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Background: Severe acute lung failure (ALF) often necessitates veno-venous extracorporeal membrane oxygenation (VV-ECMO), where identifying predictors of weaning success and mortality remains crucial yet challenging. The study aims to identify predictors of weaning success and mortality in adults undergoing VV-ECMO for severe ALF, a gap in current clinical knowledge., Methods and Analysis: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials will be searched for cohort studies examining the predictive factors of successful weaning and mortality in adult patients on VV-ECMO due to severe ALF. Risk of bias assessment will be conducted using the Newcastle-Ottawa scale for each included study. The primary outcomes will be successful weaning from VV-ECMO and all-cause mortality. Between-study heterogeneity will be evaluated using the I2 statistic. Sensitivity, subgroup, and meta-regression analyses will be performed to ascertain potential sources of heterogeneity and assess the robustness of our results. We will use the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool to recommend the level of evidence., Discussion: This study seeks to provide clinically significant insights into predictors for weaning and mortality during VV-ECMO treatment for ALF, aiming to support clinical decisions and potentially influence health policy, thereby improving patient outcomes., Ethics and Dissemination: Given the absence of direct engagement with human subjects or access to personal medical records, ethical approval for this study is deemed unnecessary. The study findings will be shared at a scientific conference either at the global or national level. Alternatively, the results will be presented for publication in a rigorously peer-reviewed journal regarding critical care medicine., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ning et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: High-flow nasal cannula (HFNC) has emerged as a promising noninvasive method for delivering oxygen to critically ill patients, particularly those with sepsis and acute lung injury. However, uncertainties persist regarding its therapeutic benefits in this specific patient population., Methods: This retrospective study utilized a propensity score-matched cohort from the Medical Information Mart in Intensive Care-IV (MIMIC-IV) database to explore the correlation between HFNC utilization and mortality in patients with sepsis-induced acute lung injury. The primary outcome was 28-day all-cause mortality., Results: In the propensity score-matched cohort, the 28-day all-cause mortality rate was 18.63% (95 out of 510) in the HFNC use group, compared to 31.18% (159 out of 510) in the non-HFNC group. The use of HFNC was associated with a lower 28-day all-cause mortality rate (hazard ratio [HR] = 0.53; 95% confidence interval [CI] = 0.41-0.69; P < 0.001). HFNC use was also associated with lower ICU mortality (odds ratio [OR] = 0.52; 95% CI = 0.38-0.71; P < 0.001) and lower in-hospital mortality (OR = 0.51; 95% CI = 0.38-0.68; P < 0.001). Additionally, HFNC use was found to be associated with a statistically significant increase in both the ICU and overall hospitalization length., Conclusions: These findings indicate that HFNC may be beneficial for reducing mortality rates among sepsis-induced acute lung injury patients; however, it is also associated with longer hospital stays., (© 2024. The Author(s).)

Salbutamol, which consists of an R-isomer and S-isomer, is an effective and widely used β 2 adrenoreceptor agonist that may possess anti-inflammatory properties in addition to its bronchodilator activity. Whether the salbutamol R-isomer has advantages over its racemic mixture and effectiveness in treating endotoxemia and endotoxin-induced lung injury has not been well studied. In this study, we investigated the preventive and therapeutic effects of R-salbutamol (R-sal), S-salbutamol (S-sal), and their racemic mixture (Rac-sal) on a mouse model of lipopolysaccharide (LPS)-induced endotoxemia. Dexamethasone (Dex) was used for comparison. The results showed that R-sal markedly improved the 7-day survival rate of endotoxic mice when administered before and after LPS treatment. Dex was toxic and accelerated the death of endotoxic mice when administered before LPS injection. Histological examination of the lungs revealed that the LPS challenge resulted in acute lung damage, including inflammatory cell infiltration, thickened alveolar septa, and congestion. R-sal pre-treatment effectively inhibited these changes, accompanied by markedly reduced lung myeloperoxidase levels, serum cytokine levels, and lactate release, significant restoration of lymphocyte count, and reduction of monocyte count. This may have occurred through inhibition of M1 macrophage inflammatory responses by enhancement of β-arrestin2 expression and suppression of NF-κB activation. Rac-sal exhibited diminished effects compared to that of R-sal, while S-sal showed enhanced release of some inflammatory cytokines. In addition, R-sal pre-treatment showed a better improvement in prognostic pulmonary function on day 4 compared to that by Rac-sal. Collectively, our results indicate the potential benefits of R-sal in regulating inflammatory responses to endotoxemia and endotoxin-induced lung injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To explore the regulation of endogenous sulfur dioxide on oxidative stress in lung injury induced by sepsis., Method: Forty male Sprague Dawley rats were divided into control, sepsis, sepsis + SO 2 , and SO 2 group randomly used to observe survival rate. The other group of twenty-eight rats were randomly divided as the same manner for mechanism research. The number of WBCS and the percentage of PMN cells were calculated. The microphotographs of morphological changes and the index of quantitative assessment (IQA) of lung tissues were calculated. The ratio of wet/dry (W/D) of lung tissues was calculated. Levels of H 2 O 2 , MDA, NO, MPO, SOD, GSH-px, and TNF- α in plasma and lung tissues were measured., Result: The number of WBCS and the percentage of PMN cells decreased in sepsis ( p all < 0.05), and rebound in sepsis+SO 2 ( p all < 0.05). The IQA and W/D of lung tissues increased in sepsis ( p for W / D < 0.05), and decreased in sepsis+SO 2 ( p all < 0.05). H 2 O 2 and MDA of plasma and lung tissues increased in sepsis ( p all < 0.05) and rebound in sepsis+SO 2 ( p for H 2 O 2 of plasma and lung tissues <0.05). NO and MPO of plasma and lung tissues increased in sepsis ( p for NO and MPO of lung tissues <0.05) and rebound in sepsis+SO 2 ( p  all < 0.05). SOD of plasma and lung tissues in sepsis group decreased ( p all <0.05) and increased in sepsis+SO 2 ( p all < 0.05). GSH-px of plasma and lung tissues decreased in sepsis ( p for plasma <0.05) and increased in sepsis+SO 2 ( p for GSH-px of lung tissues <0.05). TNF- α of plasma and lung tissues increased in sepsis ( p all<0.05) and decreased in sepsis+SO 2 ( p for lung tissue <0.05)., Conclusion: Endogenous sulfur dioxide improves the survival rate of sepsis by improving the oxidative stress response during lung injury., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Zhiwei Liu et al.)

Objective: Ginsenoside Rd (GSRd) displays a variety of pharmacological effects. However, the underlying role in acute lung injury (ALI) is not clear. In this study, the protective effect of GSRd on lipopolysaccharide (LPS)-induced ALI is investigated to explore the potential mechanisms., Methods: GSRd-target-ALI-related gene set was constructed. And bioinformatics tools were used to discover the potential mechanism. We observed the survival of subjects for 72 h. In addition, male BALB/c mice were intraperitoneal injected with GSRd (25 and 50 mg/kg) after received one intratracheal instillation of LPS. Inflammatory changes, oxidative stress, and phosphorylation were assessed to study the biological effects., Results: A total of 245 interaction genes were collected. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were enriched in immune-inflammatory system. Among them, PI3K-Akt signaling pathway was the highest-ranked pathway of inflammatory response. In vivo study, it was found that GSRd improved survival in endotoxemic mice and inhibited the major characteristic of ALI. And the p-PI3K and p-Akt expression was significantly decreased by GSRd treatment., Conclusion: GSRd could protect mice against LPS-induced ALI effectively by inhibiting the PI3K-Akt signaling pathway., Competing Interests: None of the authors have any conflicts of interest to declare., (Copyright © 2021 by the Shock Society.)

Objective: To evaluate the value of pulmonary bedside ultrasound system in the assessment of severity and prognosis of acute lung injury (ALI)., Method: Seventy-two ALI patients in the intensive care unit (ICU) of our hospital from April 2019 to April 2021 were selected as subjects. The changes of lung ultrasound score (LUS) and parameters at D1, D2, and D3 after admission were analyzed (LUS, oxygenation index (PaO 2 /FiO 2 ), Acute Physiology and Chronic Health Evaluation II (APACHE-II), and Sequential Organ Failure Assessment (SOFA) score). Pearson correlation analysis was used to assess the relationship between LUS and PaO 2 /FiO 2 , APACHE-II score, and SOFA score at D1, D2, and D3. Logistic regression analysis was used for influencing factors for the prognosis of ALI patients. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of baseline LUS, PaO 2 /FiO 2 , APACHE-II score, and SOFA score for the prognosis of ALI patients., Result: LUSs at D1, D2 and D3 showed an increasing trend with the increase of disease severity ( P < 0.05). From D1 to D3, LUS, PaO 2 /FiO 2 , APACHE-II score, and SOFA score showed a downward trend ( P < 0.05). LUS was negatively correlated with PaO 2 /FiO 2 at D1, D2, and D3 but positively correlated with APACHE-II score and SOFA score ( P < 0.05). Logistic regression analysis showed that after controlling for age, PaO 2 and PaCO 2 , an increase in baseline LUS, APACHE-II score, SOFA score, and a decrease in PaO 2 /FiO 2 were independent risk factors for death at 28 d in ALI patients ( P < 0.05). ROC curve showed that LUS, PaO 2 /FiO 2 , APACHE-II score, and SOFA score were combined to predict the prognosis of ALI patients with the highest AUC value of 0.920, corresponding sensitivity of 88.89%, and specificity of 95.56%., Conclusion: LUS can evaluate the change of pulmonary ventilation area in ALI patients, further evaluate the severity of the disease, and effectively predict the prognosis of patients., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Lei Li et al.)

Acute lung injury (ALI) has been known to be a devastating form of respiratory infection and an important contributor to mortality in intensive care, due to its lacking of effective treatment. Inflammation, oxidative stress, and pyroptosis are associated with multiple kinds of inflammatory diseases such as ALI. It is commonly accepted that Gly-Pro-Ala (GPA) peptide regulates oxidative stress and pyroptosis in different kinds of inflammatory diseases. Our study is aimed at exploring the regulatory function and protective effects of GPA peptides on ALI. In the current study, the cecal ligation and puncture (CLP) technique was used to evoke sepsis in mice, and GPA peptide was administered intraperitoneally with different concentrations (50, 100, and 150 mg/kg) after CLP. Histopathological changes and the ratio of wet-to-dry in lung were recorded and analyzed. We also investigated the level of oxidative stress, inflammation, and pyroptosis. Results showed that GPA peptide significantly ameliorated CLP-stimulated lung tissue injury, impeded proinflammatory cytokine release, and reduced inflammatory cell infiltration. Additionally, GPA peptide suppressed oxidative stress and caspase-1-dependent pyroptosis in alveolar macrophages. Furthermore, our study showed that the GPA peptide prevents alveolar macrophage from undergoing pyroptosis by attenuating ROS. In conclusion, results demonstrated that GPA peptide has protective effects in CLP-stimulated ALI by inhibiting oxidative stress as well as pyroptosis of alveolar macrophage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Yukun Liu et al.)

Objectives: Acute lung injury (ALI) not only affects pulmonary function but also leads to intestinal dysfunction, which in turn contributes to ALI. Mesenchymal stem cell (MSC) transplantation can be a potential strategy in the treatment of ALI. However, the mechanisms of synergistic regulatory effects by MSCs on the lung and intestine in ALI need more in-depth study., Materials and Methods: We evaluated the therapeutic effects of MSCs on the murine model of lipopolysaccharide (LPS)-induced ALI through survival rate, histopathology and bronchoalveolar lavage fluid. Metagenomic sequencing was performed to assess the gut microbiota. The levels of pulmonary and intestinal inflammation and immune response were assessed by analysing cytokine expression and flow cytometry., Results: Mesenchymal stem cells significantly improved the survival rate of mice with ALI, alleviated histopathological lung damage, improved intestinal barrier integrity, and reduced the levels of inflammatory cytokines in the lung and gut. Furthermore, MSCs inhibited the inflammatory response by decreasing the infiltration of CD8 + T cells in both small-intestinal lymphocytes and Peyer's patches. The gut bacterial community diversity was significantly altered by MSC transplantation. Furthermore, depletion of intestinal bacterial communities with antibiotics resulted in more severe lung and gut damages and mortality, while MSCs significantly alleviated lung injury due to their immunosuppressive effect., Conclusions: The present research indicates that MSCs attenuate lung and gut injury partly via regulation of the immune response in the lungs and intestines and gut microbiota, providing new insights into the mechanisms underlying the therapeutic effects of MSC treatment for LPS-induced ALI., (© 2021 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.)

Fructooligosaccharide was isolated from Polygonatum Cyrtonema Hua (PFOS) for the first time. Structure characterized using FT-IR, MALDI-TOF-MS, NMR, AFM, and TEM, indicated that PFOS was graminan-type fructan with a degree of polymerization ranging from 5 to 10. A murine model of lipopolysaccharide (LPS)-induced peritonitis was used to evaluate the in vivo anti-inflammatory and lung protective efficacy of PFOS. The result shown that pretreatment with PFOS (1.0 mg/mL) in peritonitis-induced mice could significantly inhibit the level of pro-inflammatory cytokines (TNF-α, IL-1β) in serum (P < 0.001), increase mice survival rate from 12.5 % to 54 % (P < 0.05), and alleviated lung injury through ameliorating the damage of the pulmonary cellular architecture and reducing inflammatory monocyte accumulation in lung tissue. This effect of oligosaccharides could explain the traditional usage of P. cyrtonema as a tonic medicine for respiratory problems and it could be used as a potential natural ingredient with anti-inflammatory activity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation. Circulating mtDNA released causes lung injury in experimental models. We hypothesized that elevated plasma mtDNA levels are associated with acute lung injury (ALI) in septic patients., Methods: We enrolled 66 patients with sepsis admitted to the Department of Critical Care Medicine of Peking Union Medical College Hospital between January 2019 and October 2019. Respiratory, hemodynamic and bedside echocardiographic parameters were recorded. Plasma mtDNA, procalcitonin, interleukin 6, and interleukin 8 levels were examined., Results: Plasma mtDNA levels within 24 h after admission were significantly increased in the group of septic patients with ALI [5.01 (3.38-6.64) vs 4.13 (3.20-5.07) log copies/µL, p 0.0172]. mtDNA levels were independently associated with mortality (hazard ratio, 3.2052; 95% CI 1.1608-8.8500; p 0.0253) and ALI risk (odds ratio 2.7506; 95% CI 1.1647-6.4959; p 0.0210). Patients with high mtDNA levels had worse outcomes, and post hoc tests showed significant differences in 28-day survival rates. Increased mtDNA levels were seen in patients with abdominal infection., Conclusions: Increased plasma mtDNA levels within 24 h after admission were significantly associated with ALI incidence and mortality in septic patients.

Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Smoke inhalation injury increases morbidity and mortality. Clinically relevant animal models are necessary for the continued investigation of the pathophysiology of inhalation injury and the development of therapeutics. The goal of our research was threefold: 1 ) to develop a reproducible survival model of smoke inhalation injury in rats that closely resembled our previous mouse model, 2 ) to validate the rat smoke inhalation injury model using a variety of laboratory techniques, and 3 ) to compare and contrast our rat model with both the well-established mouse model and previously published rat models to highlight our improvements on smoke delivery and lung injury. Mice and rats were anesthetized, intubated, and placed in custom-built smoke chambers to passively inhale woodchip-generated smoke. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for confirmatory tests. Lung sections were hematoxylin and eosin stained, lung edema was assessed with wet-to-dry (W/D) ratio, and inflammatory cell infiltration and cytokine elevation were evaluated using flow cytometry, immunohistochemistry, and ELISA. We confirmed that our mouse and rat models of smoke inhalation injury mimic the injury seen after human burn inhalation injury with evidence of pulmonary edema, neutrophil infiltration, and inflammatory cytokine elevation. Interestingly, rats mounted a more severe immunological response compared with mice. In summary, we successfully validated a reliable and clinically translatable survival model of lung injury and immune response in rats and mice and characterized the extent of this injury. These animal models allow for the continued study of smoke inhalation pathophysiology to ultimately develop a better therapeutic.

Background: In humans, respiratory complications in patients with acute pancreatitis (AP) are a common life-threatening comorbidity. Since possible lung impairment has not been individually evaluated in canine AP, the aims of the present study were to: (1) describe the prevalence, types and severity of pulmonary complications in dogs with acute presentation of AP, and (2) evaluate their association with mortality. AP diagnosis was based on compatible clinical and laboratory parameters, abnormal canine pancreatic-lipase test, and positive abdominal ultrasound within 48 h from admission. The canine acute pancreatitis severity score (CAPS) was calculated for each dog at admission. Arterial blood gas analysis and thoracic radiography were performed at admission. Thoracic radiography was classified on the basis of pulmonary pattern (normal, interstitial or alveolar) and a modified lung injury score (mLIS) was applied to the ventrodorsal projections for each dog. VetALI/VetARDS were diagnosed using current veterinary consensus. Dogs were divided into non-survivors or survivors (hospital discharge). Clinical, radiological and blood gas parameters collected at presentation were compared between survivors and non-survivors and associated with mortality., Results: This prospective cohort study included twenty-six client-owned dogs with AP. Twelve out of twenty-six dogs (46%) died or were euthanized. At admission, thirteen dogs showed respiratory distress at physical examination, which was associated with death (P < 0.001). Radiographic abnormalities were found in twenty-one dogs: alveolar (n = 11) and interstitial pattern (n = 10). Radiographic alterations and mLIS score were both associated with death (P = 0.02 and P = 0.0023). The results of the arterial blood-gas evaluation showed that non-survivors had lower PaCO 2 and HCO 3 - levels, and higher A-a gradient than survivors (P = 0.0014, P = 0.019 and P = 0.004, respectively). Specifically, three dogs had aspiration pneumonia, and VetALI was diagnosed in nine dogs (34.6%), and no dogs met the criteria for VetARDS. The presence of VetALI was associated with mortality (P < 0.001)., Conclusions: As with humans, possible lung impairments, such as VetALI, should be investigated in dogs with acute presentation of pancreatitis.

Background: Therapeutic extracorporeal membrane oxygenation (ECMO) is a challenging procedure in patients who have experienced severe trauma. Particularly, patients with traumatic lung injury and posttraumatic acute respiratory distress syndrome (ARDS) have a high risk of bleeding during this procedure. This study aimed to determine the safety and feasibility of ECMO in patients with traumatic ARDS., Methods: We retrospectively reviewed medical records and investigated the clinical outcomes of ECMO in 42 patients with traumatic ARDS, among whom near-drowning (42.9%) was the most frequent cause of injury., Results: Thirty-four of 42 patients (81%) survived and were discharged after a median hospital stay of 23 days. A multivariate analysis identified a lactate level (odds ratio: 1.493, 95% confidence interval: 1.060-2.103, P = 0.022) and veno-venous (VV) ECMO (odds ratio: 0.075, 95% confidence interval: 0.006-0.901, P = 0.041) as favorable independent predictors of survival in patients with traumatic ARDS who underwent ECMO. The optimal cut off value for pre-ECMO lactate level was 10.5 mmol/L (area under the curve = 0.929, P = 0.001). In Kaplan-Meier analysis, the survival rate at hospital discharge was significant higher among the patients with a pre-ECMO lactate level of 10.5 mmol/L or less compared with patients with pre-ECMO lactate level greater than 10.5 mmol/L (93.8% versus 40.0%, respectively; P = 0.01)., Conclusions: ECMO yielded excellent survival outcomes, particularly in patients with low pre-treatment lactate levels who received VV ECMO. Therefore, ECMO appears safe and highly feasible in a carefully selected population of trauma patients.

The purpose of this study was to investigate whether pituitary adenylate cyclase-activating polypeptide (PACAP) prevents mortality due to sepsis in mice. Mice were given PACAP at designated time points before or after cecal ligation and puncture (CLP), and organ injury and mortality were investigated. Serum inflammatory and anti-inflammatory cytokine levels were assessed after CLP. Plasma corticosterone and adrenocorticotropic hormone levels were also measured. Isolated tissue macrophages (Mfs) were incubated with or without PACAP, and production of cytokines was measured. Activation of NF-κB was investigated in tissue Mfs isolated from CLP animal in the presence and absence PACAP in vitro. PACAP treatment significantly prevented acute lung injury and mortality after CLP. Plasma endotoxin levels and bacterial load were not different between PACAP-treated and nontreated groups. Increased serum TNF-α and HMGB1 levels in animals treated with vehicle were significantly blunted in PACAP-treated animals after CLP. Furthermore, serum IL-10 levels were significantly greater in the PACAP-treated group compared with the vehicle group. Production of HMGB1 and TNF-α by isolated hepatic Mfs was significantly inhibited in the presence of PACAP, whereas production of IL-10 by isolated hepatic Mfs and interstitial lung Mfs was significantly increased. Plasma corticosterone and adrenocorticotropic hormone levels were significantly greater in the animals treated with PACAP compared with vehicle after CLP. Activation of NF-κB was significantly inhibited by PACAP in the hepatic Mfs compared with other tissue Mfs. PACAP prevents mortality due to septic peritonitis by inhibiting inflammation via NF-κB activation and possible effects on the brain., (Copyright © 2020 The Authors.)

Acute lung injury (ALI) is a life-threatening condition caused by severe inflammation of lung tissues. We hypothesized that lipopolysaccharide induced acute lung inflammation and injury in mice might be controlled by lonicerin (LCR), a plant flavonoid that impacts immunity, oxidative stress, and cell proliferation. LCR reduced pathological changes including pulmonary edema, elevation of protein in bronchoalveolar lavage, inflammation, pro-inflammatory gene expression, expression of toll-like receptor 4/nuclear factor-kappa B, apoptosis, and significantly reduced mortality. Together, the results suggest that LCR might be a potential and effective candidate for the treatment of ALI that acts by inhibiting inflammation and apoptosis.

Oxytocin (OT) has been reported to have a protective effect in lipopolysaccharide-induced experimental acute lung injury (ALI). However, its role in heat stroke-related ALI has never been investigated. Herein, we aimed to explore the therapeutic effects and potential mechanism of action of OT on heat-induced ALI. Rats were treated with OT 60 min before the start of heat stress (42 °C for 80 min). Twenty minutes after the termination of heat stress, the effects of OT on lung histopathological changes, edema, acute pleurisy and the bronchoalveolar fluid levels of inflammatory cytokines and indicators of ischemia, cellular damage, and oxidative damage were assessed. We also evaluated the influence of OT pretreatment on heat-induced hypotension, hyperthermia, ALI score, and death in a rat model of heat stroke. The results showed that OT significantly reduced heat-induced lung edema, neutrophil infiltration, hemorrhage score, myeloperoxidase activity, ischemia, and the levels of inflammatory and oxidative damage markers in bronchoalveolar lavage fluid. The survival assessment confirmed the pathophysiological and biochemical results. An OT receptor antagonist (L-368,899) was administered 10 min before the OT injection to further demonstrate the role of OT in heat-induced ALI. The results showed that OT could not protect against the aforementioned heat stroke responses in rats treated with L-368,899. Interestingly, OT treatment 80 min after the start of heat shock did not affect survival. In conclusion, our data indicate that OT pretreatment can reduce the ischemic, inflammatory and oxidative responses related to heat-induced ALI in rats.

The oleic acid (OA) models of lung injury try to simulate the findings of human Acute Respiratory Distress Syndrome (ARDS). However, these models are difficult to replicate because they vary in terms of animals species, OA doses, time for establishment of lung injury, different observation periods and settings of mechanical ventilation. The objective of this study was to evaluate a protocol of administration of OA in lung injury model, challenges in its development and its effects on respiratory mechanics, hemodynamic changes, histology, gas exchange and mortality. We then submitted ten Large White pigs to acute lung injury through intravenous infusion of acid oleic in the pulmonary artery. The mortality of the model was 50%, due to an intense hemodynamic instability during OA administration, even with early use of vasoactive drugs. Three animals required additional doses of OA to achieve criteria for acute lung injury. Histology showed findings consistent with acute lung injury. However, more pulmonary edema was observed in lower segments than in upper segments of both lungs (p = 0.01). IL-6 and IL-8 were significantly increased compared to normal lungs (p < 0.05), and IL-6 showed higher levels in upper segments compared to lower segments (p = 0.03). Positive cells for Caspase 3 were present in all samples, localized mainly in respiratory epithelial cells and macrophages. In conclusion, this model shows histological findings of acute lung injury and inflammatory response similar to those of clinical ARDS, it presents high mortality, inconsistent reproducibility and hardly controlled hemodynamic instability., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

An uncontrolled inflammation induced critical health problems with serious morbidity and death, which namely acute lung injury (ALI). Recently researchs have found the anti-inflammatory effects of emodin. Here, we investigated the potential effects of emodin on a mouse model with a lethal dose of the potential mechanisms and lipopolysaccharide (LPS)-induced inflammatory lung injury in mice. The pulmonary histological abnormalities, the Evans blue's leakage, the myeloperoxidase (MPO) activity, the grades of TNF-α, IL-6, nitric oxide (NO), lactic acid (LA) in lung tissues were determined 18 h post exposure of LPS. Based on the expression of LC3-II with BECN1 was determined using Western blotting. Besides, the LPS-exposed mice for survival rate was monitored. The results indicated that intervention with emodin was important for mitigating LPS-induced pulmonary histological change and LPS-induced leakage of Evans blue, which were associated with suppressed elevation of MPO activity and inhibited up-regulation of TNF-α, IL-6, NO with LA in lung tissues. Moreover, intervention with emodin enhanced the survival rate of LPS-exposed mice. Finally, therapy with emodin increased the LC3 and BECN1 in lungs of LPS-exposed mice. Treatment with 3-MA (the autophagy inhibitor) reversed the beneficial effects of emodin. In conclusion, emodin might provide pharmacological benefits in LPS-induced inflammatory lung injury, and the mechanisms might be related to the restoration of autophagy.

We have previously derived three related peptides, based on a nine-amino acid sequence in human or rat/mouse surfactant protein A, that inhibit the phospholipase A 2 activity of peroxiredoxin 6 (Prdx6) and prevent the activation of lung NADPH oxidase (type 2). The present study evaluated the effect of these Prdx6-inhibitory peptides (PIP) in a mouse (C57Bl/6) model of acute lung injury following lipopolysaccharide (LPS) administration. All three peptides (PIP-1, 2 and 3) similarly inhibited the production of reactive O 2 species (ROS) in isolated mouse lungs as detected by the oxidation of Amplex red. PIP-2 inhibited both the increased phospholipase A 2 activity of Prdx6 and lung reactive oxygen species (ROS) production following treatment of mice with intratracheal LPS (5 µg/g body wt.). Pre-treatment of mice with PIP-2 prevented LPS-mediated lung injury while treatment with PIP-2 at 12 or 16 h after LPS administration led to reversal of lung injury when evaluated 12 or 8 h later, respectively. With a higher dose of LPS (15 µg/g body wt.), mortality was 100% at 48 h in untreated mice but only 28% in mice that were treated at 12-24 h intervals, with PIP-2 beginning at 12 h after LPS administration. Treatment with PIP-2 also markedly decreased mortality after intraperitoneal LPS (15 µg/g body wt.), used as a model of sepsis. This study shows the dramatic effectiveness of a peptide inhibitor of Prdx6 against lung injury and mouse mortality in LPS models. We propose that the PIP nonapeptides may be a useful modality to prevent or to treat human ALI.

Background: The role of pre-existing diabetes in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is still controversial. This systematic review and meta-analysis of observational studies aimed to evaluate the effect of diabetes on the risk and mortality of ALI/ARDS., Methods: A comprehensive literature search was performed in PubMed, Scopus, Cochrane Central Register of Controlled Trails and Web of Science for their inception to September 2018. Summary risk estimates were calculated with a DerSimonian and Laird random-effects model. Heterogeneity was evaluated using Cochran chi-square test and the I statistic., Results: Ultimately, 14 studies with a total of 6613 ALI/ARDS cases were included. The risk of ALI/ARDS was not significantly reduced in diabetes patients (OR 0.82, 95% CI 0.57-1.18, P = .283), with obvious heterogeneity across studies (I = 72.5%, P < .001). Further analyses in the meta-analysis also showed no statistically significant associations between pre-existing diabetes and in-hospital mortality (OR 0.79, 95% CI 0.51-1.21, P = .282) or 60-day mortality of ALI/ARDS (OR 0.91, 95% CI 0.75-1.11, P = .352)., Conclusion: This systematic review and meta-analysis of observational studies indicates that pre-existing diabetes have no effect on the risk and mortality of ALI/ARDS.

Background: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold., Aims: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF., Methods: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A -/- ) mice 21 days after intratracheal administration of bleomycin (BLM)., Results: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A -/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response., Conclusions: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Paediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS., Methods: In this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death., Findings: Between May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14-20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10-15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26-41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16-36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62-0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58-0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58-0·70; p=0·01)., Interpretation: The PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS., Funding: University of Southern California Clinical Translational Science Institute, Sainte Justine Children's Hospital, University of Montreal, Canada, Réseau en Santé Respiratoire du Fonds de Recherche Quebec-Santé, and Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mechanical ventilation (MV) is a life-saving therapy for critically ill patients, alleviating the work of breathing and supporting adequate gas exchange. However, MV can cause ventilator induced lung injury (VILI) by baro/volu- and atelectrauma, even lead to acute respiratory distress syndrome (ARDS), and substantially augment mortality. There is a need for specific biomarkers and novel research platforms for VILI/ARDS research to study these detrimental disorders and seek ways to avoid or prevent them. Previous in vitro studies on bronchial epithelium, cultured in air-liquid interface (ALI) conditions, have generally utilized static or constant pressure.  We have developed a Cyclical Pressure ALI Device (CPAD) that enables cyclical stress on ALI cultured human bronchial cells, with the aim of mimicking the effects of MV. Using CPAD we were able to analyze differentially expressed VILI/ARDS and innate immunity associated genes along with increased expression of associated proteins. CPAD provides an easy and accessible way to analyze functional and phenotypic changes that occur during VILI and may provide a platform for future drug testing.

Critically ill patients have a high risk of sepsis. Various studies have demonstrated that propofol has anti-inflammatory effects that may benefit critically ill patients who require anesthesia. However, the mechanism and therapeutic effect remain incompletely understood. Our previous data suggest that propofol can act as a formyl peptide receptor 1 (FPR1) antagonist. Here, we hypothesize that propofol mitigates sepsis-induced acute lung injury (ALI) by inhibiting mitochondria-derived N-formyl peptide-mediated neutrophil activation. Oxidative stress caused by activated neutrophils is involved in the pathogenesis of ALI. In human neutrophils, propofol competitively reduced the release of superoxide and associated reactive oxygen species induced by fMMYALF, a human mitochondria-derived N-formyl peptide, suggesting that propofol effectively suppresses neutrophilic oxidative stress. In addition, propofol significantly inhibited fMMYALF-induced elastase release, chemotaxis, calcium mobilization, and phosphorylation of protein kinase B and mitogen-activated protein kinases. These results indicate that propofol suppresses neutrophil activation by blocking the interaction between endogenous N-formyl peptide and its receptor, FPR1, thus inhibiting downstream signaling. Furthermore, propofol alleviated alveolar wall disruption, edematous changes, and neutrophil infiltration in lipopolysaccharide-induced ALI in mice. Noticeably, propofol improved the survival of sepsis mice. This study indicates that the anti-neutrophil effects of propofol may benefit critically ill septic patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes., Methods: LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n = 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin., Results: The two-class LCA model best fit the population. Forty percent of the patients were classified as the "hyper-inflammatory" subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo., Conclusions: LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.

Acute liver injury (ALI) is frequently detected in an intensive care unit (ICU) and reportedly affects prognosis. Experimental animal studies suggested that increased extracellular histone and high morbidity group box-1 (HMGB1) levels might contribute to ALI development. Whether these damage-associated molecular patterns (DAMPs) play a crucial role in ALI remains unclear in the human clinical setting.We consecutively enrolled the patients admitted to our ICU. The patients with ALI were included in the analysis together with those without ALI by using frequency matching. Extracellular histone, HMGB1, soluble thrombomodulin (sTM), and interleukin-6 (IL-6) levels were measured in plasma collected at ICU admission. ALI was defined as an acute elevation in serum aminotransferase levels to >200 IU/L.A total of 805 patients were enrolled. Twenty ALI and forty non-ALI patients were analyzed. Plasma histone levels were significantly higher in the ALI group than in the non-ALI group, whereas HMGB1 levels were significantly lower in the ALI group. Furthermore, sTM was significantly increased in the ALI patients, whereas IL-6 levels were comparable between the groups. Multivariate logistic regression analysis demonstrated that histones were independently associated with ALI. There was no significant impact of ALI on in-hospital mortality.Extracellular histones showed an independent association with ALI. Histone elevation might be one of the possible pathogenic mechanisms in the development of ALI of ICU patients.

Background: Acute lung injury (ALI) is characterized by suppressed fibrinolytic activity in bronchoalveolar lavage fluid (BALF) attributed to elevated plasminogen activator inhibitor-1 (PAI-1). Restoring pulmonary fibrinolysis by delivering tissue-type plasminogen activator (tPA), urokinase plasminogen activator (uPA), and plasmin could be a promising approach., Objectives: To systematically analyze the overall benefit of fibrinolytic therapy for ALI reported in preclinical studies., Methods: We searched PubMed, Embase, Web of Science, and CNKI Chinese databases, and analyzed data retrieved from 22 studies for the beneficial effects of fibrinolytics on animal models of ALI., Results: Both large and small animals were used with five routes for delivering tPA, uPA, and plasmin. Fibrinolytics significantly increased the fibrinolytic activity both in the plasma and BALF. Fibrin degradation products in BALF had a net increase of 408.41 ng/ml vs controls ( P  < 0.00001). In addition, plasma thrombin-antithrombin complexes increased 1.59 ng/ml over controls ( P  = 0.0001). In sharp contrast, PAI-1 level in BALF decreased 21.44 ng/ml compared with controls ( P  < 0.00001). Arterial oxygen tension was improved by a net increase of 15.16 mmHg, while carbon dioxide pressure was significantly reduced (11.66 mmHg, P  = 0.0001 vs controls). Additionally, fibrinolytics improved lung function and alleviated inflammation response: the lung wet/dry ratio was decreased 1.49 ( P  < 0.0001 vs controls), lung injury score was reduced 1.83 ( P  < 0.00001 vs controls), and BALF neutrophils were lesser (3 × 10 4 /ml, P  < 0.00001 vs controls). The mortality decreased significantly within defined study periods (6 h to 30 days for mortality), as the risk ratio of death was 0.2-fold of controls ( P  = 0.0008)., Conclusion: We conclude that fibrinolytic therapy may be effective pharmaceutic strategy for ALI in animal models.

Background: The effects of aspirin in preventing the occurrence of acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) among adult patients are controversial. We aimed to further determine the effectiveness of aspirin in reducing the rate of ARDS/ALI., Methods: The Pubmed, Embase, Medline, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that research the role of aspirin in adult patients who have the risk of ARDS/ALI. The outcomes were the ARDS/ALI rate and the mortality. Cochrane systematic review software, Review Manager (RevMan), the R software for statistical computing version 3.2.0, and the metafor package were used to test the hypothesis by Mann-Whitney U test. The heterogeneity test and sensitivity analyses were conducted, and random-effects or fixed-effects model was applied to calculate odds ratio (OR) and mean difference (MD) for dichotomous and continuous data, respectively., Results: Six trials involving 6562 patients were pooled in our final study. No significant heterogeneity was found in outcome measures. Aspirin could reduce the rate of ARDS/ALI (OR 0.71, 95% confidence interval (CI) 0.58-0.86) but not the mortality (OR 0.87, 95% CI 0.71-1.07)., Conclusions: In patients with risk of ARDS/ALI, aspirin could provide protective effect on the rate of ARDS/ALI, but it could not reduce the mortality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury., Competing Interests: Although one of our authors is employed by a commercial company, Alector, South San Francisco, CA, the funder provided support in the form of salaries for author [MK], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Smoke inhalation-associated acute lung injury (SI-ALI) is a major cause of morbidity and mortality in victims of fire tragedies. To date, there are no evidence-based guidelines on ventilation strategies in acute respiratory distress syndrome (ARDS) after smoke inhalation. We reviewed the existing literature for clinical studies of salvage mechanical ventilation (MV) strategies in patients with SI-ALI, focusing on mortality and pneumonia as outcomes., Methods: A systematic search was designed in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Risk of bias assessment was performed using the Newcastle-Ottawa Quality Assessment Scale (NOS; 0 to 9 stars), with a score ≥7 being the threshold for inclusion in the meta-analysis. A systematic search strategy was used to search 10 databases. Clinical studies were included in which patients: (1) experienced smoke inhalation, (2) treated with MV, and (3) described a concurrent or historical control group., Results: A total of 226 potentially relevant studies were identified, of which 7 studies on high-frequency percussive ventilation (HFPV) met inclusion criteria. No studies met inclusion for meta-analysis (NOS ≥ 7). In studies comparing HFPV to conventional mechanical ventilation (CMV), mortality and pneumonia incidence improved in 3 studies and remained unchanged in 3 others. No change in ventilator days or ICU length of stay was observed; however, oxygenation and work of breathing improved with HFPV., Conclusions: Mechanical ventilation in patients with SI-ALI has not been well studied. High-frequency percussive ventilation may decrease in-hospital mortality and pneumonia incidence when compared to CMV. The absence of "good" quality evidence precluded meta-analysis. Based upon low-quality evidence, there was a very weak recommendation that HFPV use may be associated with lower mortality and pneumonia rates in patients with SI-ALI. Given SI-ALI's unique underlying pathophysiology, and its potential implications on therapy, randomized controlled studies are required to ensure that patients receive the safest and most effective care., Trial Registration: The study was registered with PROSPERO International prospective register of systematic reviews (#47015).

Antiplatelet therapy is an attractive treatment option for critically ill patients. However, more evidence on the benefit of this therapy is required. We searched the PubMed and Embase databases from their inception to June 2017 for randomized controlled trials and observational studies that assess the effect of antiplatelet therapy in critically ill patients. Antiplatelet therapy resulted in significant decreases in hospital mortality (risk ratio [RR] 0.81, 95% confidence interval [CI], 0.68-0.97; P = 0. 025), intensive care unit (ICU) mortality (RR 0.78, 95% CI, 0.63-0.97; P = 0. 027), incidence of respiratory distress syndrome or acute lung injury (RR 0.73, 95% CI, 0.58-0.91; P = 0.006), and incidence of sepsis (RR 0.81, 95% CI, 0.68-0.97; P = 0.021). A predefined subgroup analysis according to patient type suggested that hospital mortality and ICU mortality benefits were seen only in septic patients (RR 0.71, 95% CI, 0.58-0.86; P < 0.0001) and (RR 0.65, 95% CI, 0.49-0.86; P = 0.002). By network meta-analysis, the predictive interval plot showed that patients treated with aspirin and clopidogrel had lower risk of hospital mortality as compared with control group. The assessment of rank probabilities using SUCRA plots indicated that aspirin presented the greatest likelihood of having lowest hospital mortality rate. The results of this meta-analysis suggest that antiplatelet therapy is useful for the treatment in critically ill patients, and this is primarily due to an effect on septic patients. Network meta-analysis shows that the probability of being the best antiplatelet therapy for critically ill patients was aspirin.

Background: The Intensive Nutrition in Acute Lung Injury: Clinical Trial (INTACT), designed to evaluate outcomes of calorie delivery from acute respiratory distress syndrome (ARDS) diagnosis through hospital discharge, was stopped due to higher mortality in the intervention group. Post hoc analysis found timing and dose of calorie delivery influenced mortality. The objective of this retrospective cohort study was to determine if early vs late calorie exposure changed the hazard of death among a larger sample of patients with ARDS., Methods: Adult patients who met the eligibility criteria for INTACT but did not participate were included. Daily calorie delivery was collected from the date INTACT eligibility was determined to extubation or death. Cox proportional hazards regression was used to model the relationship between hazard of hospital death with average calorie exposure received over increasing study days and after day 7., Results: A total of 298 patients were included; overall mortality was 33%. Among patients who remained intubated at 1 week (n = 202), higher kcal/kg received from intensive care unit (ICU) days 1-6 increased hazards of subsequent death on days 7+ (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.01-1.06); kcal/kg received after ICU day 7 decreased the hazards of death on day 7+ (HR, 0.53; 95% CI, 0.33-0.84)., Conclusions: Higher calorie exposure between ICU days 1 and 7 was associated with higher subsequent hazard of mortality, and provision of high-calorie exposure after day 8 decreased the hazards of death., (© 2017 American Society for Parenteral and Enteral Nutrition.)

Prolonged exposure to hyperoxia results in acute lung injury (ALI). Pulmonary damage caused by oxygen toxicity occurs due to the generation of reactive oxygen species and subsequent formation of more potent oxidants. The present study demonstrated that sirtuin 3 (SIRT3) may attenuate hyperoxia‑induced ALI due to its potential antioxidative effect. In the present study, a hyperoxia‑induced acute lung injury mouse model, reverse transcription‑quantitative polymerase chain reaction, western blotting, retroviral mediated gene over‑expression and knockdown assays revealed that the expression of SIRT3 in the lung tissue of mice with hyperoxia‑induced ALI was decreased and overexpression of SIRT3 may significantly reduce hyperoxia‑induced ALI, as reflected by decreases in protein concentration, infiltrated neutrophils in bronchoalveolar lavage (BAL) fluid and wet/dry ratio of lung tissues. Furthermore, overexpression of SIRT3 increased the protein levels and enzymatic activity of manganese superoxide dismutase (MnSOD), and inhibited oxidative stress in the lungs of ALI mice. Additionally, the current study demonstrated that SIRT3 promoted the expression of MnSOD, and this regulation was crucial for the protective effect of SIRT3 on hyperoxia‑induced ALI. In summary, the results of the current study indicated that SIRT3 overexpression may effectively ameliorate hyperoxia‑induced ALI in mice, which indicates a potential application for SIRT3‑based gene therapy to treat clinical adult respiratory distress syndrome.

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 × 10 6  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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Sivelestat is widely used in treating acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), although the clinical efficacy of sivelestat remains controversial. This study aimed to evaluate the impact of sivelestat in patients with ALI/ARDS., Methods: Electronic databases, PubMed, Embase, and the Cochrane Library, were searched to identify trials through April 2017. Randomized controlled trials (RCTs) were included irrespective of blinding or language that compared patients with and without sivelestat therapy in ALI/ARDS. A random-effects model was used to process the data, and the relative risk (RR) and standard mean difference (SMD) with corresponding 95% confidence intervals (CIs) were used to evaluate the effect of sivelestat., Results: Six RCTs reporting data on 804 patients with ALI/ARDS were included. Overall, no significant difference was found between sivelestat and control for the risk of 28-30 days mortality (RR: 0.94; 95% CI: 0.71-1.23; P = 0.718). Sivelestat therapy had no significant effect on ventilation days (SMD: 0.05; 95% CI: -0.27 to 0.38; P = 0.748), arterial oxygen partial pressure (PaO2)/fractional inspired oxygen (FiO2) level (SMD: 0.48; 95% CI: -0.45 to 1.41; P = 0.315), and intensive care unit (ICU) stays (SMD: -9.87; 95% CI: -24.30 to 4.56; P = 0.180). The results of sensitivity analysis indicated that sivelestat therapy might affect the PaO 2 /FiO 2 level in patients with ALI/ARDS (SMD: 0.87; 95% CI: 0.39 to 1.35; P < 0.001)., Conclusions: Sivelestat therapy might increase the PaO 2 /FiO 2 level, while it had little or no effect on 28-30 days mortality, ventilation days, and ICU stays. These findings need to be verified in large-scale trials.

Celebrating its 50th anniversary in 2017, bronchopulmonary dysplasia (BPD)-the chronic lung disease of prematurity that follows ventilator and oxygen therapy for acute respiratory failure-remains the most frequent complication of extreme prematurity. Survival of premature infants born at increasingly earlier stages of gestation has made the prevention of lung injury increasingly challenging. BPD is postulated to be a misdirection of many functions in the developing lung, including growth factor signalling and matrix as well as cellular composition, resulting in impaired alveolar and lung vascular growth. Despite improvements in understanding the mechanisms that regulate normal lung development, BPD remains without therapies. Insights into stem cell biology have identified the repair potential of stem cells. Promising preclinical studies demonstrated the lung protective effects of stem cell-based therapies in animal models mimicking BPD, leading to early-phase clinical trials. Although the time is ripe to conduct well-designed early-phase clinical trials, much more needs to be learned about the biology of these cells to develop safe, efficient, high-quality, clinical-grade cell products. Stem cells are essential for normal organ development, maintenance, and repair. It is therefore biologically plausible that exhaustion/dysfunction of resident lung stem cells contributes to the inability of the immature lung to repair itself. Understanding how normal lung stem cells function and how these cells are perturbed in BPD may prove useful in designing superior cell products with enhanced repair capabilities to ensure the successful translation of basic research into clinical practice., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort., Methods: The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied., Results: The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined., Conclusion: We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion.

Traumatic brain injury-induced acute lung injury (TBI-ALI) is a serious complication after brain injury for which predictive factors are lacking. In this study, we found significantly elevated blood glutamate concentrations in patients with TBI or multiple peripheral trauma (MPT), and patients with more severe injuries showed higher blood glutamate concentrations and longer durations of elevated levels. Although the increase in amplitude was similar between the two groups, the duration was longer in the patients with TBI. There were no significant differences in blood glutamate concentrations in the patients with MPT with regard to ALI status, but the blood glutamate levels were significantly higher in the patients with TBI-ALI than in those without ALI. Moreover, compared to patients without ALI, patients with TBI showed a clearly enhanced inflammatory response that was closely correlated with the blood glutamate levels. The blood glutamate concentration was also found to be a risk factor (adjusted odds ratio, 2.229; 95% CI, 1.082-2.634) and was a better predictor of TBI-ALI than the Glasgow Coma Scale (GCS) score. These results indicated that dramatically increased blood glutamate concentrations were closely related to the occurrence of TBI-ALI and could be used as a predictive marker for "at-risk" patients.

Purpose: An open lung strategy (OLS) that includes positive end expiratory pressure and recruitment maneuvers during mechanical ventilation is probably an important treatment method in patients with acute respiratory distress syndrome (ARDS). However, the effect of OLS is unknown. We therefore hypothesized that patients with ARDS may benefit from OLS treatment., Methods: We identified relevant randomized controlled trials by searching through PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials updated to May 22, 2016. We performed a systematic review and meta-analysis to evaluate the effect of OLS in patients with ARDS. The primary outcome was mortality., Results: A total of 15 randomized controlled trials involving 1,563 patients in OLS group and 1,571 patients in control group were included. Pooled analysis showed that there was significant difference in hospital mortality (relative risk [RR], 0.88; 95% CI, 0.80-0.97; P = 0.009), 28-day mortality (RR, 0.83; 95% CI, 0.71-0.96; P = 0.010), and intensive care unit (ICU) mortality (RR, 0.77; 95% CI, 0.65-0.92; P = 0.003) between the OLS group and control group, with no substantial heterogeneity. There was no significant difference in ventilator-free days at 28-day (mean difference [MD]; 3.32 d; 95% CI, -0.49 to 7.12; P = 0.09) and ICU length of stay (MD; 1.60 d; 95% CI, -2.99 to 6.20; P = 0.49) between OLS group and control group., Conclusions: Results from this systematic review and meta-analysis suggest that OLS during mechanical ventilation significantly reduces mortality among patients with ARDS.

Although some data suggest favorable outcomes with use of etanercept for treatment of transplantation-related lung injury, concerns, such as development of new infections, still exist. The objective of this study was to describe the usage of etanercept at our institution and to evaluate the efficacy and safety of etanercept for this indication. Adult patients receiving at least one dose of etanercept for the treatment of pulmonary complications in patients after hematopoietic stem cell transplant from January 2005 to December 2010 were retrospectively evaluated. Outcomes included hospital mortality, incidence of new infection after etanercept administration, and time from administration of first dose of etanercept to infection. Seventeen patients who received etanercept at our institution from January 2005 to December 2010 were included. Four patients (24%) survived their hospital stay, and 3 patients (18%) were alive at both 100 days and 1 year from the initiation of etanercept therapy. Four patients (24%) developed at least one confirmed new infection after the initiation of etanercept therapy. Both moderate and long-term survival in our cohort was low. Caution and careful assessment of the risks and benefits of therapy should be taken before initiation of etanercept for transplantation-related lung injury.

Background: Mortality in acute lung injury (ALI) remains high, with outcome data arising mostly from multicenter studies. We undertook this investigation to determine hospital mortality in patients with ALI in a single center., Methods: We studied patients admitted between 2005 and 2012 with ALI and acute respiratory distress syndrome (ARDS) according to the American European Consensus Conference (AECC) criteria and recorded clinical variables. Thereafter, patients were classified as subgroups according to the AECC and Berlin definition in order to compare the clinical characteristics and outcomes., Results: In the 93 patients comprising the study, hospital mortality was 38%. Mortality at 28 days was 36%. Multivariate analysis associated hospital mortality with age and Pao 2 /Fio 2 on day 1 ( P < .001). Differences resulted between the subgroups of AECC (ALI vs ARDS) and Berlin (mild vs moderate vs severe ARDS) in the lung injury score, Pao 2 /Fio 2 , Pao 2 /P A o 2 , PaCo 2 on day 1, and hospital mortality., Conclusion: The overall hospital mortality (38%) was similar to that of other studies and according to the presence of ARDS (Pao 2 /Fio 2 ≤ 200), we found significant differences between ALI and ARDS (AECC) and between mild and moderate or severe ARDS (Berlin) in baseline respiratory variables and mortality.

Background: Hemopexin (HPX) has been identified as an anti-inflammatory agent, but its role in endotoxemia is unclear. The purpose of this study was to determine whether HPX suppresses systemic and lung inflammation in a mouse model of endotoxemia., Materials and Methods: At 30 min of intraperitoneal administration of lipopolysaccharide (LPS; 10 mg/kg), either distilled water (LPS-only treated animals) or HPX (5 mg/kg) was injected into mice via the tail vein, and the survival rates were analyzed after 36 h. Furthermore, the serum levels of tumor necrosis factor-α, interleukin-6 (IL-6), and HPX were determined at 0, 3, and 6 h, and the expression levels and DNA binding activities of phosphorylated cytoplasmic inhibitor κB-α, nuclear factor-κB (NF-κB), and the p65 subunit of NF-κB were evaluated and compared with the rates of histologic lung injury after 6 h., Results: Serum tumor necrosis factor-α and interleukin-6 levels were decreased in HPX-treated animals at 3 and 6 h (P < 0.05). HPX suppressed the NF-κB pathway (P < 0.05) and reduced acute lung injury at 6 h, and 36 h after initial treatment, the survival rate was higher in HPX-treated animals than that in LPS-treated animals (P < 0.05)., Conclusions: HPX downregulated proinflammatory cytokine production and acute lung injury as well as improved survival rates in a mouse model of endotoxemia. These effects were associated with HPX-mediated suppression of the NF-κB pathway., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes., Design: Multicenter prospective observational study., Setting: We enrolled patients from five academic PICUs between 2008 and 2015., Patients: Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome., Interventions: Eight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin., Measurements and Main Results: We measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70-0.83] vs 0.70 [0.62-0.77]; p = 0.042)., Conclusions: In pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.

Acute inflammatory diseases are the leading causes of mortality in intensive care units. Myeloid differentiation 2 (MD-2) is required for recognizing lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and represents an attractive therapeutic target for LPS-induced inflammatory diseases. In this study, we report a chalcone derivative, L2H21, as a new MD2 inhibitor, which could inhibit LPS-induced inflammation both in vitro and in vivo. We identify that L2H21 as a direct inhibitor of MD-2 by binding to Arg 90 and Tyr 102 residues in MD-2 hydrophobic pocket using a series of biochemical experiments, including surface plasmon response, molecular docking and amino acid mutation. L2H21 dose dependently inhibited LPS-induced inflammatory cytokine expression in primary macrophages. In mice with LPS intratracheal instillation, L2H21 significantly decreased LPS-induced pulmonary oedema, pathological changes in lung tissue, protein concentration increase in bronchoalveolar lavage fluid, inflammatory cells infiltration and inflammatory gene expression, accompanied with the decrease in pulmonary TLR4/MD-2 complex. Meanwhile, administration with L2H21 protects mice from LPS-induced mortality at a degree of 100%. Taken together, this study identifies a new MD2 inhibitor L2H21 as a promising candidate for the treatment of acute lung injury (ALI) and sepsis, and validates that inhibition of MD-2 is a potential therapeutic strategy for ALI., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: The effects of body mass index (BMI) on the prognosis of acute respiratory distress syndrome (ARDS) are controversial. We aimed to further determine the relationship between BMI and the acute outcomes of patients with ARDS., Methods: We searched the Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL), and ISI Web of Science for trials published between 1946 and July 2016, using "BMI" or "body mass index" or "overweight" or "obese" and "ARDS" or "ALI" or "acute respiratory distress syndrome" or "acute lung injury", without limitations on publication type or language. Heterogeneity and sensitivity analyses were conducted, and a random-effects model was applied to calculate the odds ratio (OR) or mean difference (MD). Review Manager (RevMan) was used to test the hypothesis using the Mann-Whitney U test. The primary outcome was unadjusted mortality, and secondary outcomes included mechanical ventilation (MV)-free days and length of stay (LOS) in the intensive care unit (ICU) and in hospital., Results: Five trials with a total of 6268 patients were pooled in our final analysis. There was statistical heterogeneity between normal-weight and overweight patients in LOS in the ICU (I 2  = 71%, χ 2  = 10.27, P = 0.02) and in MV-free days (I 2  = 89%, χ 2  = 18.45, P < 0.0001). Compared with normal weight, being underweight was associated with higher mortality (OR 1.59, 95% confidence interval (CI) 1.22, 2.08, P = 0.0006), while obesity and morbid obesity were more likely to result in lower mortality (OR 0.68, 95% CI 0.57, 0.80, P < 0.00001; OR 0.72, 95% CI 0.56, 0.93, P = 0.01). MV-free days were much longer in patients with morbid obesity (MD 2.64, 95% CI 0.60, 4.67, P = 0.01), but ICU and hospital LOS were not influenced by BMI. An important limitation of our analysis is the lack of adjustment for age, sex, illness severity, comorbid illness, and interaction of outcome parameters., Conclusions: Obesity and morbid obesity are associated with lower mortality in patients with ARDS.

Background: Our trial INTACT (Intensive Nutrition in Acute Lung Injury Trial) was designed to compare the impact of feeding from acute lung injury (ALI) diagnosis to hospital discharge, an interval that, to our knowledge, has not yet been explored. It was stopped early because participants who were randomly assigned to energy intakes at nationally recommended amounts via intensive medical nutrition therapy experienced significantly higher mortality hazards than did those assigned to standard nutrition support care that provided energy at 55% of recommended concentrations., Objective: We assessed the influence of dose and timing of feeding on hospital mortality., Design: Participants (n = 78) were dichotomized as died or discharged alive. Associations between the energy and protein received overall, early (days 1-7), and late (days ≥8) and the hazards of hospital mortality were evaluated between groups with multivariable analysis methods., Results: Higher overall energy intake predicted significantly higher mortality (OR: 1.14, 95% CI: 1.02, 1.27). Among participants enrolled for ≥8 d (n = 66), higher early energy intake significantly increased the HR for mortality (HR: 1.17, 95% CI: 1.07, 1.28), whereas higher late energy intake was significantly protective (HR: 0.91, 95% CI: 0.83, 1.0). Results were similar for early but not late protein (grams per kilogram) exposure (early-exposure HR: 8.9, 95% CI: 2.3, 34.3; late-exposure HR: 0.15, 95% CI: 0.02, 1.1). Threshold analyses indicated early mean intakes ≥18 kcal/kg significantly increased subsequent mortality., Conclusions: Providing kilocalories per kilogram or grams of protein per kilogram early post-ALI diagnosis at recommended levels was associated with significantly higher hazards for mortality, whereas higher late energy intakes reduced mortality hazards. This time-varying effect violated the Cox proportionality assumption, indicating that feeding trials in similar populations should extend beyond 7 d and use time-varying statistical methods. Future trials are required for corroboration. INTACT was registered at clinicaltrials.gov as NCT01921101., (© 2017 American Society for Nutrition.)

The incidence and mortality of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still very high, but stem cells show some promise for its treatment. Here we found that intratracheal administration of human umbilical cord-mesenchymal stem cells (UC-MSCs) significantly improved survival and attenuated the lung inflammation in lipopolysaccharide (LPS)-induced ALI mice. We also used the proteins-chip and bioinformatics to analyze interactions between UC-MSCs treatment and immune-response alternations of ALI mice. Then we demonstrated that UC-MSCs could inhibit the inflammatory response of mouse macrophage in ALI mice, as well as enhance its IL-10 expression. We provide data to support the concept that the therapeutic capacity of UC-MSCs for ALI was primarily through paracrine secretion, particularly of prostaglandin-E2 (PGE2). Furthermore, we showed that UC-MSCs might secrete a panel of factors including GM-CSF, IL-6 and IL-13 to ameliorate ALI. Our study suggested that UC-MSCs could protect LPS-induced ALI model by immune regulation and paracrine factors, indicating that UC-MSCs should be a promising strategy for ALI/ARDS.