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/)

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

The role of extracellular vesicles and gap junctions in inter-cellular mitochondrial transfer

This chapter focuses on the mechanisms of mitochondrial transfer through extracellular vesicles (EVs) and gap junctions and the implications of such transfer to the functionality of recipient cells.Mitochondrial donation is the efficient physiological mechanism to replace dysfunctional mitochondria and attenuate disease severity. Intercellular mitochondria transfer can occur via tunneling nanotubes and EVs, while some evidence suggests the involvement of the gap junctions. Recently, mechanisms of EV-mediated transfer of mitochondrial cargo have been clarified showing an active and selective packaging of mitochondrial proteins into EVs resulting in the blocking of mitochondrial damage and prevention of the release of proinflammatory oxidized mitochondrial content.Formation of small vesicular carriers that transport mitochondrial proteins and lipids to other intracellular organelles and could be secreted into extracellular space (mitochondrial-derived vesicles, MDVs) will also be discussed here.<br/

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