Effects of mechanical ventilation on the interstitial extracellular matrix in healthy lungs and lungs affected by acute respiratory distress syndrome: a narrative review.

BACKGROUND: Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation. MAIN TEXT: Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs. CONCLUSIONS: This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.

Proteomics of serum-derived extracellular vesicles are associated with the severity and different clinical profiles of patients with COVID-19: An exploratory secondary analysis.

BACKGROUND AIMS: Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical manifestations with the potential to progress to multiple organ dysfunction in severe cases. Extracellular vesicles (EVs) carry a range of biological cargoes, which may be used as biomarkers of disease state. METHODS: An exploratory secondary analysis of the SARITA-2 and SARITA-1 datasets (randomized clinical trials on patients with mild and moderate/severe COVID-19) was performed. Serum-derived EVs were used for proteomic analysis to identify enriched biological processes and key proteins, thus providing insights into differences in disease severity. Serum-derived EVs were separated from patients with COVID-19 by size exclusion chromatography and nanoparticle tracking analysis was used to determine particle concentration and diameter. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to identify and quantify protein signatures. Bioinformatics and multivariate statistical analysis were applied to distinguish candidate proteins associated with disease severity (mild versus moderate/severe COVID-19). RESULTS: No differences were observed in terms of the concentration and diameter of enriched EVs between mild (n = 14) and moderate/severe (n = 30) COVID-19. A total of 414 proteins were found to be present in EVs, of which 360 were shared while 48 were uniquely present in severe/moderate compared to mild COVID-19. The main biological signatures in moderate/severe COVID-19 were associated with platelet degranulation, exocytosis, complement activation, immune effector activation, and humoral immune response. Von Willebrand factor, serum amyloid A-2 protein, histone H4 and H2A type 2-C, and fibrinogen ß-chain were the most differentially expressed proteins between severity groups. CONCLUSION: Exploratory proteomic analysis of serum-derived EVs from patients with COVID-19 detected key proteins related to immune response and activation of coagulation and complement pathways, which are associated with disease severity. Our data suggest that EV proteins may be relevant biomarkers of disease state and prognosis.

Antiviral, Cytoprotective, and Anti-Inflammatory Effect of Ampelozizyphus amazonicus Ducke Ethanolic Wood Extract on Chikungunya Virus Infection.

Chikungunya fever, a debilitating disease caused by Chikungunya virus (CHIKV), is characterized by a high fever of sudden onset and an intense arthralgia that impairs individual regular activities. Although most symptoms are self-limited, long-term persistent arthralgia is observed in 30-40% of infected individuals. Currently, there is no vaccine or specific treatment against CHIKV infection, so there is an urgent need for the discovery of new therapeutic options for CHIKF chronic cases. This present study aims to test the antiviral, cytoprotective, and anti-inflammatory activities of an ethanol extract (FF72) from Ampelozizyphus amazonicus Ducke wood, chemically characterized using mass spectrometry, which indicated the major presence of dammarane-type triterpenoid saponins. The major saponin in the extract, with a deprotonated molecule ion m/z 897 [M-H]-, was tentatively assigned as a jujubogenin triglycoside, a dammarane-type triterpenoid saponin. Treatment with FF72 resulted in a significant reduction in both virus replication and the production of infective virions in BHK-21-infected cells. The viability of infected cells was assessed using an MTT, and the result indicated that FF72 treatment was able to revert the toxicity mediated by CHIKV infection. In addition, FF72 had a direct effect on CHIKV, since the infectivity was completely abolished in the presence of the extract. FF72 treatment also reduced the expression of the major pro-inflammatory mediators overexpressed during CHIKV infection, such as IL-1ß, IL-6, IL-8, and MCP-1. Overall, the present study elucidates the potential of FF72 to become a promising candidate of herbal medicine for alphaviruses infections.

Anti-inflammatory therapies for acute respiratory distress syndrome.

INTRODUCTION: Treatments for the acute respiratory distress syndrome (ARDS) are mainly supportive, and ventilatory management represents a key approach in these patients. Despite progress in pharmacotherapy, anti-inflammatory strategies for the treatment of ARDS have shown controversial results. Positive outcomes with pharmacologic and nonpharmacologic treatments have been found in two different biological subphenotypes of ARDS, suggesting that, with a personalized medicine approach, pharmacotherapy for ARDS can be effective. AREAS COVERED: This article reviews the literature concerning anti-inflammatory therapies for ARDS, focusing on pharmacological and stem-cell therapies, including extracellular vesicles. EXPERT OPINION: Despite advances, ARDS treatments remain primarily supportive. Ventilatory and fluid management are important strategies in these patients that have demonstrated significant impacts on outcome. Anti-inflammatory drugs have shown some benefits, primarily in preclinical research and in specific clinical scenarios, but no recommendations are available from guidelines to support their use in patients with ARDS, except in particular settings such as different subphenotypes, specific etiologies, or clinical trials. Personalized medicine seems promising insofar as it may identify specific subgroups of patients with ARDS who may benefit from anti-inflammatory treatment. However, additional efforts are needed to move subphenotype characterization from bench to bedside.

Dexmedetomidine compared to low-dose ketamine better protected not only the brain but also the lungs in acute ischemic stroke.

BACKGROUND: Dexmedetomidine (DEX) and low-dose ketamine (KET) present neuroprotective effects in acute ischemic stroke (AIS); however, to date, no studies have evaluated which has better protective effects not only on the brain but also lungs in AIS. METHODS: AIS-induced Wistar rats (390 ± 30 g) were randomized after 24-h, receiving dexmedetomidine (STROKE-DEX, n = 10) or low-dose S(+)-ketamine (STROKE-KET, n = 10). After 1-h protective ventilation, perilesional brain tissue and lungs were removed for histologic and molecular biology analysis. STROKE animals (n = 5), receiving sodium thiopental but not ventilated, had brain and lungs removed for molecular biology analysis. Effects of DEX and KET mean plasma concentrations on alveolar macrophages, neutrophils, and lung endothelial cells, extracted primarily 24-h after AIS, were evaluated. RESULTS: In perilesional brain tissue, apoptosis did not differ between groups. In STROKE-DEX, compared to STROKE-KET, tumor necrosis factor (TNF)-α and vascular cell adhesion molecule-1 (VCAM-1) expressions were reduced, but no changes in nuclear factor erythroid 2-related factor-2 (Nrf2) and super oxide dismutase (SOD)-1 were observed. In lungs, TNF-α and VCAM-1 were reduced, whereas Nrf2 and SOD-1 were increased in STROKE-DEX. In alveolar macrophages, TNF-α and inducible nitric oxide synthase (M1 macrophage phenotype) were lower and arginase and transforming growth factor-ß (M2 macrophage phenotype) higher in STROKE-DEX. In lung neutrophils, CXC chemokine receptors (CXCR2 and CXCR4) were higher in STROKE-DEX. In lung endothelial cells, E-selectin and VCAM-1 were lower in STROKE-DEX. CONCLUSIONS: In the current AIS model, dexmedetomidine compared to low-dose ketamine reduced inflammation and endothelial cell damage in both brain and lung, suggesting greater protection.

Tyrosine-Mutant AAV8 Vector Mediated Efficient and Safe Gene Transfer of Pigment Epithelium-Derived Factor to Mouse Lungs.

BACKGROUND/AIMS: Recombinant adeno-associated viruses (rAAV) are an important tool for lung targeted gene therapy. Substitution of tyrosine with phenylalanine residues (Y-F) in the capsid have been shown to protect the AAV vector from ubiquitin/proteasome degradation, increasing transduction efficiency. We tested the mutant Y733F-AAV8 vector for mucus diffusion, as well as the safety and efficacy of pigment epithelium-derived factor (PEDF) gene transfer to the lung. METHODS: For this purpose, Y733F-AAV8-PEDF (1010 viral genome) was administered intratracheally to C57BL/6 mice. Lung mechanics, morphometry, and inflammation were evaluated 7, 14, 21, and 28 days after injection. RESULTS: The tyrosine-mutant AAV8 vector was efficient at penetrating mucus in ex vivo assays and at transferring the gene to lung cells after in vivo instillation. Increased levels of transgene mRNA were observed 28 days after vector administration. Overexpression of PEDF did not affect in vivo lung parameters. CONCLUSION: These findings provide a basis for further development of Y733F-AAV8-based gene therapies for safe and effective delivery of PEDF, which has anti-angiogenic, anti-inflammatory and anti-fibrotic activities and might be a promising therapy for lung inflammatory disorders.

Comparison between sevoflurane and propofol on immunomodulation in an in vitro model of sepsis.

Introduction: Patients with sepsis often require sedation and/or anesthesia. Although the immunomodulatory effects of anesthetics have been increasingly recognized, the molecular mechanisms require better elucidation. We compared the effects of sevoflurane with propofol on the expression of pro- and anti-inflammatory biomarkers released by monocytes/macrophages and blood/bronchoalveolar lavage fluid (BALF) neutrophils, the phagocytic capacity of monocytes/ macrophages, and neutrophil migration, as well as mediators associated with alveolar epithelial and endothelial cells obtained from rats with sepsis. Methods: Polymicrobial sepsis was induced by cecal ligation and puncture in nine male Wistar rats. After 48 h, animals were euthanized and their monocytes/alveolar macrophages, blood and BALF neutrophils, as well as alveolar epithelial and endothelial cells were extracted, and then exposed to (1) sevoflurane (1 minimal alveolar concentration), (2) propofol (50 µM), or (3) saline, control (CTRL) for 1 h. Results: Sevoflurane reduced interleukin (IL)-6 mRNA expression in monocytes and alveolar macrophages (p = 0.007, p = 0.029), whereas propofol decreased IL-6 mRNA only in alveolar macrophages (p = 0.027) compared with CTRL. Sevoflurane increased IL-10 expression (p = 0.0002) in monocytes compared with propofol and increased IL-10 mRNA and transforming growth factor (TGF)-ß mRNA (p = 0.037, p = 0.045) compared with CTRL. Both sevoflurane and propofol did not affect mRNA expression of IL-10 and TGF-ß in alveolar macrophages. The phagocytic capacity of monocytes (p = 0.0006) and alveolar macrophages (p = 0.0004) was higher with sevoflurane compared with propofol. Sevoflurane, compared with CTRL, reduced IL-1ß mRNA (p = 0.003, p = 0.009) and C-X-C chemokine receptor 2 mRNA (CXCR2, p = 0.032 and p = 0.042) in blood and BALF neutrophils, and increased CXCR4 mRNA only in BALF neutrophils (p = 0.004). Sevoflurane increased blood neutrophil migration (p = 0.015) compared with propofol. Both sevoflurane and propofol increased zonula occludens-1 mRNA (p = 0.046, p = 0.003) in alveolar epithelial cells and reduced Toll-like receptor 4 mRNA (p = 0.043, p = 0.006) in alveolar endothelial cells compared with CTRL. Only propofol reduced surfactant protein B mRNA (p = 0.028) in alveolar epithelial cells. Discussion: Sevoflurane, compared with propofol, increased anti-inflammatory biomarkers in monocytes, but not in alveolar macrophages, enhanced monocyte/alveolar macrophage phagocytic capacity and increased neutrophil migration in in vitro experimental sepsis. Both propofol and sevoflurane protected lung epithelial and endothelial cells.

A specific combination of laboratory data is associated with overweight lungs in patients with COVID-19 pneumonia at hospital admission: secondary cross-sectional analysis of a randomized clinical trial.

Background: Lung weight may be measured with quantitative chest computed tomography (CT) in patients with COVID-19 to characterize the severity of pulmonary edema and assess prognosis. However, this quantitative analysis is often not accessible, which led to the hypothesis that specific laboratory data may help identify overweight lungs. Methods: This cross-sectional study was a secondary analysis of data from SARITA2, a randomized clinical trial comparing nitazoxanide and placebo in patients with COVID-19 pneumonia. Adult patients (≥18 years) requiring supplemental oxygen due to COVID-19 pneumonia were enrolled between April 20 and October 15, 2020, in 19 hospitals in Brazil. The weight of the lungs as well as laboratory data [hemoglobin, leukocytes, neutrophils, lymphocytes, C-reactive protein, D-dimer, lactate dehydrogenase (LDH), and ferritin] and 47 additional specific blood biomarkers were assessed. Results: Ninety-three patients were included in the study: 46 patients presented with underweight lungs (defined by ≤0% of excess lung weight) and 47 patients presented with overweight lungs (>0% of excess lung weight). Leukocytes, neutrophils, D-dimer, and LDH were higher in patients with overweight lungs. Among the 47 blood biomarkers investigated, interferon alpha 2 protein was higher and leukocyte inhibitory factor was lower in patients with overweight lungs. According to CombiROC analysis, the combinations of D-dimer/LDH/leukocytes, D-dimer/LDH/neutrophils, and D-dimer/LDH/leukocytes/neutrophils achieved the highest area under the curve with the best accuracy to detect overweight lungs. Conclusion: The combinations of these specific laboratory data: D-dimer/LDH/leukocytes or D-dimer/LDH/neutrophils or D-dimer/LDH/leukocytes/neutrophils were the best predictors of overweight lungs in patients with COVID-19 pneumonia at hospital admission. Clinical trial registration: Brazilian Registry of Clinical Trials (REBEC) number RBR-88bs9x and ClinicalTrials.gov number NCT04561219.

Extracellular Vesicles from Different Sources of Mesenchymal Stromal Cells Have Distinct Effects on Lung and Distal Organs in Experimental Sepsis.

The effects of the administration of mesenchymal stromal cells (MSC) may vary according to the source. We hypothesized that MSC-derived extracellular vesicles (EVs) obtained from bone marrow (BM), adipose (AD), or lung (L) tissues may also lead to different effects in sepsis. We profiled the proteome from EVs as a first step toward understanding their mechanisms of action. Polymicrobial sepsis was induced in C57BL/6 mice by cecal ligation and puncture (SEPSIS) and SHAM (control) animals only underwent laparotomy. Twenty-four hours after surgery, animals in the SEPSIS group were randomized to receive saline or 3 × 106 MSC-derived EVs from BM, AD, or L. The diffuse alveolar damage was decreased with EVs from all three sources. In kidneys, BM-, AD-, and L-EVs reduced edema and expression of interleukin-18. Kidney injury molecule-1 expression decreased only in BM- and L-EVs groups. In the liver, only BM-EVs reduced congestion and cell infiltration. The size and number of EVs from different sources were not different, but the proteome of the EVs differed. BM-EVs were enriched for anti-inflammatory proteins compared with AD-EVs and L-EVs. In conclusion, BM-EVs were associated with less organ damage compared with the other sources of EVs, which may be related to differences detected in their proteome.

Early effects of bone marrow-derived mononuclear cells on lung and kidney in experimental sepsis.

BACKGROUND: In experimental sepsis, functional and morphological effects of bone marrow-derived mononuclear cell (BMDMC) administration in lung tissue have been evaluated 1 and 7 days after therapy. However, to date no study has evaluated the early effects of BMDMCs in both lung and kidney in experimental polymicrobial sepsis. MATERIAL AND METHODS: Twenty-five female C57BL/6 mice were randomly divided into the following groups: 1) cecal ligation and puncture (CLP)-induced sepsis; and 2) Sham (surgical procedure without CLP). After 1 h, CLP animals received saline (NaCl 0.9%) (CLP-Saline) or 106 BMDMCs (CLP-Cell) via the jugular vein. At 6, 12, and 24 h after saline or BMDMC administration, lungs and kidneys were removed for histology and molecular biology analysis. RESULTS: In lungs, CLP-Saline, compared to Sham, was associated with increased lung injury score (LIS) and keratinocyte chemoattractant (KC) mRNA expression at 6, 12, and 24 h. BMDMCs were associated with reduced LIS and KC mRNA expression regardless of the time point of analysis. Interleukin (IL)- 10 mRNA content was higher in CLP-Cell than CLP-Saline at 6 and 24 h. In kidney tissue, CLP-Saline, compared to Sham, was associated with tubular cell injury and increased neutrophil gelatinase-associated lipocalin (NGAL) levels, which were reduced after BMDMC therapy at all time points. Surface high-mobility-group-box (HMGB)- 1 levels were higher in CLP-Saline than Sham at 6, 12, and 24 h, whereas nuclear HMGB-1 levels were increased only at 24 h. BMDMCs were associated with decreased surface HMGB-1 and increased nuclear HMGB-1 levels. Kidney injury molecule (KIM)- 1 and IL-18 gene expressions were reduced in CLP-Cell compared to CLP-Saline at 12 and 24 h. CONCLUSION: In the present experimental polymicrobial sepsis, early intravenous therapy with BMDMCs was able to reduce lung and kidney damage in a time-dependent manner. BMDMCs thus represent a potential therapy in well-known scenarios of sepsis induction. PURPOSE: To evaluate early bone marrow-derived mononuclear cell (BMDMC) therapy on lung and kidney in experimental polymicrobial sepsis. METHODS: Twenty-five female C57BL/6 mice were randomly divided into the following groups: cecal ligation and puncture (CLP)-induced sepsis; and sham (surgical procedure without CLP). After 1 h, CLP animals received saline (CLP-saline) or 106 BMDMCs (CLP-cell) via the jugular vein. Lungs and kidneys were evaluated for histology and molecular biology after 6, 12, and 24 h. RESULTS: In lungs, BMDMCs reduced the lung injury score and keratinocyte chemoattractant mRNA expression regardless of the time point of analysis; interleukin-10 mRNA content was higher in CLP-cell than CLP-saline at 6 and 24 h. In kidneys, BMDMCs reduced neutrophil gelatinase-associated lipocalin levels at all time points. BMDMCs decreased surface high mobility group box (HMGB)- 1 but increased nuclear HMGB-1 levels. CONCLUSION: Early BMDMC therapy reduced lung and kidney damage in a time-dependent manner.

Nitazoxanide in Patients Hospitalized With COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Nitazoxanide exerts antiviral activity in vitro and in vivo and anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is uncertain. Methods: A multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was intensive care unit admission due to the need for invasive mechanical ventilation. Secondary outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and adverse events within 14 days. Results: Of the 498 patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in the analyses. Admission to the intensive care unit did not differ between the groups (hazard ratio [95% confidence interval], 0.68 [0.38-1.20], p = 0.179); death rates also did not differ. Nitazoxanide improved the clinical outcome (2.75 [2.21-3.43], p < 0.0001), time to hospital discharge (1.37 [1.11-1.71], p = 0.005), and reduced oxygen requirements (0.77 [0.64-0.94], p = 0.011). C-reactive protein, D-dimer, and ferritin levels were lower in the nitazoxanide group than the placebo group on day 7. No serious adverse events were observed. Conclusions: Nitazoxanide, compared with placebo, did not prevent admission to the intensive care unit for patients hospitalized with COVID-19 pneumonia. Clinical Trial Registration: Brazilian Registry of Clinical Trials (REBEC) RBR88bs9x; ClinicalTrials.gov, NCT04561219.

Comparative effects of dexmedetomidine and propofol on brain and lung damage in experimental acute ischemic stroke.

Acute ischemic stroke is associated with pulmonary complications, and often dexmedetomidine and propofol are used to decrease cerebral metabolic rate. However, it is unknown the immunomodulatory actions of dexmedetomidine and propofol on brain and lungs during acute ischemic stroke. The effects of dexmedetomidine and propofol were compared on perilesional brain tissue and lung damage after acute ischemic stroke in rats. Further, the mean amount of both sedatives was directly evaluated on alveolar macrophages and lung endothelial cells primarily extracted 24-h after acute ischemic stroke. In twenty-five Wistar rats, ischemic stroke was induced and after 24-h treated with sodium thiopental (STROKE), dexmedetomidine and propofol. Dexmedetomidine, compared to STROKE, reduced diffuse alveolar damage score [median(interquartile range); 12(7.8-15.3) vs. 19.5(18-24), p = 0.007)], bronchoconstriction index [2.28(2.08-2.36) vs. 2.64(2.53-2.77), p = 0.006], and TNF-α expression (p = 0.0003), while propofol increased VCAM-1 expression compared to STROKE (p = 0.0004). In perilesional brain tissue, dexmedetomidine, compared to STROKE, decreased TNF-α (p = 0.010), while propofol increased VCAM-1 compared to STROKE (p = 0.024). In alveolar macrophages and endothelial cells, dexmedetomidine decreased IL-6 and IL-1ß compared to STROKE (p = 0.002, and p = 0.040, respectively), and reduced IL-1ß compared to propofol (p = 0.014). Dexmedetomidine, but not propofol, induced brain and lung protection in experimental acute ischemic stroke.

Noninvasive respiratory support and patient self-inflicted lung injury in COVID-19: a narrative review.

COVID-19 pneumonia is associated with hypoxaemic respiratory failure, ranging from mild to severe. Because of the worldwide shortage of ICU beds, a relatively high number of patients with respiratory failure are receiving prolonged noninvasive respiratory support, even when their clinical status would have required invasive mechanical ventilation. There are few experimental and clinical data reporting that vigorous breathing effort during spontaneous ventilation can worsen lung injury and cause a phenomenon that has been termed patient self-inflicted lung injury (P-SILI). The aim of this narrative review is to provide an overview of P-SILI pathophysiology and the role of noninvasive respiratory support in COVID-19 pneumonia. Respiratory mechanics, vascular compromise, viscoelastic properties, lung inhomogeneity, work of breathing, and oesophageal pressure swings are discussed. The concept of P-SILI has been widely investigated in recent years, but controversies persist regarding its mechanisms. To minimise the risk of P-SILI, intensivists should better understand its underlying pathophysiology to optimise the type of noninvasive respiratory support provided to patients with COVID-19 pneumonia, and decide on the optimal timing of intubation for these patients.

The impact of fluid status and decremental PEEP strategy on cardiac function and lung and kidney damage in mild-moderate experimental acute respiratory distress syndrome.

BACKGROUND: We evaluated the effects of abrupt versus gradual PEEP decrease, combined with standard versus high-volume fluid administration, on cardiac function, as well as lung and kidney damage in an established model of mild-moderate acute respiratory distress syndrome (ARDS). METHODS: Wistar rats received endotoxin intratracheally. After 24 h, they were treated with Ringer's lactate at standard (10 mL/kg/h) or high (30 mL/kg/h) dose. For 30 min, all animals were mechanically ventilated with tidal volume = 6 mL/kg and PEEP = 9 cmH2O (to keep alveoli open), then randomized to undergo abrupt or gradual (0.2 cmH2O/min for 30 min) PEEP decrease from 9 to 3 cmH2O. Animals were then further ventilated for 10 min at PEEP = 3 cmH2O, euthanized, and their lungs and kidneys removed for molecular biology analysis. RESULTS: At the end of the experiment, left and right ventricular end-diastolic areas were greater in animals treated with high compared to standard fluid administration, regardless of PEEP decrease rate. However, pulmonary arterial pressure, indicated by the pulmonary acceleration time (PAT)/pulmonary ejection time (PET) ratio, was higher in abrupt compared to gradual PEEP decrease, independent of fluid status. Animals treated with high fluids and abrupt PEEP decrease exhibited greater diffuse alveolar damage and higher expression of interleukin-6 (a pro-inflammatory marker) and vascular endothelial growth factor (a marker of endothelial cell damage) compared to the other groups. The combination of standard fluid administration and gradual PEEP decrease increased zonula occludens-1 expression, suggesting epithelial cell preservation. Expression of club cell-16 protein, an alveolar epithelial cell damage marker, was higher in abrupt compared to gradual PEEP decrease groups, regardless of fluid status. Acute kidney injury score and gene expression of kidney injury molecule-1 were higher in the high versus standard fluid administration groups, regardless of PEEP decrease rate. CONCLUSION: In the ARDS model used herein, decreasing PEEP abruptly increased pulmonary arterial hypertension, independent of fluid status. The combination of abrupt PEEP decrease and high fluid administration led to greater lung and kidney damage. This information adds to the growing body of evidence that supports gradual transitioning of ventilatory patterns and warrants directing additional investigative effort into vascular and deflation issues that impact lung protection.

Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema.

Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) from patients with chronic obstructive pulmonary disease (COPD) appear to be phenotypically and functionally similar to BM-MSCs from healthy sources in vitro, the impact of COPD on MSC metabolism and mitochondrial function has not been evaluated. In this study, we aimed to comparatively characterize MSCs from healthy and emphysematous donors (H-MSCs and E-MSCs) in vitro and to assess the therapeutic potential of these MSCs and their extracellular vesicles (H-EVs and E-EVs) in an in vivo model of severe emphysema. For this purpose, C57BL/6 mice received intratracheal porcine pancreatic elastase once weekly for 4 weeks to induce emphysema; control animals received saline under the same protocol. Twenty-four hours after the last instillation, animals received saline, H-MSCs, E-MSCs, H-EVs, or E-EVs intravenously. In vitro characterization demonstrated that E-MSCs present downregulation of anti-inflammatory (TSG-6, VEGF, TGF-ß, and HGF) and anti-oxidant (CAT, SOD, Nrf2, and GSH) genes, and their EVs had larger median diameter and lower average concentration. Compared with H-MSC, E-MSC mitochondria also exhibited a higher respiration rate, were morphologically elongated, expressed less dynamin-related protein-1, and produced more superoxide. When co-cultured with alveolar macrophages, both H-MSCs and E-MSCs induced an increase in iNOS and arginase-1 levels, but only H-MSCs and their EVs were able to enhance IL-10 levels. In vivo, emphysematous mice treated with E-MSCs or E-EVs demonstrated no amelioration in cardiorespiratory dysfunction. On the other hand, H-EVs, but not H-MSCs, were able to reduce the neutrophil count, the mean linear intercept, and IL-1ß and TGF-ß levels in lung tissue, as well as reduce pulmonary arterial hypertension and increase the right ventricular area in a murine model of elastase-induced severe emphysema. In conclusion, E-MSCs and E-EVs were unable to reverse cardiorespiratory dysfunction, whereas H-EVs administration was associated with a reduction in cardiovascular and respiratory damage in experimental severe emphysema.

Immunomodulators in anesthesia.

PURPOSE OF REVIEW: Anesthetics are known to have immunomodulatory effects. These can be detrimental, inducing immunosuppression and facilitating the development of opportunistic infections, especially when used at high doses, for prolonged periods, or in patients with preexisting immune deficiency; or beneficial, modulating the inflammatory response, particularly in critical illness and systemic hyperinflammatory states. RECENT FINDINGS: Anesthetics can have microbicidal properties, and both anti- and pro-inflammatory effects. They can act directly on immune cells as well as modulate immunity through indirect pathways, acting on the neuroimmune stress response, and have recently been described to interact with the gut microbiota. SUMMARY: Anesthesiologists should take into consideration the immunomodulatory properties of anesthetic agents in addition to their hemodynamic, neuroprotective, and other impacts. In future, patient stratification according to the perioperative assessment of serum biomarkers associated with postoperative complications may be used to guide anesthetic agent selection based on their immunomodulatory properties.

Time-Controlled Adaptive Ventilation Versus Volume-Controlled Ventilation in Experimental Pneumonia.

OBJECTIVES: We hypothesized that a time-controlled adaptive ventilation strategy would open and stabilize alveoli by controlling inspiratory and expiratory duration. Time-controlled adaptive ventilation was compared with volume-controlled ventilation at the same levels of mean airway pressure and positive end-release pressure (time-controlled adaptive ventilation)/positive end-expiratory pressure (volume-controlled ventilation) in a Pseudomonas aeruginosa-induced pneumonia model. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Twenty-one Wistar rats. INTERVENTIONS: Twenty-four hours after pneumonia induction, Wistar rats (n = 7) were ventilated with time-controlled adaptive ventilation (tidal volume = 8 mL/kg, airway pressure release ventilation for a Thigh = 0.75-0.85 s, release pressure (Plow) set at 0 cm H2O, and generating a positive end-release pressure = 1.6 cm H2O applied for Tlow = 0.11-0.14 s). The expiratory flow was terminated at 75% of the expiratory flow peak. An additional 14 animals were ventilated using volume-controlled ventilation, maintaining similar time-controlled adaptive ventilation levels of positive end-release pressure (positive end-expiratory pressure=1.6 cm H2O) and mean airway pressure = 10 cm H2O. Additional nonventilated animals (n = 7) were used for analysis of molecular biology markers. MEASUREMENTS AND MAIN RESULTS: After 1 hour of mechanical ventilation, the heterogeneity score, the expression of pro-inflammatory biomarkers interleukin-6 and cytokine-induced neutrophil chemoattractant-1 in lung tissue were significantly lower in the time-controlled adaptive ventilation than volume-controlled ventilation with similar mean airway pressure groups (p = 0.008, p = 0.011, and p = 0.011, respectively). Epithelial cell integrity, measured by E-cadherin tissue expression, was higher in time-controlled adaptive ventilation than volume-controlled ventilation with similar mean airway pressure (p = 0.004). Time-controlled adaptive ventilation animals had bacteremia counts lower than volume-controlled ventilation with similar mean airway pressure animals, while time-controlled adaptive ventilation and volume-controlled ventilation with similar positive end-release pressure animals had similar colony-forming unit counts. In addition, lung edema and cytokine-induced neutrophil chemoattractant-1 gene expression were more reduced in time-controlled adaptive ventilation than volume-controlled ventilation with similar positive end-release pressure groups. CONCLUSIONS: In the model of pneumonia used herein, at the same tidal volume and mean airway pressure, time-controlled adaptive ventilation, compared with volume-controlled ventilation, was associated with less lung damage and bacteremia and reduced gene expression of mediators associated with inflammation.

Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial.

BACKGROUND: Nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro. However, there is no evidence of its impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: In a multicentre, randomised, double-blind, placebo-controlled trial, adult patients presenting up to 3 days after onset of coronavirus disease 2019 (COVID-19) symptoms (dry cough, fever and/or fatigue) were enrolled. After confirmation of SARS-CoV-2 infection using reverse transcriptase PCR on a nasopharyngeal swab, patients were randomised 1:1 to receive either nitazoxanide (500 mg) or placebo, three times daily, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, laboratory tests, serum biomarkers of inflammation and hospitalisation rate. Adverse events were also assessed. RESULTS: From June 8 to August 20, 2020, 1575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analysed. Median (interquartile range) time from symptom onset to first dose of study drug was 5 (4-5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was reduced after nitazoxanide compared to placebo (p=0.006). The percentage viral load reduction from onset to end of therapy was higher with nitazoxanide (55%) than placebo (45%) (p=0.013). Other secondary outcomes were not significantly different. No serious adverse events were observed. CONCLUSIONS: In patients with mild COVID-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.

Iso-Oncotic Albumin Mitigates Brain and Kidney Injury in Experimental Focal Ischemic Stroke.

Background: There is widespread debate regarding the use of albumin in ischemic stroke. We tested the hypothesis that an iso-oncotic solution of albumin (5%), administered earlier after acute ischemic stroke (3 h), could provide neuroprotection without causing kidney damage, compared to a hyper-oncotic albumin (20%) and saline. Objective: To compare the effects of saline, iso-oncotic albumin, and hyper-oncotic albumin, all titrated to similar hemodynamic targets, on the brain and kidney. Methods: Ischemic stroke was induced in anesthetized male Wistar rats (n = 30; weight 437 ± 68 g) by thermocoagulation of pial blood vessels of the primary somatosensory, motor, and sensorimotor cortices. After 3 h, animals were anesthetized and randomly assigned (n = 8) to receive 0.9% NaCl (Saline), iso-oncotic albumin (5% ALB), and hyper-oncotic albumin (20% ALB), aiming to maintain hemodynamic stability (defined as distensibility index of inferior vena cava <25%, mean arterial pressure >80 mmHg). Rats were then ventilated using protective strategies for 2 h. Of these 30 animals, 6 were used as controls (focal ischemic stroke/no fluid). Results: The total fluid volume infused was higher in the Saline group than in the 5% ALB and 20% ALB groups (mean ± SD, 4.3 ± 1.6 vs. 2.7 ± 0.6 and 2.6 ± 0.5 mL, p = 0.03 and p = 0.02, respectively). The total albumin volume infused (g/kg) was higher in the 20% ALB group than in the 5% ALB group (1.4 ± 0.6 vs. 0.4 ± 0.2, p < 0.001). Saline increased neurodegeneration (Fluoro-Jade C staining), brain inflammation in the penumbra (higher tumor necrosis factor-alpha expression), and blood-brain barrier damage (lower gene expressions of claudin-1 and zona occludens-1) compared to both iso-oncotic and hyper-oncotic albumins, whereas it reduced the expression of brain-derived neurotrophic factor (a marker of neuroregeneration) compared only to iso-oncotic albumin. In the kidney, hyper-oncotic albumin led to greater damage as well as higher gene expressions of kidney injury molecule-1 and interleukin-6 than 5% ALB (p < 0.001). Conclusions: In this model of focal ischemic stroke, only iso-oncotic albumin had a protective effect against brain and kidney damage. Fluid therapy thus requires careful analysis of impact not only on the brain but also on the kidney.

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells.

Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function were compared with effects of BALF collected from healthy volunteers. CF BALF samples that cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon signaling, antimicrobial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.