Biomarkers of mitochondrial dysfunction in acute respiratory distress syndrome: A systematic review and meta-analysis

IntroductionAcute respiratory distress syndrome (ARDS) is one of the main causes of Intensive Care Unit morbidity and mortality. Metabolic biomarkers of mitochondrial dysfunction are correlated with disease development and high mortality in many respiratory conditions, however it is not known if they can be used to assess risk of mortality in patients with ARDS.ObjectivesThe aim of this systematic review was to examine the link between recorded biomarkers of mitochondrial dysfunction in ARDS and mortality.MethodsA systematic review of CINAHL, EMBASE, MEDLINE, and Cochrane databases was performed. Studies had to include critically ill ARDS patients with reported biomarkers of mitochondrial dysfunction and mortality. Information on the levels of biomarkers reflective of energy metabolism and mitochondrial respiratory function, mitochondrial metabolites, coenzymes, and mitochondrial deoxyribonucleic acid (mtDNA) copy number was recorded. RevMan5.4 was used for meta-analysis. Biomarkers measured in the samples representative of systemic circulation were analyzed separately from the biomarkers measured in the samples representative of lung compartment. Cochrane risk of bias tool and Newcastle-Ottawa scale were used to evaluate publication bias (Prospero protocol: CRD42022288262).ResultsTwenty-five studies were included in the systematic review and nine had raw data available for follow up meta-analysis. Biomarkers of mitochondrial dysfunction included mtDNA, glutathione coupled mediators, lactate, malondialdehyde, mitochondrial genetic defects, oxidative stress associated markers. Biomarkers that were eligible for meta-analysis inclusion were: xanthine, hypoxanthine, acetone, N-pentane, isoprene and mtDNA. Levels of mitochondrial biomarkers were significantly higher in ARDS than in non-ARDS controls (P = 0.0008) in the blood-based samples, whereas in the BAL the difference did not reach statistical significance (P = 0.14). mtDNA was the most frequently measured biomarker, its levels in the blood-based samples were significantly higher in ARDS compared to non-ARDS controls (P = 0.04). Difference between mtDNA levels in ARDS non-survivors compared to ARDS survivors did not reach statistical significance (P = 0.05).ConclusionIncreased levels of biomarkers of mitochondrial dysfunction in the blood-based samples are positively associated with ARDS. Circulating mtDNA is the most frequently measured biomarker of mitochondrial dysfunction, with significantly elevated levels in ARDS patients compared to non-ARDS controls. Its potential to predict risk of ARDS mortality requires further investigation.Systematic review registration[https://www.crd.york.ac.uk/prospero], identifier [CRD42022288262]

Expression pattern of arenicins—the antimicrobial peptides of polychaete Arenicola marina

Immune responses of invertebrate animals are mediated through innate mechanisms, among which production of antimicrobial peptides play an important role. Although evolutionary Polychaetes represent an interesting group closely related to a putative common ancestor of other coelomates, their immune mechanisms still remain scarcely investigated. Previously our group has identified arenicins - new antimicrobial peptides of the lugworm Arenicola marina, since then these peptides were thoroughly characterized in terms of their structure and inhibitory potential. In the present study we addressed the question of the physiological functions of arenicins in the lugworm body. Using molecular and immunocytochemical methods we demonstrated that arencins are expressed in the wide range of the lugworm tissues - coelomocytes, body wall, extravasal tissue and the gut. The expression of arenicins is constitutive and does not depend on stimulation of various infectious stimuli. Most intensively arenicins are produced by mature coelomocytes where they function as killing agents inside the phagolysosome. In the gut and the body wall epithelia arenicins are released from producing cells via secretion as they are found both inside the epithelial cells and in the contents of the cuticle. Collectively our study showed that arenicins are found in different body compartments responsible for providing a first line of defence against infections, which implies their important role as key components of both epithelial and systemic branches of host defence

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial):A Multicentre, Randomised, Controlled Trial

RationaleMesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).ObjectivesWe investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.MethodsThis multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MeasurementsThe primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit and hospital stays, and mortality were collected. Long-term follow up included diagnosis of interstitial lung disease at 1 year, and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at day 0, 4 and 7.Main results60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.ConclusionORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

Therapeutic targeting of metabolic alterations in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) remains a significant source of mortality in critically ill patients. Characterised by acute, widespread alveolar inflammation and pulmonary oedema, its pathophysiological heterogeneity has meant that targeted treatments have remained elusive. Metabolomic analysis has made initial steps in characterising the underlying metabolic derangements of ARDS as an indicator of phenotypical class and has identified mitochondrial dysfunction as a potential therapeutic target. Mesenchymal stem cells and their derived extracellular vesicles have shown significant promise as potential therapies in delivering mitochondria in order to redivert metabolism onto physiological pathways

Novel organoid model of distal lung based on primary human cells to study mechanisms of lung diseases and responses to treatment

IntroductionDespite impressive progress in development of human pulmonary organoid models,majority of these models are comprised predominantly of epithelial cells, with just a few reporting presence of supporting mesenchymal cells. These organoids do not yet recapitulate the complex structure and cellular interactions of the highly vascularized alveolar region. Therefore, more complex models utilizing the entirety of the lung architecture are required.MethodsWe have devised a novel organoid model system that better recapitulates normal distal lung complexity. This model is based on the self-aggregation of primary human small airway epithelial cells (SAECs), pulmonary microvascular endothelia cells (HPMECs) and lung mesenchymal stromal cells (MSCs) in Matrigel.ResultsThese organoids develop alveoli-like budding structures with a lumen, which are positive for alveolar epithelial markers (Surfactant Protein C (SPC) and Aquaporin5, markers of Alveolar Type II (ATII) and Type I (ATI), respectively, and reach 200µm in diameter (this size is comparable to the size of human alveolus), remarkably, these organoids support the presence of endothelial cells up to21 day. To test the ability of these model to recapitulate features of human disease, MSCs from healthy lungs were replaced by MSCs isolated from lungs of patients with COPD. Organoids seeded with MSCs derived from COPD lungs are characterised by non-symmetrical morphology and smaller size compared to organoids seeded with MSCs isolated from lungs of healthy donors and were unable to support endothelial cells, recapitulating loss of vasculature in emphysema. Both COPD lung MSCs and COPD organoids had lower levels of HGF10 secretion compared to their healthy lung counterparts which also is a characteristic feature of emphysema. Furthermore, organoids composed of COPD MSCs also demonstrate increased deposition of collagen compared to organoids composed of healthy MSCs. We also show that this model is amenable to model lung fibrosis and lung responses to treatment. Exposure of organoids to bleomycin (15 µg/ml for 72 hrs) resulted in increased accumulation of 1A1 collagen, which was reduced by the treatment with mesenchymal stromal cell derived extracellular vesicles.Discussion &amp; ConclusionsCondensation of primary pulmonary cells provides a physiologically relevant distal lung organoid model that features endothelial cell presence. Lung MSCs are critical to support growth of endothelial cells and regular spatial organisation of the alveolar epithelial cells.<br/