Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Since most cases of ALI resolve spontaneously, understanding the endogenous mechanisms that promote ALI resolution is important to developing effective therapies. Previous studies have implicated extracellular adenosine signaling in tissue adaptation and wound healing. Therefore, we hypothesized a functional contribution for the endogenous production of adenosine during ALI resolution. As a model, we administered intratracheal LPS and observed peak lung injury at 3 d, with resolution by d 14. Treatment with pegylated adenosine‐deaminase to enhance extracellular adenosine breakdown revealed impaired ALI resolution. Similarly, genetic deletion of cd73 , the pacemaker for extracellular adenosine generation, was associated with increased mortality (0% wild‐type and 40% in cd73 ^–/– mice; P <0.05) and failure to resolve ALI adequately. Studies of inflammatory cell trafficking into the lungs during ALI resolution revealed that regulatory T cells (Tregs) express the highest levels of CD73. While Treg numbers in cd73 ^–/– mice were similar to controls, cd73 ‐deficient Tregs had attenuated immunosuppressive functions. Moreover, adoptive transfer of cd73 ‐deficient Tregs into Rag ^–/– mice emulated the observed phenotype in cd73 ^–/– mice, while transfer of wild‐type Tregs was associated with normal ALI resolution. Together, these studies implicate CD73‐dependent adenosine generation in Tregs in promoting ALI resolution.—Ehrentraut, H., Clambey, E. T., McNamee, E. N., Brodsky, K. S., Ehrentraut, S. F., Poth, J. M., Riegel, A. K., Westrich, J. A., Colgan, S. P., Eltzschig, H. K. CD73 ⁺ regulatory T cells contribute to adenosine‐mediated resolution of acute lung injury. FASEB J. 27, 2207–2219 (2013). www.fasebj.org

Objective: To assess the incidence and significance of invasive fungal diseases (IFD) during veno-venous (VV) ECMO support for acute respiratory distress syndrome (ARDS). Methods: Retrospective analysis from January 2013 to April 2021 of all ECMO cases for ARDS at a German University Hospital. In patients with IFD (IFD patients), type of IFD, time of IFD, choice of antifungal agent, duration, and success of therapy were investigated. For comparison, patients without IFD (non-IFD patients) were selected by propensity score matching using treatment-independent variables (age, gender, height, weight, and the Sequential Organ Failure Assessment (SOFA) score at ICU admission). Demographics, hospital and ICU length of stay, duration of ECMO therapy, days on mechanical ventilation, prognostic scores (Charlson Comorbidity Index (CCI), Therapeutic Intervention Scoring System (TISS), and length of survival were assessed. Results: A total of 646 patients received ECMO, 368 patients received VV ECMO. The incidence of IFD on VV ECMO was 5.98%, with 5.43% for Candida bloodstream infections (CBSI) and 0.54% for invasive aspergillosis (IA). In IFD patients, in-hospital mortality was 81.8% versus 40.9% in non-IFD patients. The hazard ratio for death was 2.5 (CI 1.1–5.4; p: 0.023) with IFD. Conclusions: In patients on VV ECMO for ARDS, about one in 17 contracts an IFD, with a detrimental impact on prognosis. Further studies are needed to address challenges in the diagnosis and treatment of IFD in this population.

Cytosolic DNA receptor cyclic GMP‐AMP (cGAMP) synthase (cGAS) has been shown to be critically involved in the detection of cytosolic, self‐ and non‐self‐DNA, initiating a type I IFN response through the adaptor protein Stimulator of Interferon Genes (STING) and interferon regulatory factor 3 (IRF3). Current studies propose that canonical binding of dsDNA by cGAS depends on DNA length, but not on base sequence. In contrast, activation of TLR9 is sequence dependent. It requires unmethylated CpG dinucleotides in microbial DNA, which is mimicked by synthetic oligodeoxynucleotides (ODN). Here, we provide evidence that d‐type ODN (D‐ODN), but not K‐type ODN (K‐ODN), bind to human cGAS and activate downstream signaling. Transfection of D‐ODN into a TLR9‐deficient, human monocytic cell line (THP‐1) induced phosphorylation of IRF3 and secretion of IFN. This response was absent in cells with CRISPR/Cas9‐mediated cGAS‐ or STING‐deficiency. Utilizing a protein pulldown approach, we further demonstrate direct binding of D‐ODN to cGAS. Induction of a type I IFN response by D‐ODN was confirmed in human primary monocytes and monocyte‐derived macrophages. These results are relevant to our understanding of self–nonself‐discrimination by cGAS and to the pharmacologic effects of ODN, which currently are investigated in clinical studies.