Induction Of Acute Respiratory Distress Syndrome Research Articles

Pirfenidone Alleviates Inflammation and Fibrosis of Acute Respiratory Distress Syndrome by Modulating the Transforming Growth Factor-β/Smad Signaling Pathway.

Acute respiratory distress syndrome (ARDS) occurs as an acute onset condition, and patients present with diffuse alveolar damage, refractory hypoxemia, and non-cardiac pulmonary edema. ARDS progresses through an initial exudative phase, an inflammatory phase, and a final fibrotic phase. Pirfenidone, a powerful anti-fibrotic agent, is known as an agent that inhibits the progression of fibrosis in idiopathic pulmonary fibrosis. In this study, we studied the treatment efficiency of pirfenidone on lipopolysaccharide (LPS) and bleomycin-induced ARDS using rats. The ARDS rat model was created by the intratracheal administration of 3 mg/kg LPS of and 3 mg/kg of bleomycin dissolved in 0.2 mL of normal saline. The pirfenidone treatment group was administered 100 or 200 mg/kg of pirfenidone dissolved in 0.5 mL distilled water orally 10 times every 2 days for 20 days. The administration of LPS and bleomycin intratracheally increased lung injury scores and significantly produced pro-inflammatory cytokines. ARDS induction increased the expressions of transforming growth factor (TGF)-β1/Smad-2 signaling factors. Additionally, matrix metalloproteinase (MMP)-9/tissue inhibitor of metalloproteinase (TIMP)-1 imbalance occurred, resulting in enhanced fibrosis-related factors. Treatment with pirfenidone strongly suppressed the expressions of TGF-β1/Smad-2 signaling factors and improved the imbalance of MMP-9/TIMP-1 compared to the untreated group. These effects led to a decrease in fibrosis factors and pro-inflammatory cytokines, promoting the recovery of damaged lung tissue. These results of this study showed that pirfenidone administration suppressed inflammation and fibrosis in the ARDS animal model. Therefore, pirfenidone can be considered a new early treatment for ARDS.

Pulmonary inflammation decreases with ultra-protective ventilation in experimental ARDS under VV-ECMO: a positron emission tomography study.

Experimentally, ultra-protective ventilation (UPV, tidal volumes [VT] < 4 mL.kg-1) strategies in conjunction with veno-venous extracorporeal membrane oxygenation (VV-ECMO) are associated with lesser ventilator-induced lung injuries (VILI) during acute respiratory distress syndrome (ARDS). However, whether these strategies reduce lung inflammation more effectively than protective ventilation (PV) remains unclear. We aimed to demonstrate that a UPV strategy decreases acute lung inflammation in comparison with PV in an experimental swine model of ARDS. ARDS was induced by tracheal instillation of chlorhydric acid in sedated and paralyzed animals under mechanical ventilation. Animals were randomized to receive either UPV (VT 1 mL.kg-1, positive end-expiration pressure [PEEP] set to obtain plateau pressure between 20 and 25 cmH2O and respiratory rate [RR] at 5 min-1 under VV-ECMO) or PV (VT 6 mL.kg-1, PEEP set to obtain plateau pressure between 28 and 30 cmH2O and RR at 25 min-1) during 4 h. After 4 h, a positron emission tomography with [11C](R)-PK11195 (ligand to TSPO-bearing macrophages) injection was realized, coupled with quantitative computerized tomography (CT). Pharmacokinetic multicompartment models were used to quantify regional [11C](R)-PK11195 lung uptake. [11C](R)-PK11195 lung uptake and CT-derived respiratory variables were studied regionally across eight lung regions distributed along the antero-posterior axis. Five pigs were randomized to each study group. Arterial O2 partial pressure to inspired O2 fraction were not significantly different between study groups after experimental ARDS induction (75 [68-80] mmHg in a PV group vs. 87 [69-133] mmHg in a UPV group, p = 0.20). Compared to PV animals, UPV animals exhibited a significant decrease in the regional non-aerated compartment in the posterior lung levels, in mechanical power, and in regional dynamic strain and no statistical difference in tidal hyperinflation after 4 h. UPV animals had a significantly lower [11C](R)-PK11195 uptake, compared to PV animals (non-displaceable binding potential 0.35 [IQR, 0.20-0.59] in UPV animals and 1.01 [IQR, 0.75-1.59] in PV animals, p = 0.01). Regional [11C](R)-PK11195 uptake was independently associated with the interaction of regional tidal hyperinflation and regional lung compliance. In an experimental model of ARDS, 4 h of UPV strategy significantly decreased lung inflammation, in relation to the control of VT-derived determinants of VILI.

An appraisal of lung computer tomography in very early anti-inflammatory treatment of two different ovine ARDS phenotypes

Mortality and morbidity of Acute Respiratory Distress Syndrome (ARDS) are largely unaltered. A possible new approach to treatment of ARDS is offered by the discovery of inflammatory subphenotypes. In an ovine model of ARDS phenotypes, matching key features of the human subphenotypes, we provide an imaging characterization using computer tomography (CT). Nine animals were randomized into (a) OA (oleic acid, hypoinflammatory; n = 5) and (b) OA-LPS (oleic acid and lipopolysaccharides, hyperinflammatory; n = 4). 48 h after ARDS induction and anti-inflammatory treatment, CT scans were performed at high (H) and then low (L) airway pressure. After CT, the animals were euthanized and lung tissue was collected. OA-LPS showed a higher air fraction and OA a higher tissue fraction, resulting in more normally aerated lungs in OA-LPS in contrast to more non-aerated lung in OA. The change in lung and air volume between H and L was more accentuated in OA-LPS, indicating a higher recruitment potential. Strain was higher in OA, indicating a higher level of lung damage, while the amount of lung edema and histological lung injury were largely comparable. Anti-inflammatory treatment might be beneficial in terms of overall ventilated lung portion and recruitment potential, especially in the OA-LPS group.

Оценка экспрессии эндотелиальных и некоторых маркеров воспаления в экспериментальной модели острого респираторного дистресс-синдрома

Introduction. In the pathogenesis of acute respiratory distress syndrome (ARDS), signaling molecules such as cytokines play an important role in initiating, enhancing, and consolidating the inflammatory response. We aimed to identify the most indicative immunohistochemical markers for ARDS and the areas of studying them and to establish the optimal age of animals (i.e., rats) for ARDS induction. Materials and methods. We conducted a histological and immunohistochemical study of rats’ lung sections in two intact groups and two groups with a lipopolysaccharide-induced model of ARDS in three areas: bronchial epithelium, lung consolidation, and unchanged parenchyma. The rats were also divided into two age groups. We compared a microscopic appearance, the number of goblet cells, and immunohistochemical expression of IL-1β, IL-6, TNF-α, Ki-67, and CD31. Results. Both groups saw a significant increase in the number of goblet cells. At 8–10 weeks of age, the rats developed increased basal levels of IL-1β and proliferative activity in the lungs; the area of the capillary network decreased. In the experimental groups, the animals aged 4–6 weeks showed an increase in the level of IL-1β in all lung areas; however, in the animals aged 8–10 weeks, we observed this growth only in the area of unchanged parenchyma. The relative density of the capillary lung network decreased in the ARDS group aged 4–6 weeks. Conclusion. We would recommend IL-1β as an inflammatory cytokine and CD31 as endothelial marker, which reflects changes in vascular density, as immunohistochemical markers of ARDS severity on day 4 of its development. Marker changes are more stable in the 4–6-week-old animals. Keywords: IL-1b, TNF-α, Ki-67, CD31, respiratory distress syndrome, lipopolysaccharide, lung

Indirect cardiac output assessment in a swine pediatric acute respiratory distress syndrome model

PurposeTo investigate the correlation between volume of carbon dioxide elimination (V̇CO2) and end-tidal carbon dioxide (PETCO2) with cardiac output (CO) in a swine pediatric acute respiratory distress syndrome (ARDS) model. MethodsRespiratory and hemodynamic variables were collected from twenty-six mechanically ventilated juvenile pigs under general anesthesia before and after inducing ARDS, using oleic acid infusion. ResultsPrior to ARDS induction, mean (SD) CO, V̇CO2, PETCO2, and dead space to tidal volume ratio (Vd/Vt) were 4.16 (1.10) L/min, 103.69 (18.06) ml/min, 40.72 (3.88) mmHg and 0.25 (0.09) respectively. Partial correlation coefficients between average CO, V̇CO2, and PETCO2 were 0.44 (95% confidence interval: 0.18–0.69) and 0.50 (0.18–0.74), respectively. After ARDS induction, mean CO, V̇CO2, PETCO2, and Vd/Vt were 3.33 (0.97) L/min, 113.71 (22.97) ml/min, 50.17 (9.73) mmHg and 0.40 (0.08). Partial correlations between CO and V̇CO2 was 0.01 (−0.31 to 0.37) and between CO and PETCO2 was 0.35 (−0.002 to 0.65). ConclusionARDS may limit the utility of volumetric capnography to monitor CO.

THE IL-33/ST2 AXIS PROMOTES ACUTE RESPIRATORY DISTRESS SYNDROME BY NATURAL KILLER T CELLS.

Acute respiratory distress syndrome (ARDS) is characterized by uncontrolled inflammation, which manifests as leukocyte infiltration and lung injury. However, the molecules that initiate this infiltration remain incompletely understood. We evaluated the effect of the nuclear alarmin IL-33 on lung damage and the immune response in LPS-induced lung injury. We established a LPS-induced lung injury mouse model. We used genetically engineered mice to investigate the relationship among the IL-33/ST2 axis, NKT cells, and ARDS. We found that IL-33 was localized to the nucleus in alveolar epithelial cells, from which it was released 1 h after ARDS induction in wild-type (WT) mice. Mice lacking IL-33 (IL-33 - / - ) or ST2 (ST2 - / - ) exhibited reduced neutrophil infiltration, alveolar capillary leakage, and lung injury in ARDS compared with WT mice. This protection was associated with decreased lung recruitment and activation of invariant nature killer (iNKT) cells and activation of traditional T cells. Then, we validated that iNKT cells were deleterious in ARDS in CD1d - / - and Vα14Τg mice. Compared with WT mice, Vα14Τg mice exhibited increased lung injury in ARDS, and the CD1d - / - mice showed outcomes opposite those of the Vα14Τg mice. Furthermore, we administered a neutralizing anti-ST2 antibody to LPS-treated WT and Vα14Τg mice 1 h before LPS administration. We found that IL-33 promoted inflammation through NKT cells in ARDS. In summary, our results demonstrated that the IL-33/ST2 axis promotes the early uncontrolled inflammatory response in ARDS by activating and recruiting iNKT cells. Therefore, IL-33 and NKT cells may be therapeutic target molecules and immune cells, respectively, in early ARDS cytokine storms.

Safety and efficacy of clinical-grade, cryopreserved menstrual blood mesenchymal stromal cells in experimental acute respiratory distress syndrome.

Background: Treatment for critical care conditions, such as acute respiratory distress syndrome (ARDS), requires ready-to-administer injectable mesenchymal stromal cells (MSCs). A validated cryopreserved therapy based on MSCs derived from menstrual blood (MenSCs) is an attractive option that offers advantages over freshly cultured cells and allows its use as an off-the-shelf therapy in acute clinical conditions. The main goal of this study is to provide evidence on the impact of cryopreservation on different biological functions of MenSCs and to determine the optimal therapeutic dose, safety, and efficacy profile of clinical-grade, cryopreserved (cryo)-MenSCs in experimental ARDS. Methods: Biological functions of fresh versus cryo-MenSCs were compared in vitro. The effects of cryo-MenSCs therapy were evaluated in vivo in ARDS-induced (Escherichia coli lipopolysaccharide) C57BL/6 mice. After 24 h, the animals were treated with five doses ranging from 0.25×105 to 1.25×106 cells/animal. At 2 and 7 days after induction of ARDS, safety and efficacy were evaluated. Results: Clinical-grade cryo-MenSCs injections improved lung mechanics and reduced alveolar collapse, tissue cellularity, and remodelling, decreasing elastic and collagen fiber content in alveolar septa. In addition, administration of these cells modulated inflammatory mediators and promoted pro-angiogenic and anti-apoptotic effects in lung-injured animals. More beneficial effects were observed with an optimal dose of 4×106 cells/Kg than with higher or lower doses. Conclusion: From a translational perspective, the results showed that clinical-grade cryopreserved MenSCs retain their biological properties and exert a therapeutic effect in mild to moderate experimental ARDS. The optimal therapeutic dose was well-tolerated, safe, and effective, favouring improved lung function. These findings support the potential value of an off-the-shelf MenSCs-based product as a promising therapeutic strategy for treating ARDS.

Pre-clinical validation of a turbine-based ventilator for invasive ventilation-The ACUTE-19 ventilator.

The Severe Acute Respiratory Syndrome (SARS)-Coronavirus 2 (CoV-2) pandemic pressure on healthcare systems can exhaust ventilator resources, especially where resources are restricted. Our objective was a rapid preclinical evaluation of a newly developed turbine-based ventilator, named the ACUTE-19, for invasive ventilation. Validation consisted of (a) testing tidal volume (V_T) delivery in 11 simulated models, with various resistances and compliances; (b) comparison with a commercial ventilator (VIVO-50) adapting the United Kingdom Medicines and Healthcare products Regulatory Agency-recommendations for rapidly manufactured ventilators; and (c) in vivo testing in a sheep before and after inducing acute respiratory distress syndrome (ARDS) by saline lavage. Differences in V_T in the simulated models were marginally different (largest difference 33ml [95%-confidence interval (CI) 31-36]; P&lt;.001ml). Plateau pressure (P_plat) was not different (-0.3cmH₂O [95%-CI -0.9 to 0.3]; P=.409), and positive end-expiratory pressure (PEEP) was marginally different (0.3 cmH₂O [95%-CI 0.2 to 0.3]; P&lt;.001) between the ACUTE-19 and the commercial ventilator. Bland-Altman analyses showed good agreement (mean bias, -0.29, [limits of agreement, 0.82 to -1.42], and mean bias 0.56 [limits of agreement, 1.94 to -0.81], at a P_plat of 15 and 30cmH₂O, respectively). The ACUTE-19 achieved optimal oxygenation and ventilation before and after ARDS induction. The ACUTE-19 performed accurately in simulated and animal models yielding a comparable performance with a VIVO-50 commercial device. The acute 19 can provide the basis for the development of a future affordable commercial ventilator.

A clinically relevant model of acute respiratory distress syndrome in human-size swine.

ABSTRACTDespite over 30 years of intensive research for targeted therapies, treatment of acute respiratory distress syndrome (ARDS) remains supportive in nature. With mortality upwards of 30%, a high-fidelity pre-clinical model of ARDS, on which to test novel therapeutics, is urgently needed. We used the Yorkshire breed of swine to induce a reproducible model of ARDS in human-sized swine to allow the study of new therapeutics, from both mechanistic and clinical standpoints. For this, animals were anesthetized, intubated and mechanically ventilated, and pH-standardized gastric contents were delivered bronchoscopically, followed by intravenous infusion of Escherichia coli-derived lipopolysaccharide. Once the ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FIO2) had decreased to <150, the animals received standard ARDS treatment for up to 48 h. All swine developed moderate to severe ARDS. Chest radiographs taken at regular intervals showed significantly worse lung edema after induction of ARDS. Quantitative scoring of lung injury demonstrated time-dependent increases in interstitial and alveolar edema, neutrophil infiltration, and mild to moderate alveolar membrane thickening. This pre-clinical model of ARDS in human-sized swine recapitulates the clinical, radiographic and histopathologic manifestations of ARDS, providing a tool to study therapies for this highly morbid lung disease.

Lung-brain 'cross-talk': systemic propagation of cytokines in the ARDS via the bloodstream using a blood transfusion model does not influence cerebral inflammatory response in pigs.

BackgroundInterorgan cross-talk describes the phenomenon in which a primarily injured organ causes secondary damage to a distant organ. This cross-talk is well known between the lung and brain. One theory suggests that the release and systemic distribution of cytokines via the bloodstream from the primarily affected organ sets in motion proinflammatory cascades in distant organs. In this study, we analysed the role of the systemic distribution of cytokines via the bloodstream in a porcine ARDS model for organ cross-talk and possible inflammatory changes in the brain.MethodsAfter approval of the State and Institutional Animal Care Committee, acute respiratory distress syndrome (ARDS) induction with oleic acid injection was performed in seven animals. Eight hours after ARDS induction, blood (35–40 ml kg–1) was taken from these seven ‘ARDS donor’ pigs. The collected ‘ARDS donor’ blood was transfused into seven healthy ‘ARDS-recipient’ pigs. Three animals served as a control group, and blood from these animals was transfused into three healthy pigs after an appropriate ventilation period. All animals were monitored for 8 h using advanced cardiorespiratory monitoring. Postmortem assessment included cerebral (hippocampal and cortex) mediators of early inflammatory response (IL-6, TNF-alpha, iNOS, sLCN-2), wet-to-dry ratio and lung histology. TNF-alpha serum concentration was measured in all groups.ResultsARDS was successfully induced in the ‘ARDS donor’ group, and serum TNF-alpha levels were elevated compared with the ‘ARDS-recipient’ group. In the ‘ARDS-recipient’ group, neither significant ARDS alterations nor upregulation of inflammatory mediators in the brain tissue were detected after high-volume random allogenic ‘ARDS-blood’ transfusion. The role of the systemic distribution of inflammatory cytokines from one affected organ to another could not be confirmed in this study.

Nitric oxide releasing nanoparticles reduce inflammation in a small animal model of ARDS

Acute respiratory distress syndrome (ARDS) is a condition hallmarked by high permeability pulmonary edema and hypoxemic respiratory failure and is associated with high mortality. Current treatment protocols rely on improving O2 delivery, decreasing O2 consumption, and treating the underlying cause of the initial insult. In this study, we used a small rodent model of ARDS, where we induced lung injury with inhalation of lipopolysaccharide (LPS). We investigated three different treatments, namely inhaled NO at 70 ppm, inhaled NO at 140 ppm, and NO-np (10 mg/mL), compared with untreated rodents 72 h after initial insult. Concurrent with treatment, the fraction of inspired O2 was increased after 30 min from 21% to 40% and finally to 60%. At an FiO2 of 60% and 72 h post induction of ARDS, NO-np treated mice had an arterial PO2 (PaO2) of 142 ± 9 mmHg, higher than mice treated with inhaled NO at 70 ppm (87 ± 5 mmHg, p = 8.4 × 10-8) and inhaled NO at 140 ppm (107 ± 6 mmHg, p = 6.1 × 10-6). Neutrophils in both the periphery (1.6 × 105 ± 0.4 × 105 cells) and bronchoalveolar lavage fluid (BALF; 2.7 × 105 ± 0.8 × 105 cells) were reduced in NO-np treated mice compared to mice treated with inhaled NO at 70 ppm (p = 0.0097, 2.4 × 105 ± 0.5 × 105 cells for periphery, p = 0.0075, 3.8 × 105 ± 0.8 × 105 cells for BALF). In summary, we found that treatment with NO-np improved arterial PO2 at a high FiO2 compared to inhaled NO alone and NO-np reduced both circulating and pulmonary interstitial neutrophil count, while inhaled NO did not. Future studies should aim to elucidate the precise mechanisms behind how NO-np mediate neutrophilic inflammation in ARDS.

Validación preclínica de un respirador de turbina para la ventilación invasiva: el respirador ACUTE-19

BackgroundThe severe acute respiratory syndrome-coronavirus 2 pandemic pressure on healthcare systems can exhaust ventilator resources, especially where resources are restricted. Our objective was a rapid preclinical evaluation of a newly developed turbine-based ventilator, named the ACUTE-19, for invasive ventilation. MethodsValidation consisted of (a) testing tidal volume delivery in 11 simulated models, with various resistances and compliances; (b) comparison with a commercial ventilator (VIVO-50) adapting the United Kingdom Medicines and Healthcare products Regulatory Agency-recommendations for rapidly manufactured ventilators; and (c) in vivo testing in a sheep before and after inducing acute respiratory distress syndrome by saline lavage. ResultsDifferences in tidal volume in the simulated models were marginally different (largest difference 33ml [95% CI 31 to 36]; P<.001). Plateau pressure was not different (−0.3cmH2O [95% CI −0.9 to 0.3]; P=.409), and positive end-expiratory pressure was marginally different (0.3cmH2O [95% CI 0.2 to 0.3]; P<.001) between the ACUTE-19 and the commercial ventilator. Bland-Altman analyses showed good agreement (mean bias −0.29 [limits of agreement 0.82 to −1.42], and mean bias 0.56 [limits of agreement 1.94 to −0.81], at a plateau pressure of 15 and 30cmH2O, respectively). The ACUTE-19 achieved optimal oxygenation and ventilation before and after acute respiratory distress syndrome induction. ConclusionsThe ACUTE-19 performed accurately in simulated and animal models yielding a comparable performance with a VIVO-50 commercial device. The ACUTE-19 can provide the basis for the development of a future affordable commercial ventilator.

Investigating the effect of captopril on reducing the severity of symptoms of acute respiratory distress syndrome in rats

Introduction: Acute respiratory distress syndrome (ARDS) occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in the lungs. Objectives: This study aimed to investigate the effect of captopril in reducing the symptoms of ARDS induced by oleic acid in experimental rats. Materials and Methods: This experimental study was conducted on 14 Wistar male rats of 6-7 weeks weighing 200-250 g. In the first group, they received 1.25 mg/kg of captopril daily in glucose solution for one week, but the second group did not. After one week, these rats were anesthetized by 5% isoflurane respiration and oleic acid (0.1 mg/kg) was injected intraperitoneal for ARDS induction. During the first 6 hours after starting ARDS, the rats were randomly selected and after anesthesia with ether and autopsy, they were cut and the lung histology was conducted. Results: Intensity of lung tissue edema in the group receiving captopril (Cap) was 2.83 ± 0.41 and in the captopril group with oleic acid (Cap+OA) was 2.50±0.55. Additionally, 83.3% of the rats had severe pulmonary edema in the OA group which was statistically significant (P=0.003). The "severity of inflammation and bleeding" in the OA+Cap group was significantly less than OA group (P=0.026). Conclusion: Captopril can play a significant role in reducing the damage of the lung tissue and severity of tissue edema and inflammation and bleeding. Therefore, it may be possible to use this drug in human samples with acute respiratory distress syndrome to prevent further damage.

Molecular mechanisms underlying MSC-NTF (nurown®) exosome benefits in a mouse LPS-induced ards model

Background & Aim: One of the most severe complications of the current COVID-19 pandemic is acute respiratory distress syndrome (ARDS). ARDS is mediated by increased amounts of pro-inflammatory cytokines, leading to lung damage. ARDS remains an important unmet medical need. Mesenchymal stem cells (MSCs) and MSC-derived small extracellular vesicles (sEVs) have been suggested as a potential treatment for ARDS due to their significant immunomodulatory properties. While MSCs and their sEVs share immunomodulatory properties, sEVs have the added advantages of increased safety and improved tissue penetration. Methods, Results & Conclusion: In this study we compared the effect of two types of sEVs: sEVs isolated from naive MSC (Exo MSC) or sEVs isolated from MSCs which were induced to secrete increased levels of neurotrophic and immunomodulatory factors (Exo MSC-NTF). Exo MSC or Exo MSC-NTF were administered intratracheally to mice following induction of ARDS using lipopolysaccharide. We found that the beneficial effect of Exo MSC-NTF was superior to Exo MSC in multiple parameters, including increase in blood oxygen saturation and reduction in lung pathology, neutrophil infiltration and bronchoalveolar lavage fluid (BALF) levels of proinflammatory cytokines. Specifically, Exo MSC-NTF significantly decreased interferon gamma (IFN-γ), interleukin 6 (IL-6), and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) levels, while Exo MSC were not able to do so. To explore the differences between Exo MSC and Exo MSC-NTF we evaluated modifications in protein cargo. ELISA measurements revealed that amphiregulin (AREG) was 16-fold higher and leukemia inhibitory factor (LIF) was greater than 3-fold higher in Exo MSC-NTF than in Exo MSC. Both AREG and LIF are reported to have beneficial effects in ARDS models, either through immunomodulation or cellular repair. The observed positive preclinical results suggest that intratracheal administration of Exo MSC-NTF may be suitable as a therapy for ARDS due to COVID-19 or other causes, and may be more effective at modifying ARDS physiological, pathological, and biochemical outcomes than sEVs isolated from naive MSCs. Increased expression of LIF and AREG in Exo MSC-NTF may contribute to the effectiveness of this innovative treatment modality.

Inhalationally Administered Semifluorinated Alkanes (SFAs) as Drug Carriers in an Experimental Model of Acute Respiratory Distress Syndrome.

Aerosol therapy in patients suffering from acute respiratory distress syndrome (ARDS) has so far failed in improving patients’ outcomes. This might be because dependent lung areas cannot be reached by conventional aerosols. Due to their physicochemical properties, semifluorinated alkanes (SFAs) could address this problem. After induction of ARDS, 26 pigs were randomized into three groups: (1) control (Sham), (2) perfluorohexyloctane (F6H8), and (3) F6H8-ibuprofen. Using a nebulization catheter, (2) received 1 mL/kg F6H8 while (3) received 1 mL/kg F6H8 with 6 mg/mL ibuprofen. Ibuprofen plasma and lung tissue concentration, bronchoalveolar lavage (BAL) fluid concentration of TNF-α, IL-8, and IL-6, and lung mechanics were measured. The ibuprofen concentration was equally distributed to the dependent parts of the right lungs. Pharmacokinetic data demonstrated systemic absorption of ibuprofen proofing a transport across the alveolo-capillary membrane. A significantly lower TNF-α concentration was observed in (2) and (3) when compared to the control group (1). There were no significant differences in IL-8 and IL-6 concentrations and lung mechanics. F6H8 aerosol seemed to be a suitable carrier for pulmonary drug delivery to dependent ARDS lung regions without having negative effects on lung mechanics.

Physiologically variable ventilation reduces regional lung inflammation in a pediatric model of acute respiratory distress syndrome

BackgroundBenefits of variable mechanical ventilation based on the physiological breathing pattern have been observed both in healthy and injured lungs. These benefits have not been characterized in pediatric models and the effect of this ventilation mode on regional distribution of lung inflammation also remains controversial. Here, we compare structural, molecular and functional outcomes reflecting regional inflammation between PVV and conventional pressure-controlled ventilation (PCV) in a pediatric model of healthy lungs and acute respiratory distress syndrome (ARDS).MethodsNew-Zealand White rabbit pups (n = 36, 670 ± 20 g [half-width 95% confidence interval]), with healthy lungs or after induction of ARDS, were randomized to five hours of mechanical ventilation with PCV or PVV. Regional lung aeration, inflammation and perfusion were assessed using x-ray computed tomography, positron-emission tomography and single-photon emission computed tomography, respectively. Ventilation parameters, blood gases and respiratory tissue elastance were recorded hourly.ResultsMechanical ventilation worsened respiratory elastance in healthy and ARDS animals ventilated with PCV (11 ± 8%, 6 ± 3%, p < 0.04), however, this trend was improved by PVV (1 ± 4%, − 6 ± 2%). Animals receiving PVV presented reduced inflammation as assessed by lung normalized [18F]fluorodeoxyglucose uptake in healthy (1.49 ± 0.62 standardized uptake value, SUV) and ARDS animals (1.86 ± 0.47 SUV) compared to PCV (2.33 ± 0.775 and 2.28 ± 0.3 SUV, respectively, p < 0.05), particularly in the well and poorly aerated lung zones. No benefit of PVV could be detected on regional blood perfusion or blood gas parameters.ConclusionsVariable ventilation based on a physiological respiratory pattern, compared to conventional pressure-controlled ventilation, reduced global and regional inflammation in both healthy and injured lungs of juvenile rabbits.

Prophylactic and Therapeutic Administration of Leutragin Increases the Survival Rate of Animals in a Model of Fatal Acute Respiratory Distress Syndrome

This study aims to investigate effects of leutragin, an opioid peptide analogue of endogenous dynorphin 1-6, on animal survival in an experimental model of “cytokine storm” and fatal acute respiratory distress syndrome (ARDS) in C57Bl/6Y mice under different administration regimens. The aforementioned factors cause a severe course of COVID-19, which explains the current interest in seeking new treatments for ARDS. It was shown that both the prophylactic (before ARDS induction) and therapeutic (after ARDS induction) administration of leutragin in a combined mode — intramuscular injection plus inhalation leads to a statistically significant increase in the survival rate of animals. Compared to the control, leutragin significantly reduced the risk of death in animals with ARDS. The discovered prophylactic effect of leutragin deserves special attention due to its potential in preventing the onset of the disease and impeding the development of severe lung damage, thus reducing the risk of ARDS and fatal outcomes. Thus, the use of leutragin can be seen as a new effective approach to the treatment and prevention of respiratory diseases associated with a “cytokine storm” and ARDS, including the coronavirus infection COVID-19.

Leutragin Inhibits Expression of Cytokines, Including Interleukin-6, in a “Cytokine Storm” Model in C57BL/6Y Mice with Induced Acute Respiratory Distress Syndrome

This study aims to investigate effects of leutragin, an analogue of endogenous hexapeptide dynorphin 1-6, on the expression of pro-inflammatory cytokines and type I interferons in an experimental model of fatal acute respiratory distress syndrome (ARDS) in C57BL/6Y mice. The expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumour necrosis factor (TNF-α), interferons α (IFN-α) and β (IFN-β) in the lungs was assessed by real-time PCR. The induction of ARDS using α-galactosylceramide and E. coli lipopolysaccharide led to a multifold increase in the expression of the cytokines in the lungs. The administration of leutragin in a combined mode — intramuscular injection plus inhalation — led to a statistically significant decrease in the mRNA levels of cytokines within three hours after the start of administration. The average mRNA levels of IL-6, a key cytokine in the development of severe acute respiratory syndrome, decreased by 4.7 times (p<0.01) to reach values close to those observed in intact animals. Given the crucial role of elevated IL-6 concentrations in the development of severe forms of COVID-19, the use of leutragine for suppressing “cytokine storm” syndromes may be an effective approach to the treatment of this coronavirus infection.

Immunomodulation by an Omega-6 Fatty Acid Reduced Mixed Lipid Emulsion in Murine Acute Respiratory Distress Syndrome.

Background: Acute respiratory distress syndrome (ARDS) is associated with both high morbidity and mortality in intensive care units worldwide. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. In the present study, we assessed the immunomodulatory and apoptotic effects of a modern, n-6-reduced lipid emulsion mixture in murine ARDS. Methods: Mice received an infusion of either normal saline solution, pure long-chain triglyceride (LCT) emulsion, or SMOF (soybean oil, medium-chain triglycerides, olive oil, and fish oil) before a lipopolysaccharide (LPS) challenge. Mice were sacrificed at different time points (0, 24, or 72 h) after ARDS induction, and an analysis of inflammatory cytokines, protein concentrations, and the cellular composition of the alveolar and interstitial compartments was performed with special focus on alveolar apoptosis and necrosis. Results: Mice infused with SMOF showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in alveolar spaces after LPS challenge compared to animals that received LCT. There were fewer cells in the lung interstitium of the SMOF group compared to the LCT group. Both lipid emulsions exerted pro-apoptotic and pro-necrotic properties on alveolar immune cells, with significantly increased necrosis in mice infused with LCT compared to SMOF. Conclusion: SMOF has both anti-inflammatory and pro-resolving influences in murine ARDS. Partial replacement of n-6 fatty acids with n-3/n-9 fatty acids may therefore benefit critically ill patients at risk for ARDS who require parenteral nutrition.

Effect of mechanical ventilation versus spontaneous breathing on abdominal edema and inflammation in ARDS: an experimental porcine model

BackgroundMechanical ventilation (MV), compared to spontaneous breathing (SB), has been found to increase abdominal edema and inflammation in experimental sepsis. Our hypothesis was that in primary acute respiratory distress syndrome (ARDS) MV would enhance inflammation and edema in the abdomen.MethodsThirteen piglets were randomized into two groups (SB and MV) after the induction of ARDS by lung lavage and 1 h of injurious ventilation.1. SB: continuous positive airway pressure 15 cmH2O, fraction of inspired oxygen (FIO2) 0.5 and respiratory rate (RR) maintained at about 40 cycles min− 1 by titrating remifentanil infusion.2. MV: volume control, tidal volume 6 ml kg− 1, positive end-expiratory pressure 15 cmH2O, RR 40 cycles min− 1, FIO2 0.5.Main outcomes: abdominal edema, assessed by tissues histopathology and wet-dry weight; abdominal inflammation, assessed by cytokine concentration in tissues, blood and ascites, and tissue histopathology.ResultsThe groups did not show significant differences in hemodynamic or respiratory parameters. Moreover, edema and inflammation in the abdominal organs were similar. However, blood IL6 increased in the MV group in all vascular beds (p < 0.001). In addition, TNFα ratio in blood increased through the lungs in MV group (+ 26% ± 3) but decreased in the SB group (− 17% ± 3).ConclusionsThere were no differences between the MV and SB group for abdominal edema or inflammation. However, the systemic increase in IL6 and the TNFα increase through the lungs suggest that MV, in this model, was harmful to the lungs.