Background There is no effective pharmacotherapy for the acute respiratory distress syndrome (ARDS), and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. The aim of this phase one clinical trial was to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS. Methods The STem cells for ARDS Treatment (START) trial was a multi-center, open-label, dose-escalation phase one clinical trial of a single dose of intravenous MSCs in patients with moderate-to-severe ARDS. The trial is registered with clinicaltrials.gov number [NCT01775774]. The first three patients were treated with low dose MSCs (1million cells/kg predicted body weight (PBW)); the next three patients received intermediate dose MSCs (5 million cells/kg PBW); and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of pre-specified infusion associated events and serious adverse events. Secondary outcomes included standard respiratory and systemic endpoints, 28- and 60-day mortality, and measurement of biologic markers of inflammation and endothelial and epithelial injury. The trial completed enrollment in January 2014. Findings There were no pre-specified infusion associated events or treatment-related adverse events in any of the nine patients in this trial. Serious adverse events (SAEs) were subsequently observed in three patients during in the weeks following the infusion: two patients expired >seven days after the MSC infusion, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate but thought to have occurred prior the MSC infusion based on MRI results. None of these SAEs were thought to be MSC-related. Interpretation A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in 9 patients with moderate to severe ARDS. Based on this phase one experience, we have proceeded to phase two testing of MSCs for moderate to severe ARDS. Funding The trial was funded by the National Heart, Lung and Blood Institute (NHLBI U01HL10871301).

Background-Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.Methods-We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with

Neutrophils dominate the early immune response in pathogen-induced acute lung injury, but efforts to harness their responses have not led to therapeutic advancements. Neutrophil extracellular traps (NETs) have been proposed as an innate defense mechanism responsible for pathogen clearance, but there are concerns that NETs may induce collateral damage to host tissues. Here, we detected NETs in abundance in mouse models of severe bacterial pneumonia/acute lung injury and in human subjects with acute respiratory distress syndrome (ARDS) from pneumonia or sepsis. Decreasing NETs reduced lung injury and improved survival after DNase I treatment or with partial protein arginine deiminase 4 deficiency (PAD4+/-). Complete PAD4 deficiency (PAD4-/-) reduced NETs and lung injury but was counterbalanced by increased bacterial load and inflammation. Importantly, we discovered that the lipoxin pathway could be a potent modulator of NET formation, and that mice deficient in the lipoxin receptor (Fpr2-/-) produced excess NETs leading to increased lung injury and mortality. Lastly, we observed in humans that increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the development of sepsis-induced ARDS. We conclude that a critical balance of NETs is necessary to prevent lung injury and to maintain microbial control, which has important therapeutic implications.

MA. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am

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In summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.

Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. Objectives: To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. Methods: Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 mg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. Measurements and Main Results: APC increased plasma protein C levels (P 5 0.002) and decreased pulmonary dead space fraction (P 5 0.02). However, there was no statistically significant difference between patients receiving placebo (n 5 38) or APC (n 5 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P 5 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P 5 1.0). There were no differences in the number of bleeding events between the two groups. Conclusions: APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity. Clinical trial registered with www.clinicaltrials.gov (NCT 00112164).