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Recent studies have indicated that extracellular vesicles (EVs) may play a role in the pathogenesis of acute respiratory distress syndrome (ARDS). EVs have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within bronchoalveolar lavage (BAL) fluid of patients with ARDS, and to determine whether BAL EV could be used as a potential biomarker in ARDS. BAL was collected from patients with sepsis with and without ARDS, and from esophagectomy patients postoperatively (of whom a subset later developed ARDS during hospital admission). BAL EVs were characterized with regard to size, number, and cell of origin. Patients with sepsis-related ARDS had significantly higher numbers of CD14+/CD81+ monocyte-derived BAL EV than patients with sepsis without ARDS ( P = 0.015). However, the converse was observed in esophagectomy patients who later developed ARDS ( P = 0.003). Esophagectomy patients who developed ARDS also had elevated CD31+/CD63+ and CD31+/CD81+ endothelial-derived BAL EV ( P ≤ 0.02) compared with esophagectomy patients who did not develop ARDS. Further studies are required to determine whether CD31+ BAL EV may be a predictive biomarker for ARDS in esophagectomy patients. CD14+/CD81+ BAL EV numbers were significantly higher in those patients with sepsis-related ARDS who died during the 30 days following intensive care unit admission ( P = 0.027). Thus, CD14+/CD81+ BAL EVs are a potential biomarker for disease severity and mortality in sepsis-related ARDS. These findings provide the impetus to further elucidate the contribution of these EVs to ARDS pathogenesis.

Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound anuclear structures that carry important intercellular communication mechanisms, allowing targeted transfer of diverse biologic cargo, including protein, mRNA, and microRNA, among several different cell types. In this review, we discuss the important role EVs play in both inducing and attenuating inflammatory lung injury in ARDS as well as in sepsis, the most important clinical cause of ARDS. We discuss the translational challenges that need to be overcome before EVs can also be used as prognostic biomarkers in patients with ARDS and sepsis. We also consider how EVs may provide a platform for novel therapeutics in ARDS.

Acute respiratory distress syndrome (ARDS) is an inflammatory disorder of the lungs, with sepsis as the predominant aetiology. Despite advances in ventilation strategies, mortality for moderate to severe ARDS remains at 40–46% [1]. ARDS is associated with neutrophil influx into alveoli. Persistently high neutrophil and low alveolar macrophage (AM) numbers in bronchoalveolar lavage (BAL) fluid are associated with greater mortality [2]. While the inflammatory alveolar environment of early ARDS initially delays apoptosis, these neutrophils ultimately undergo apoptosis within alveoli [3]. Efficient efferocytosis of apoptotic neutrophils by AMs is critical for resolution of inflammation [3]. Apoptotic neutrophils may accumulate in ARDS due to defective AM efferocytosis and/or overwhelmed efferocytosis capacity, then undergo secondary necrosis, releasing inflammatory mediators into the alveolar space [4]. This may contribute to the prolonged inflammation observed in ARDS. No study has previously assessed AM efferocytosis in ARDS; however, monocyte-derived macrophages (MDMs) from ARDS patients do have impaired efferocytosis [5]. We investigated whether ARDS patients have impaired AM efferocytosis and increased alveolar neutrophil apoptosis., ARDS patients have decreased alveolar macrophage efferocytosis, which is associated with increased alveolar inflammation, and may contribute to worse clinical outcomes, including mortality. Upregulation of efferocytosis may offer a therapeutic strategy. https://bit.ly/2Q7REdM

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses. Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care. Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation. Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics. Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm. Clinical trial registered with EudraCT (2012-00343-29).

International audience; Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.

IntroductionAcute respiratory distress syndrome (ARDS) is the major cause of mortality in patients with SARS-CoV-2 pneumonia. It appears that development of ‘cytokine storm’ in patients with SARS-CoV-2 pneumonia precipitates progression to ARDS. However, severity scores on admission do not predict severity or mortality in patients with SARS-CoV-2 pneumonia. Our objective was to determine whether patients with SARS-CoV-2 ARDS are clinically distinct, therefore requiring alternative management strategies, compared with other patients with ARDS. We report a single-centre retrospective study comparing the characteristics and outcomes of patients with ARDS with and without SARS-CoV-2.MethodsTwo intensive care unit (ICU) cohorts of patients at the Queen Elizabeth Hospital Birmingham were analysed: SARS-CoV-2 patients admitted between 11 March and 21 April 2020 and all patients with community-acquired pneumonia (CAP) from bacterial or viral infection who developed ARDS between 1 January 2017 and 1 November 2019. All data were routinely collected on the hospital’s electronic patient records.ResultsA greater proportion of SARS-CoV-2 patients were from an Asian ethnic group (p=0.002). SARS-CoV-2 patients had lower circulating leucocytes, neutrophils and monocytes (pDiscussionThe clinical syndromes and respiratory mechanics of SARS-CoV-2 and CAP-ARDS are broadly similar. However, SARS-CoV-2 patients initially have a lower requirement for vasopressor support, fewer circulating leukocytes and require prolonged ventilation support. Further studies are required to determine whether the dysregulated inflammation observed in SARS-CoV-2 ARDS may contribute to the increased duration of respiratory failure.

Acute respiratory distress syndrome (ARDS) has a significant impact on post-operative morbidity and mortality following oesophagectomy. Smoking is a risk factor for the development of ARDS, although the mechanism is unclear. We examined the effect of smoking on alveolar and systemic inflammation, in addition to alveolar–capillary permeability, leading to ARDS in patients undergoing oesophagectomy. We compared clinical, biomarker and PiCCO system data between current smokers (n=14) and ex-smokers (n=36) enrolled into a translational substudy of the BALTI-P (Beta Agonist Lung Injury Trial Prevention) trial. Current smokers compared with ex-smokers had significantly higher numbers of circulating neutrophils, elevated bronchoalveolar lavage (BAL) interleukin (IL)-1 receptor antagonist (IL-1ra), soluble tumour necrosis factor receptor-1 and pre-operative plasma soluble intercellular adhesion molecule-1, and lower BAL vascular endothelial growth factor and post-operative plasma IL-17 (p, Patients who smoke at the time of oesophagectomy have dysregulated immune function, greater post-operative alveolar oedema, higher incidence of ARDS and poorer long-term survival http://ow.ly/EsEh30nbO0R

Epithelial–mesenchymal transition (EMT) is a process when epithelial cells gradually transform into mesenchymal-like cells losing their epithelial functionality and characteristics. EMT is thought to be involved in the pathogenesis of numerous lung diseases ranging from developmental disorders, fibrotic tissue remodelling to lung cancer. The most important question—namely what is the importance and contribution of EMT in the pathogenesis of several chronic lung conditions (asthma, COPD, bronchiolitis obliterans syndrome and lung fibrosis)—is currently intensely debated. This review gives a brief insight into the mechanism and assessment methods of EMT in various pulmonary diseases and summarises the recent literature highlighting the controversial experimental data and conclusions.

Idiopathic pulmonary fibrosis (IPF), sarcoidosis and systemic sclerosis can each cause diffuse parenchymal lung disease involving alveolar epithelial abnormalities, and manifest as interstitial lung fibrosis. Systemic sclerosis is an autoimmune connective tissue disease and sarcoidosis is a multisystem granulomatous disease; the development of lung fibrosis in both conditions generally indicates a poor prognosis. IPF is a progressive disease which is thought to occur after recurrent injury to the alveolar epithelium followed by dysregulation of cellular homoeostasis, abnormal repair and excessive deposition of extracellular matrix, ultimately leading to loss of lung function.1 Mortality 3–5 years after diagnosis of IPF is 50%, and treatment options are currently limited. Seibold et al 2 have previously shown that a variant single-nucleotide polymorphism (SNP) in the promoter region of an airway mucin gene ( MUC5B ) is associated with greatly increased production of MUC5B, and with pulmonary fibrosis. This suggested that dysregulated MUC5B expression in the lung may be key to the pathogenesis of pulmonary fibrosis. One hypothesis is that an excess of MUC5B causes bronchiolar plugging and impairs mucosal host defence, reducing clearance …

Introduction and objectives Mesenchymal stem cells (MSC) have well-established anti-inflammatory properties and could potentially be used therapeutically in Acute Respiratory Distress Syndrome (ARDS).1 MSC conditioned medium (MSC-CM) has been found to reproduce the beneficial effects of MSCs.2 However, the impact of expansion on MSC secretome remains elusive. In the present study we assessed the expression of four potent MSC paracrine factors after prolonged in vitro culture, while investigating the effects of passaging on the in vitro properties of MSCs. Methods Human Bone marrow-derived MSCs were expanded in vitro in αMEM with 16% FBS. Conditioned medium was collected from each passage and stored at −40°C. Scratch assays were undertaken using A549 cells treated with MSC-CM and control media. Proliferation of A549 cells was assessed via BrdU assay. Gene expression of expanded MSCs was assessed by RT-qPCR. VEGF and Angiopoietin in the MSC-CM were quantified by ELISA. Results RT-qPCR revealed that MSCs express the anti-inflammatory genes PTGES2, FGF7 and ANGPT1. The expression of these genes doubled after 8 days in culture and subsequently decreased. (P Conclusion We conclude that MSCs of early passages are more potent angiogenic inducers, while promoting wound healing in vitro. Thus, we provide important insights into the changes occurring after prolonged in vitro expansion, underlining the importance of using low passage MSCs in clinical trials for ARDS. In agreement with published data, we also found that MSCs do not induce cellular proliferation in the absence of stimulation. References Antunes MA, et al. Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem 2014;115:1023–1032. Kordelas L, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. LeukaemiaLeukemia 2014;28:970–973.

Lung transplantation is a well-established treatment option for selected patients with end-stage lung disease, leading to improved survival and improved quality of life. The last 20 years have seen a steady growth in number of lung transplantation procedures performed worldwide. The increase in clinical activity has been associated with tremendous progress in the understanding of cellular and molecular processes that limit both short- and long-term outcomes. This review gives a comprehensive overview of the current status of lung transplantation for the referring physician. It demonstrates that careful selection of potential recipients, optimisation of their condition prior to transplant, use of carefully assessed donor organs, excellent surgery and meticulous long-term follow-up are all essential ingredients in determining a successful outcome.

Introduction Survival after lung transplantation is limited to a median of 5-year due to development of bronchiolitis obliterans syndrome (BOS). BOS is the clinical manifestation of chronic allograft dysfunction, characterised by inflammation and fibrosis of small/medium-sized airways leading to airflow obstruction. Numerous insults to the transplanted lungs have been associated with BOS development. Alarmins are cell derived danger signals released from damaged tissue which activate innate and adaptive immune responses. We hypothesised that the release of alarmins into the airway compartment after lung transplantation may contribute to BOS pathogenesis. Methods A retrospective longitudinal study of 52 lung transplant recipients from 2005 to present was performed (26 recipients developed BOS; 26 remained free from BOS). All recipients had lung function and bronchoalveolar lavage (BAL) performed at 1, 3, 6 and 12 months post transplant. Further samples were taken if the diagnostic criteria for BOS were fulfilled. A total of 214 BAL samples were analysed by ELISA for the alarmins Interleukin-1a (IL-1a) and High Motility Group-Box1 (HMG-B1). Data were analysed using Mann–Whitney tests. Results Both BOS and non-BOS recipients with culture positive BAL samples had significantly higher concentrations of IL-1a and HMG-B1 than culture negative samples. Due to the confounding effect of infection, our analysis excluded 90 BAL samples with positive cultures. Concentrations of IL-1a were significantly higher in culture negative BAL from BOS patients (median 2.411, range [AJF1] 0.073–19.078 pg/ml) than from Non-BOS patients (median 1.424, range [AJF2] 1.159–17.41 pg/ml; p=0.001). No significant difference in HMG-B1 concentrations between the two groups was observed (BOS median 58.906, range 0–197.5; Non-BOS median 76.25, range 0–211.563 ng/ml; p=0.2378). Longitudinal measurements of IL-1a in BOS patients showed significantly higher levels 3 months before or after BOS diagnosis (median 3.935, range 1.122–13.544 pg/ml), compared to >3 months before BOS diagnosis (median 2.015, range 0.073–14.669 pg/ml; p=0.0153). There was no such difference in HMG-B1 concentrations (p=0.9164). Conclusions An increase in the alarmin IL-1a, but not HMG-B1, is associated with BOS development. The cellular source of IL-1a requires further evaluation but may be a marker of airway epithelial injury and/or play a mechanistic role in BOS development via its secretion by other cell types.

Background Activation of the innate immune system plays a key role in exacerbations of chronic lung disease. Myeloid cells are classically considered to drive innate immune responses yet the potential of fibroblasts to act as immune cells has been postulated. We hypothesized that alarmins released from lung epithelium during environmental insults such as oxidant injury and viral infection might induce innate immune responses in lung fibroblasts. Methods Human bronchial epithelial cells (BECs) and human lung fibroblasts (HLFs) were cultured from brushings taken from lung transplant recipients and resected lung tissue respectively. Cytokine concentrations were measured by ELISA or multiplex platform (MSD). Gene expression was assessed by qRT-PCR. Wild-type and Il1a-/- mice were infected with Influenza (PR8). Data were analysed using t-Student or Mann-Whitney U Test. Correlations were assessed using Spearman rank correlation coefficient. Results Conditioned media from PBECs subjected to oxidant injury contained elevated levels of alarmins. Treatment of HLFs with conditioned media significantly upregulated proinflammatory cytokine expression. Anti-IL-1α or IL-1Ra significantly reduced induction of IL-8 (93% and 95%), IL-6 (90% and 91%), MCP-1 (92% and 93%) and GM-CSF (95% and 94%). Anti-IL-1β had no effect. Co-stimulation with Poly I:C significantly accentuated the IL-1 α induced inflammatory phenotype in HLFs. Bronchoalveolar lavage (BAL) form Influenza infected wild-type mice contains elevated levels of IL-1α and activates innate immune signalling in wild-type murine lung fibroblasts (MLFs) but not Il1r1-/- MLFs. BAL from Il1a-/- mice had no effect on MLFs and demonstrated a blunted neutrophilic response to Influenza. Clinically we show that IL-1α is increased in BAL of lung transplant recipients with infections and within 3 months of developing bronchiolitis obliterans syndrome (BOS) (p Conclusions We propose a new paradigm of innate immune signalling in exacerbations of lung disease, where epithelial damage triggers a potent inflammatory phenotype in resident fibroblasts. The pivotal role of IL-1α in this process is accentuated in the presence of viral infection. This novel pathway warrants further evaluation of its therapeutic potential to limit the repeated cycles of injury and exacerbation in chronic lung diseases.

Prospective Evaluation of Alveolar and Bronchiolar C4d Expression in Transbronchial Biopsies from Lung Transplanted Recipients J. Majo, R. Mahida, N. Thampy, F. Black, G. Meachery, J.L. Lordan, P.A. Corris, A.J. Fisher. Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, England, United Kingdom; Institute of Cellular Medecine, Newcastle University, Newcastle upon Tyne, England, United Kingdom.