Hippophae rhamnoides Prevents Oleic Acid-Induced Acute Respiratory Distress Syndrome by Releasing Acetylcholinesterase Activity and Mitigation of Angiotensin-Converting Enzyme Level.

Hippophae rhamnoides exhibit a wide variety of medicinal and pharmacological effects. The present study aims to determine the role of ethanol extract of H. rhamnoides on oleic acid (OA)-induced acute respiratory distress syndrome (ARDS) in rats. Male rats were randomly divided into the following groups: (I) Control, (II) OA, and (III) OA+H. rhamnoides. H. rhamnoides extract (500 mg/kg) was given orally for 2 weeks before OA in Group III. Levels of total antioxidant capacity, total oxidant status (TOS), myeloperoxidase (MPO), mitogen-activated protein kinase (MAPK), acetylcholinesterase (AChE), and angiotensin-converting enzyme (ACE) were quantified by enzyme-linked immunosorbent assay (ELISA). Real time quantitative polymerase chain reaction was utilized to evaluate the expression of nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and matrix metalloproteinase 2 (MMP2). Also, Caspase-3 immunostaining and expression were performed to evaluate apoptosis. Compared with the OA group, there was a significantly decrease in the levels of MPO, TOS, MAPK, and ACE and in the expression of NF-κB, TNF-α, IL-6, MMP2, and Caspase-3 in the H. rhamnoides administration group. Moreover, the activity of AChE and level of TAS were substantially higher in the H. rhamnoides administration compared with the OA group. The findings in the study suggest that the protective effect of H. rhamnoides pretreatment may act through inhibition of the ACE activity, releasing AChE, regulation of inflammatory cytokine levels, and suppression of apoptotic process in ARDS.

Energy Achievement Rate Is an Independent Factor Associated with Intensive Care Unit Mortality in High-Nutritional-Risk Patients with Acute Respiratory Distress Syndrome Requiring Prolonged Prone Positioning Therapy.

Early enteral nutrition (EN) and a nutrition target >60% are recommended for patients in the intensive care unit (ICU), even for those with acute respiratory distress syndrome (ARDS). Prolonged prone positioning (PP) therapy (>48 h) is the rescue therapy of ARDS, but it may worsen the feeding status because it requires the heavy sedation and total paralysis of patients. Our previous studies demonstrated that energy achievement rate (EAR) >65% was a good prognostic factor in ICU. However, its impact on the mortality of patients with ARDS requiring prolonged PP therapy remains unclear. We retrospectively analyzed 79 patients with high nutritional risk (modified nutrition risk in the critically ill; mNUTRIC score ≥5); and identified factors associated with ICU mortality by using a Cox regression model. Through univariate analysis, mNUTRIC score, comorbid with malignancy, actual energy intake, and EAR (%) were associated with ICU mortality. By multivariate analysis, EAR (%) was a strong predictive factor of ICU mortality (HR: 0.19, 95% CI: 0.07-0.56). EAR >65% was associated with lower 14-day, 28-day, and ICU mortality after adjustment for confounding factors. We suggest early EN and increase EAR >65% may benefit patients with ARDS who required prolonged PP therapy.

Analysis of the Efficacy and Mechanism of Action of Xuebijing Injection on ARDS Using Meta-Analysis and Network Pharmacology.

OBJECTIVE: Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process known as cytokine storm. Xuebijing injection (hereinafter referred to as Xuebijing) is a patent drug that was used to treat ARDS or severe pneumonia (SP) in China. However, its efficacy and mechanism of actions remain unclear. In this study, we used meta-analysis and network pharmacology to assess these traits of Xuebijing. METHODS: We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang databases for randomized controlled trials (RCTs) that evaluated Xuebijing therapy for ARDS or SP. The outcomes were total mortality, intensive care unit (ICU) stay time, and TNF-α and IL-6 levels. We performed a meta-analysis using RevMan 5.3 software. The putative targets, top 10 proteins, and possible pathway of Xuebinjing on ARDS were analyzed by network pharmacology. TNF-α and IL-6 were further docked with the six main active components of Xuebinjing using AutoDock 4.2.6 and PyMol 1.5.0.3 software. RESULTS: Fifteen RCTs involving 2778 patients (13 ARDS and 2 SP) were included. Compared with the control, Xuebijing treatment significantly reduced the mortality rate (risk ratio, 0.64 (95% credible interval (CrI), 0.54-0.77)), reduced the ICU stay time (mean difference (MD), -4.51 (95% CrI, -4.97--4.06)), reduced the TNF-α ((MD), -1.23 (95% CrI, -1.38--1.08)) and IL-6 ((MD), -1.15 (95% CrI, -1.52--0.78)) levels. The 56 putative targets, top 10 proteins (MAPK1 (mitogen-activated protein kinase 1), MAPK8 (mitogen-activated protein kinase 8), RELA (transcription factor p65), NFKB1 (nuclear factor NF-kappa-B p105 subunit), JUN (transcription factor AP-1), SRC (proto-oncogene tyrosine-protein kinase), TNF (tumor necrosis factor), HRAS (GTPase HRas), IL6 (interleukin-6), and APP (amyloid-beta A4 protein)), and possible pathways (Ret tyrosine kinase, IL2-mediated signaling events, CD4+/CD8+ T cell-related TCR signaling, p75(NTR)-mediated signaling, CXCR4-mediated signaling events, LPA receptor-mediated events, IL12-mediated signaling events, FAS (CD95) signaling pathway, and immune system) of Xuebinjing's action on ARDS were obtained. The molecular docking results showed that all the six components of Xuebinjing docked with TNF-α, and two components docked with IL-6 got the binding energies lower than -5. CONCLUSION: Our results recommended Xuebijing treatment for patients with ARDS. Xuebijing has therapeutic effects on ARDS patients partly by regulating the immune cell/cytokine pathways and thus inhibiting the cytokine storm. TNF-α is the cytokine both directly and indirectly inhibited by Xuebijing, and IL-6 is the cytokine mainly indirectly inhibited by Xuebijing.

Postexposure Liponucleotide Prophylaxis and Treatment Attenuates Acute Respiratory Distress Syndrome in Influenza-infected Mice.

There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for de novo phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 µg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 µg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.

SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage.

PURPOSE: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. METHODS: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. RESULTS: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. CONCLUSIONS: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.

Vitamin D supplementation as a rational pharmacological approach in the COVID-19 pandemic.

The COVID-19 pandemic has reached most of the countries worldwide causing death, which often results from an inflammatory storm associated with severe acute respiratory syndrome (SARS). This has prompted researchers to seek specific novel and definitive treatments urgently. In this context, it is interesting to evaluate the preventive and therapeutic effects of existing pharmacological agents that could be useful. In this regard, vitamin D supplementation, particularly in individuals likely to be deficient, may be a promising option. Vitamin D is a hormone that modulates many of the same inflammatory and oxidative signaling pathways triggered during COVID-19. For example, vitamin D suppresses the actions of the renin-angiotensin system, which has a determining role in the pathophysiology of the inflammatory response related to COVID-19. This paper analyzes the evidence that vitamin D supplementation might be a valuable preventive/therapeutic measure in groups at risk for or infected with COVID-19. It also discusses how clinical studies could be best designed to evaluate the possible advantages of vitamin D supplementation for the benefit of public health during the pandemic.

Acupoint Catgut Embedding Improves the Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Rats.

BACKGROUND: This study investigated the potential therapeutic effects of acupoint catgut embedding (ACE) at ST36 and BL13 on lipopolysaccharide- (LPS-) induced acute respiratory distress syndrome (ARDS) in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomized into the normal saline (NS group with a sham procedure), lipopolysaccharide (LPS group with a sham procedure), and LPS plus ACE (LPS+ACE with ACE at bilateral BL13 and ST36 acupoints one day before LPS injection) groups. After intratracheal instillation of normal saline or LPS (0.5 mg/kg), all rats were subjected to mechanical ventilation for 4 h. Their blood gas was analyzed before and after lung injury, and their lung pressure-volumes were measured longitudinally. The levels of TNF-α, IL-6, IL-10, and phosphatidylcholine (PC) and total proteins (TP) in bronchial alveolar lavage fluid (BALF) were assessed. Their wet to dry lung weight ratios, histology, myeloperoxidase (MPO), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) levels were measured. Their lung aquaporin 1 (AQP1) and Occludin protein levels were analyzed. RESULTS: LPS administration significantly decreased the ratios of PaO2/FiO2 and pressure-volumes and induced lung inflammation and injury by increased concentrations of TNF-α, IL-6, IL-10, and TP in BALF and MPO and MDA in the lung but decreased PC in BALF and SOD activity in the lungs. LPS also reduced AQP1 and Occludin protein levels in the lung of rats. In contrast, ACE significantly mitigated the LPS-induced lung injury, inflammation, and oxidative stress and preserved the AQP1 and Occludin contents in the lung of rats. CONCLUSIONS: ACE significantly improved respiratory function by mitigating inflammation and oxidative stress and preserving AQP1 and Occludin expression in the lung in a rat model of LPS-induced ARDS.

Mitochondrial bioenergetics and pulmonary dysfunction: Current progress and future directions.

This review summarizes current understanding of mitochondrial bioenergetic dysfunction applicable to mechanisms of lung diseases and outlines challenges and future directions in this rapidly emerging field. Although the role of mitochondria extends beyond the term of cellular "powerhouse", energy generation remains the most fundamental function of these organelles. It is not counterintuitive to propose that intact energy supply is important for favorable cellular fate following pulmonary insult. In this review, the discussion of mitochondrial dysfunction focuses on those molecular mechanisms that alter cellular bioenergetics in the lungs: (a) inhibition of mitochondrial respiratory chain, (b) mitochondrial leak and uncoupling, (c) alteration of mitochondrial Ca2+ handling, (d) mitochondrial production of reactive oxygen species and self-oxidation. The discussed lung diseases were selected according to their pathological nature and relevance to pediatrics: Acute lung injury (ALI), defined as acute parenchymal lung disease associated with cellular demise and inflammation (Acute Respiratory Distress Syndrome, ARDS, Pneumonia), alveolar developmental failure (Bronchopulmonary Dysplasia, BPD or chronic lung disease in premature infants), obstructive airway diseases (Bronchial asthma) and vascular remodeling affecting pulmonary circulation (Pulmonary Hypertension, PH). The analysis highlights primary mechanisms of mitochondrial bioenergetic dysfunction contributing to the disease-specific pulmonary insufficiency and proposes potential therapeutic targets.

Oral administration of Ulmus davidiana extract suppresses interleukin-1ß expression in LPS-induced immune responses and lung injury.

BACKGROUND: Ulmus davidiana (UD) is a traditional Korean herb medicine that is used to treat inflammatory disorders. UD has been shown to modulate a number of inflammatory processes in vitro or in vivo studies. However, the molecular mechanisms of UD on lipopolysaccharide (LPS)-induced acute lung injury remain to be understood. OBJECTIVE: The primary objective of this study is to determine the effect of UD bark water extract on LPS-induced immune responses and lung injury using both in vitro and in vivo models. METHODS: RAW 264.7 cells and a rat model of acute lung injury (ALI) were used to study the effects of UD on several parameters. Nitrite level, lactate dehydrogenase (LDH) level, and superoxide dismutase (SOD) activities were measured. Tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and plasma transaminase activities in blood were also determined. Pathological investigations were also performed. RESULTS: LPS infusion resulted in elevated IL-1ß mRNA expression, nitrite levels, TNF-α expression, and IL-1ß expression in RAW 264.7 cells. LPS infusion also increased levels of nitrite/nitrate, total protein, LDH, and TNF-α in bronchoalveolar lavage fluid, but reduced SOD levels in ex vivo and in vivo models. UD administration ameliorated all these inflammatory markers. In particular, treatment with UD reduced LPS-induced nitrite production in RAW 264.7 cells in a dose-dependent manner. UD treatment also counteracted the LPS-induced increase in alanine aminotransferase (ALT) and aspartate transaminase (AST) activity in rat plasma, leading to a significant reduction in ALT and AST activity. CONCLUSIONS: The results revealed that UD treatment reduces LPS-induced nitrite production, IL-1ß mRNA expression, and TNF-α expression. In addition, LPS-induced decrease in SOD level is significantly elevated by UD administration. These results indicate that UD extract merits consideration as a potential drug for treating and/or preventing ALI.

Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome.

Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin-/- mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.

The Effect of Intravenous Selenium on Oxidative Stress in Critically Ill Patients with Acute Respiratory Distress Syndrome.

OBJECTIVE: To modulate the inflammatory response in respiratory distress syndrome (ARDS) with selenium. BACKGROUND: Selenium replenishes the glutathione peroxidase proteins that are the first line of defense for an oxidative injury to the lungs. METHODS: Forty patients with ARDS were randomized into two groups: the SEL+ group being administered sodium selenite and the SEL- group receiving normal saline for 10 days. Blood samples were taken on Day-0, DAY-7, and Day-14 for assessment of IL-1 beta, IL-6, C-reactive protein, GPx-3, and selenium. Ferric reducing antioxidant power (FRAP) was measured in the bronchial wash fluids. Pearson correlation and repeated measure analysis were performed to examine the effects of selenium on the inflammatory markers. RESULTS: Sodium selenite replenished selenium levels in the SEL+ group. Selenium concentrations were linearly correlated to serum concentrations of GPx3 (R value: 0.631; P < 0.001), and FRAP (R value: -0.785; P < 0.001). Serum concentrations of both IL 1-beta (R value: -0.624; P < 0.001) and IL-6 (R value: -0.642; P < 0.001) were inversely correlated to the serum concentrations of selenium. There was a meaningful difference between two groups in airway resistance and pulmonary compliance changes (P values 0.008 and 0.028, respectively). CONCLUSION: Selenium restored the antioxidant capacity of the lungs, moderated the inflammatory responses, and meaningfully improved the respiratory mechanics. Despite these changes, it had no effect on the overall survival, the duration of mechanical ventilation, and ICU stay. Selenium can be used safely; however, more trials are essential to examine its clinical effectiveness.

Alternative and Natural Therapies for Acute Lung Injury and Acute Respiratory Distress Syndrome.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a complex clinical syndrome characterized by acute inflammation, microvascular damage, and increased pulmonary vascular and epithelial permeability, frequently resulting in acute respiratory failure and death. Current best practice for ARDS involves "lung-protective ventilation," which entails low tidal volumes and limiting the plateau pressures in mechanically ventilated patients. Although considerable progress has been made in understanding the pathogenesis of ARDS, little progress has been made in the development of specific therapies to combat injury and inflammation. AREAS COVERED: In recent years, several natural products have been studied in experimental models and have been shown to inhibit multiple inflammatory pathways associated with acute lung injury and ARDS at a molecular level. Because of the pleiotropic effects of these agents, many of them also activate antioxidant pathways through nuclear factor erythroid-related factor 2, thereby targeting multiple pathways. Several of these agents are prescribed for treatment of inflammatory conditions in the Asian subcontinent and have shown to be relatively safe. EXPERT COMMENTARY: Here we review natural remedies shown to attenuate lung injury and inflammation in experimental models. Translational human studies in patients with ARDS may facilitate treatment of this devastating disease.

Timing of valproic acid in acute lung injury: prevention is the best therapy?

BACKGROUND: Acute lung injury and respiratory distress syndrome is characterized by uncontrolled inflammation of the lungs after a severe inflammatory stimulus. We have previously demonstrated an ameliorated syndrome and improved survival in mice with early administration of valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, while studies in humans have shown no benefit when anti-inflammatories are administered late. The current study tested the hypothesis that early treatment would improve outcomes in our gram-negative pneumonia-induced acute lung injury. MATERIALS AND METHODS: Mice (C57BL/6) had 50 × 106 Escherichia coli (strain 19,138) instilled endotracheally and VPA (250 mg/kg) administered intraperitoneally 3, 4, 6, and 9 h (n = 12/group) later. Six hours after VPA administration, the animals were sacrificed, and bronchoalveolar lavage (BAL) fluid interleukin-6 (IL-6), tumor necrosis factor, neutrophils and macrophages as well as the E coli colony-forming units were quantified. Plasma IL-6 was also measured. A separate group of mice (n = 12/group) were followed prospectively for 7 days to assess survival. RESULTS: BAL IL-6 and tumor necrosis factor as well as plasma IL-6 were significantly lower in the animals administered VPA within 3 h (P < 0.05) but not when administered later (4, 6, 9 h). There was no difference in the BAL E coli colony-forming units, macrophage, or neutrophil numbers at any time point. Survival improved only when VPA was administered within 3 h. CONCLUSIONS: A narrow therapeutic window exists in this murine model of gram-negative pneumonia-induced acute lung injury and likely explains the lack of response in studies with late administration of anti-inflammatory therapies in clinical studies.

The Protective Effects of HJB-1, a Derivative of 17-Hydroxy-Jolkinolide B, on LPS-Induced Acute Distress Respiratory Syndrome Mice.

Acute respiratory distress syndrome (ARDS),which is inflammatory disorder of the lung, which is caused by pneumonia, aspiration of gastric contents, trauma and sepsis, results in widespread lung inflammation and increased pulmonary vascular permeability. Its pathogenesis is complicated and the mortality is high. Thus, there is a tremendous need for new therapies. We have reported that HJB-1, a 17-hydroxy-jolkinolide B derivative, exhibited strong anti-inflammatory effects in vitro. In this study, we investigated its impacts on LPS-induced ARDS mice. We found that HJB-1 significantly alleviated LPS-induced pulmonary histological alterations, inflammatory cells infiltration, lung edema, as well as the generation of inflammatory cytokines TNF-α, IL-1ß and IL-6 in BALF. In addition, HJB-1 markedly suppressed LPS-induced IκB-α degradation, nuclear accumulation of NF-κB p65 subunit and MAPK phosphorylation. These results suggested that HJB-1 improved LPS-induced ARDS by suppressing LPS-induced NF-κB and MAPK activation.

The Role of Omega-3 Polyunsaturated Fatty Acids in the Treatment of Patients with Acute Respiratory Distress Syndrome: A Clinical Review.

Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process. Recent report on the prognostic value of eicosanoids in patients with ARDS suggests that modulating the inflammatory response through the use of polyunsaturated fatty acids may be a useful strategy for ARDS treatment. The use of enteral diets enriched with eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) has reported promising results, showing an improvement in respiratory variables and haemodynamics. However, the interpretation of the studies is limited by their heterogeneity and methodology and the effect of ω-3 fatty acid-enriched lipid emulsion or enteral diets on patients with ARDS remains unclear. Therefore, the routine use of ω-3 fatty acid-enriched nutrition cannot be recommended and further large, homogeneous, and high-quality clinical trials need to be conducted to clarify the effectiveness of ω-3 polyunsaturated fatty acids.

The Omega-3 Fatty Acid Docosahexaenoic Acid Modulates Inflammatory Mediator Release in Human Alveolar Cells Exposed to Bronchoalveolar Lavage Fluid of ARDS Patients.

BACKGROUND: This study investigated whether the 1 : 2 ω-3/ω-6 ratio may reduce proinflammatory response in human alveolar cells (A549) exposed to an ex vivo inflammatory stimulus (bronchoalveolar lavage fluid (BALF) of acute respiratory distress syndrome (ARDS) patients). Methods. We exposed A549 cells to the BALF collected from 12 ARDS patients. After 18 hours, fatty acids (FA) were added as docosahexaenoic acid (DHA, ω-3) and arachidonic acid (AA, ω-6) in two ratios (1 : 2 or 1 : 7). 24 hours later, in culture supernatants were evaluated cytokines (TNF-α, IL-6, IL-8, and IL-10) and prostaglandins (PGE2 and PGE3) release. The FA percentage content in A549 membrane phospholipids, content of COX-2, level of PPARγ, and NF-κB binding activity were determined. RESULTS: The 1 : 2 DHA/AA ratio reversed the baseline predominance of ω-6 over ω-3 in the cell membranes (P < 0.001). The proinflammatory cytokine release was reduced by the 1 : 2 ratio (P < 0.01 to <0.001) but was increased by the 1 : 7 ratio (P < 0.01). The 1 : 2 ratio reduced COX-2 and PGE2 (P < 0.001) as well as NF-κB translocation into the nucleus (P < 0.01), while it increased activation of PPARγ and IL-10 release (P < 0.001). Conclusion. This study demonstrated that shifting the FA supply from ω-6 to ω-3 decreased proinflammatory mediator release in human alveolar cells exposed to BALF of ARDS patients.

Embelia ribes ameliorates lipopolysaccharide-induced acute respiratory distress syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Embelia ribes Burm. f. (Fam. Myrsinaceae) locally known as Vidanga have been used for treating tumors, ascites, bronchitis, jaundice, diseases of the heart and brain in traditional Indian medicine. However, no scientific studies providing new insights in its pharmacological properties with respect to acute respiratory distress syndrome have been investigated. AIM: The present investigation aimed to elucidate the effectiveness of Embelin isolated from Embelia ribes seeds on attenuation of LPS-induced acute respiratory distress syndrome in murine models. METHODS: Embelin (5, 10 and 20 mg/kg/day, i.p.) and Roflumilast (1 mg/kg/day, p.o.) were administered for four days and prior to LPS in rats (i.t.). Four hour after LPS challenge animals were anesthesized and bronchoalveolar lavage was done with ice-cold phosphate buffer. Assessment of BAL fluid was done for albumin, total protein, total cell and neutrophil count, TNF-α levels, nitrosoative stress. Superior lobe of right lung was used for histopathologic evaluation. Inferior lobe of right lung was used to obtain lung edema. Left lung was used for myeloperoxidase estimation. Arterial blood was collected immediately and analyzed for pH, pO2 and pCO2 were estimated. RESULTS: Pretreatment with embelin (5, 10 and 20 mg/kg, i.p.) decreased lung edema, mononucleated cellular infiltration, nitrate/nitrite, total protein, albumin concentrations, TNF-α in the bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenate. Embelin markedly prevented pO2 down-regulation and pCO2 augmentation. Additionally, it attenuated lung histopathological changes in acute respiratory distress syndrome model. CONCLUSION: The study demonstrates the effectiveness of Embelia ribes Burm. f. (Fam. Myrsinaceae) seeds in acute respiratory distress syndrome possibly related to its anti-inflammatory and protective effect against LPS induced airway inflammation by reducing nitrosative stress, reducing physiological parameters of blood gas change, TNF-α and mononucleated cellular infiltration indicating it as a potential therapeutic agent for acute respiratory distress syndrome.

Heat stress-induced disruption of endothelial barrier function is via PAR1 signaling and suppressed by Xuebijing injection.

Increased vascular permeability leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is central to the pathogenesis of heatstroke. Protease-activated receptor 1 (PAR1), the receptor for thrombin, plays a key role in disruption of endothelial barrier function in response to extracellular stimuli. However, the role of PAR1 in heat stress-induced endothelial hyper-permeability is unknown. In this study, we measured PAR1 protein expression in heat-stressed human umbilical venous endothelial cells (HUVECs), investigated the influences of PAR1 on endothelial permeability, F-actin rearrangement, and moesin phosphorylation by inhibiting PAR1 with its siRNA, neutralizing antibody (anti-PAR1), specific inhibitor(RWJ56110), and Xuebijing injection (XBJ), a traditional Chinese medicine used for sepsis treatment, and evaluated the role of PAR1 in heatstroke-related ALI/ARDS in mice by suppressing PAR1 with RWJ56110, anti-PAR1and XBJ. We found that heat stress induced PAR1 protein expression 2h after heat stress in endothelial cells, caused the release of endothelial matrix metalloprotease 1, an activator of PAR1, after 60 or 120 min of heat stimulation, as well as promoted endothelial hyper-permeability and F-actin rearrangement, which were inhibited by suppressing PAR1 with RWJ56110, anti-PAR1 and siRNA. PAR1 mediated moesin phosphorylation, which caused F-actin rearrangement and disruption of endothelial barrier function. To corroborate findings from in vitro experiments, we found that RWJ56110 and the anti-PAR1 significantly decreased lung edema, pulmonary microvascular permeability, protein exudation, and leukocytes infiltrations in heatstroke mice. Additionally, XBJ was found to suppress PAR1-moesin signal pathway and confer protective effects on maintaining endothelial barrier function both in vitro and in vivo heat-stressed model, similar to those observed above with the inhibition of PAR1. These results suggest that PAR1 is a potential therapeutic target in heatstroke.

Evaluation of lung and bronchoalveolar lavage fluid oxidative stress indices for assessing the preventing effects of safranal on respiratory distress in diabetic rats.

We investigated the effects of antioxidant activity of safranal, a constituent of Crocus sativus L., against lung oxidative damage in diabetic rats. The rats were divided into the following groups of 8 animals each: control, diabetic, and three diabetic + safranal-treated (0.25, 0.50, and 0.75 mg/kg/day) groups. Streptozotocin (STZ) was injected intraperitoneally (i.p.) at a single dose of 60 mg/kg for diabetes induction. Safranal was administered (i.p.) from 3 days after STZ administration to the end of the study. At the end of the 4-week period, malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) contents, activity of superoxide dismutase (SOD), and catalase (CAT) were measured in the bronchoalveolar lavage fluid (BALF) and lung tissue. Safranal in the diabetic groups inhibited the level of MDA and NO in BALF supernatant and lung homogenate. The median effective dose (ED50) values were 0.42, 0.58, and 0.48, 0.71 mg/kg, respectively. Safranal in the diabetic groups increased the level of GSH and the activity of CAT and SOD in BALF supernatant and lung homogenate. The ED50 values were 0.25, 0.33, 0.26 in BALF and 0.33, 0.35, 0.46 mg/kg in lung, respectively. Thus, safranal may be effective to prevent lung distress by amelioration oxidative damage in STZ diabetic rats.

[Effects of xuebijing on nitric oxide and VEGF-A in exhaled breath condensate of patients with ALI/ARDS].

OBJECTIVE: To observe the clinical significance of changes of nitric oxide (NO) and vascular endothelial growth factor A (VEGF-A) in exhaled breath condensate (EBC) of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) after they were treated by Xuebijing (XBJ), and to evaluate the effect of the EBC detection technology. METHODS: Totally 32 ALI/ARDS patients receiving mechanical ventilation at intensive care unit (ICU) were randomly assigned to the treatment group and the control group, 16 cases in each group. Patients in the control group were treated by routine therapy, while those in the treatment group were treated by routine therapy + XBJ. The therapeutic course for all was 5 days. The EBC sample was collected by improved EcoScreen condenser within 24 h after confirmed diagnosis of ALI/ARDS and on the fifth day of medication. The levels of NO and VEGF-A were measured by EIA in EBC and serum. The changes of NO and VEGF-A in EBC were observed before and after treatment. RESULTS: Compared with before treatment, the level of NO in EBC and serum decreased and VEGF-A increased after treatment, showing statistical difference (P < 0.05, P < 0.01). After treatment the level of NO in EBC and serum was lower in the treatment group than in the control group (P < 0.05). The VEGF-A in EBC was higher in the treatment group than in the control group (P < 0.05). There was no statistical difference in the serum VEGF-A level between the two groups (P > 0.05). CONCLUSIONS: XBJ was an effective therapeutic drug capable to control the in vivo inflammation reaction in patients with ALI/ARDS. The detection of changes of VEGF-A and NO levels by EBC could judge the inflammatory reaction degree in ALI/ARDS patients, and help evaluating the therapeutic effect.