was 0.5 in all groups. HVT and LVT mice were ventilated with either I:E of 1:2 (LVT 1:2, HVT 1:2) or 1:1 (LVT 1:1, HVT 1:1) for 4 hours or until an alternative end point, defined as mean arterial blood pressure below 40 mm Hg. Dynamic hyperinflation due to the increased I:E ratio was excluded in a separate group of animals. Survival, lung compliance, oxygenation, pulmonary permeability, markers of pulmonary and systemic inflammation (leukocyte differentiation in lung and blood, analyses of pulmonary interleukin-6, interleukin-1β, keratinocyte-derived chemokine, monocyte chemoattractant protein-1), and histopathologic pulmonary changes were analyzed. Results LVT 1:2 or LVT 1:1 did not result in VILI, and all individuals survived the ventilation period. HVT 1:2 decreased lung compliance, increased pulmonary neutrophils and cytokine expression, and evoked marked histologic signs of lung injury. All animals survived. HVT 1:1 caused further significant worsening of oxygenation, compliance and increased pulmonary proinflammatory cytokine expression, and pulmonary and blood neutrophils. In the HVT 1:1 group, significant mortality during mechanical ventilation was observed. Conclusion According to the “baby lung” concept, mechanical ventilation-associated stress and strain in overinflated regions of ARDS lungs was simulated by using high tidal-volume ventilation. Increase of inspiratory time and I:E ratio significantly aggravated VILI in mice, suggesting an impact of a “stress/strain × time product” for the pathogenesis of VILI. Thus increasing the inspiratory time and I:E ratio should be critically considered.

Objectives Anti-inflammatory functions of antibiotics may counteract deleterious hyperinflammation in pneumonia. Moxifloxacin reportedly exhibits immunomodulatory properties, but experimental evidence in pneumonia is lacking. Therefore, we investigated moxifloxacin in comparison with ampicillin regarding pneumonia-associated pulmonary and systemic inflammation and lung injury. Methods Ex vivo infected human lung tissue and mice with pneumococcal pneumonia were examined regarding local inflammatory response and bacterial growth. In vivo, clinical course of the disease, leucocyte dynamics, pulmonary vascular permeability, lung pathology and systemic inflammation were investigated. In addition, transcellular electrical resistance of thrombin-stimulated endothelial cell monolayers was quantified. Results Moxifloxacin reduced cytokine production in TNF-α-stimulated, but not in pneumococci-infected, human lung tissue. In vivo, moxifloxacin treatment resulted in reduced bacterial load as compared with ampicillin, whereas inflammatory parameters and lung pathology were not different. Moxifloxacin-treated mice developed less pulmonary vascular permeability during pneumonia, but neither combination therapy with moxifloxacin and ampicillin in vivo nor examination of endothelial monolayer integrity in vitro supported direct barrier-stabilizing effects of moxifloxacin. Conclusions The current experimental data do not support the hypothesis that moxifloxacin exhibits potent anti-inflammatory properties in pneumococcal pneumonia.

Rationale: Lung protective ventilation in order to minimize ventilator-induced lung injury (VILI) reduced ARDS mortality. Besides limiting tidal volumes, avoiding high plateau pressures and applying adequate positive end expiratory pressure (PEEP), adjustment of ventilatory pattern aiming at lung protective ventilation is not defined to date. Increasing the inspiratory time and thereby the inspiratory/expiratory ratio (I:E ratio) may improve oxygenation due to a prolonged gas exchange period, but may also be harmful as the absolute stress over time increases. We thus hypothesized that increasing inspiratory time and I:E ratio aggravates VILI. Methods: VILI was induced in mice by high tidal volume ventilation (HVT 34 ml/kg). Low tidal volume ventilation (LVT 8 ml/kg) was used in control groups. HVT and LVT mice were ventilated with either I:E of 1:2 (LVT 1:2, HVT 1:2) or 1:1 (LVT 1:1, HVT 1:1) for 4h or until an alternative endpoint, defined as dropping of the mean arterial blood pressure below 40 mmHg. Survival, lung compliance, oxygenation, pulmonary permeability, markers of pulmonary and systemic inflammation (leukocyte differentiation in lung and blood, RTqPCR analyses of pulmonary IL-6, IL-1β, KC, CCL2) and histopathology was analysed. Results: LVT 1:2 or LVT 1:1 did not result in VILI, and all individuals survived the ventilation period. HVT 1:2 induced a decrease of pulmonary compliance, increased pulmonary neutrophils and cytokine expression and evoked marked ultrastructural signs of lung injury. All animals survived. HVT 1:1 caused a further significant worsening of oxygenation, compliance, pulmonary proinflammatory cytokine expression, BALF and blood neutrophils, and ultrastructural sings of lung injury. In the HVT 1:1 group, significant mortality during MV was observed. Conclusion: According to the “baby lung” concept, mechanical ventilation associated stress in overinflated regions of ARDS lungs was simulated using high tidal volume ventilation. Increase of inspiratory time and I:E ratio significantly augmented VILI in mice. Thus, increasing the inspiratory time and I:E ratio in ARDS patients during MV should be critically reconsidered.

Defense mechanisms against intracellular bacterial pathogens are incompletely understood. Our study characterizes a type I IFN-dependent cell-autonomous defense pathway directed against Legionella pneumophila, an intracellular model organism and frequent cause of pneumonia. We show that macrophages infected with L. pneumophila produced IFNβ in a STING- and IRF3-dependent manner. Paracrine type I IFNs stimulated up-regulation of IFN-stimulated genes and a cell-autonomous defense pathway acting on replicating and non-replicating Legionella within their specialized vacuole. Our infection experiments in mice lacking receptors for type I and/or II IFNs show that type I IFNs contribute to expression of IFN-stimulated genes and to bacterial clearance as well as resistance in L. pneumophila pneumonia in addition to type II IFN. Overall, our study shows that paracrine type I IFNs mediate defense against L. pneumophila, and demonstrates a protective role of type I IFNs in in vivo infections with intracellular bacteria.

International audience; Lung barrier protection by Sphingosine-1 Phosphate (S1P) has been demonstrated experimentally, but recent evidence suggests barrier-disruptive properties of high systemic S1P concentrations. The S1P analog FTY720 recently gained an FDA approval for treatment of multiple sclerosis. In case of FTY720 treated patients experiencing multiple organ dysfunction syndrome the drug may accumulate due to liver failure, and the patients may receive ventilator therapy. Whereas low doses of FTY720 enhanced endothelial barrier function, data on effects of increased FTY720 concentrations are lacking. We measured transendothelial resistance (TER) of human umbilical vein endothelial cell (HUVEC) monolayers, performed morphologic analysis and measured apoptosis by TUNEL staining and procaspase-3 degradation in HUVECs stimulated with FTY720 (0.01-100 μM). Healthy C57BL/6 mice and mice ventilated with 17ml/kg tidal volume and 100% oxygen for 2 h were treated with 0.1 or 2 mg/kg FTY720 or solvent, and lung permeability, oxygenation and leukocyte counts in BAL and blood were quantified. Further, electron microscopic analysis of lung tissue was performed. We observed barrier protective effects of FTY720 on HUVEC cell layers at concentrations up to 1 μM while higher concentrations induced irreversible barrier breakdown accompanied by induction of apoptosis. Low FTY720 concentrations (0.1 mg/kg) reduced lung permeability in mechanically ventilated mice, but 2 mg/kg FTY720 increased pulmonary vascular permeability in ventilated mice accompanied by endothelial apoptosis, while not affecting permeability in non-ventilated mice. Moreover, hyperoxic mechanical ventilation sensitized the pulmonary vasculature to a barrier disrupting effect of FTY720, resulting in worsening of ventilator induced lung injury. In conclusion, the current data suggest FTY720-induced endothelial barrier dysfunction, which was probably caused by proapoptotic effects and enhanced by mechanical ventilation.

Rationale: Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to attenuate ventilator induced lung injury (VILI). Intermedin/Adrenomedullin II (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methods: Human umbilical vein endothelial cell (HUVEC) monolayers were incubated with IMD and transendothelial electrical resistance was measured to quantify endothelial barrier function. Expression and localisation of endogenous pulmonary IMD, and its receptor complexes composed of CRLR und RAMP1-3 were analyzed by qPCR and immunoflourescence in unventilated mouse lungs and in lungs ventilated for 6h. In untreated and IMD treated mice, lung permeability and pulmonary leukocyte recruitment was assessed after mechanical ventilation. Results: IMD stabilized endothelial barrier function in HUVECs. Mechanical ventilation reduced the expression of RAMP 3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung permeability, which was ameliorated by IMD treatment. IMD did not reduce VILI associated pulmonary leukocyte recruitment. Conclusion: We showed for the first time that IMD had endothelial barrier stabilizing properties in vivo. IMD may possibly provide a new approach to attenuate ventilator-induced lung injury.

Die maschinelle Beatmung birgt das Risiko, Lungenschaden (ventilator-induced lung injury; VILI) zu verursachen oder zu aggravieren. Insbesondere in vorgeschadigten Lungen konnen lungenprotektive Beatmungsstrategien VILI limitieren, jedoch nicht verhindern. Adjuvante pharmakologische Interventionen konnten VILI uber protektive Beatmung hinaus reduzieren. In vitro-Studien legen barrierestabilisierende Eigenschaften des endogenen Peptids Intermedin (IMD) nahe. Humane umbilikalvenose Endothelzellen (HUVECs) wurden mit IMD inkubiert und der transendotheliale elektrische Widerstand (TER) als Mas der Integritat der endothelialen Barriere gemessen. Der Einfluss von Beatmung auf die pulmonale Expression von endogenem IMD, CRLR und RAMP1–3 wurde mittels qPCR und Immunhistochemie analysiert. Ferner wurden Mause mit Tidalvolumina von 12ml/kg fur 6h beatmet und mit IMD (25µg/kg x h) oder Placebo behandelt. In HUVECs fuhrte IMD zur Stabilisierung der endothelialen Barrierefunktion. Beatmung induzierte pulmonalvaskulare Hyperpermeabilitat und eine pulmonale und systemische Inflammation. Endogenes IMD und seine Rezeptorkomplexe aus CRLR und RAMP1–3 waren im pulmonalvaskularen Endothel lokalisierbar. Durch Beatmung nahm die Expression von RAMP3 ab, wahrend IMD, CRLR und RAMP1–2 nicht messbar reguliert wurden. Exogenes IMD reduzierte die VILI-assoziierte Hyperpermeabilitat, ohne die Rekrutierung von Leukozyten in die Lunge zu beeinflussen. Im Rahmen dieser Untersuchung wurde unseres Wissens nach erstmals die Reduktion pulmonalvaskularer Permeabilitat durch IMD in vivo beobachtet.

Der Nobelpreis fur Physiologie oder Medizin 2006 geht an die Molekularbiologen Andrew Fire (Stanford University, USA) und Craig Mello (University of Massachusetts, USA) fur die Entdeckung der RNA-Interferenz im Fadenwurm Caenorhabditis elegans. Durch diesen Mechanismus konnen Gene spezifisch ausgeschaltet werden.

Background Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methodology/Principal Findings Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. Conclusions/Significance IMD may possibly provide a new approach to attenuate VILI.

Introduction Mechanical ventilation (MV) is a life saving intervention in acute respiratory failure without alternative. However, particularly in pre-injured lungs, even protective ventilation strategies may evoke ventilator-induced lung injury (VILI), which is characterized by pulmonary inflammation and vascular leakage. Adjuvant pharmacologic strategies in addition to lung protective ventilation to attenuate VILI are lacking. Simvastatin exhibited anti-inflammatory and endothelial barrier stabilizing properties in vitro and in vivo. Methods Mice were ventilated (12 ml/kg; six hours) and subjected to simvastatin (20 mg/kg) or sham treatment. Pulmonary microvascular leakage, oxygenation, pulmonary and systemic neutrophil and monocyte counts and cytokine release in lung and blood plasma were assessed. Further, lung tissue was analyzed by electron microscopy. Results Mechanical ventilation induced VILI, displayed by increased pulmonary microvascular leakage and endothelial injury, pulmonary recruitment of neutrophils and Gr-1high monocytes, and by liberation of inflammatory cytokines in the lungs. Further, VILI associated systemic inflammation characterized by blood leukocytosis and elevated plasma cytokines was observed. Simvastatin treatment limited pulmonary endothelial injury, attenuated pulmonary hyperpermeability, prevented the recruitment of leukocytes to the lung, reduced pulmonary cytokine levels and improved oxygenation in mechanically ventilated mice. Conclusions High-dose simvastatin attenuated VILI in mice by reducing MV-induced pulmonary inflammation and hyperpermeability.