OBJECTIVE: To identify the underlying mechanism by which quercetin (Que) alleviates sepsis-related acute respiratory distress syndrome (ARDS). METHODS: In vivo, C57BL/6 mice were assigned to sham, cecal ligation and puncture (CLP), and CLP+Que (50 mg/kg) groups (n=15 per group) by using a random number table. The sepsisrelated ARDS mouse model was established using the CLP method. In vitro, the murine alveolar macrophages (MH-S) cells were classified into control, lipopolysaccharide (LPS), LPS+Que (10 μmol/L), and LPS+Que+acetylcysteine (NAC, 5 mmol/L) groups. The effect of Que on oxidative stress, inflammation, and apoptosis in mice lungs and MH-S cells was determined, and the mechanism with reactive oxygen species (ROS)/p38 mitogen-activated protein kinase (MAPK) pathway was also explored both in vivo and in vitro. RESULTS: Que alleviated lung injury in mice, as reflected by a reversal of pulmonary histopathologic changes as well as a reduction in lung wet/dry weight ratio and neutrophil infiltration (P<0.05 or P<0.01). Additionally, Que improved the survival rate and relieved gas exchange impairment in mice (P<0.01). Que treatment also remarkedly reduced malondialdehyde formation, superoxide dismutase and catalase depletion, and cell apoptosis both in vivo and in vitro (P<0.05 or P<0.01). Moreover, Que treatment diminished the release of inflammatory factors interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 both in vivo and in vitro (P<0.05 or P<0.01). Mechanistic investigation clarifified that Que administration led to a decline in the phosphorylation of p38 MAPK in addition to the suppression of ROS expression (P<0.01). Furthermore, in LPS-induced MH-S cells, ROS inhibitor NAC further inhibited ROS/p38 MAPK pathway, as well as oxidative stress, inflammation, and cell apoptosis on the basis of Que treatment (P<0.05 or P<0.01). CONCLUSION Que was found to exert anti-oxidative, anti-inflammatory, and anti-apoptotic effects by suppressing the ROS/p38 MAPK pathway, thereby conferring protection for mice against sepsis-related ARDS.
Animals ; Sepsis/drug therapy* ; Quercetin/therapeutic use* ; Respiratory Distress Syndrome/enzymology* ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism* ; Apoptosis/drug effects* ; Male ; Oxidative Stress/drug effects* ; MAP Kinase Signaling System/drug effects* ; Lung/drug effects* ; Mice ; Lipopolysaccharides ; Macrophages, Alveolar/pathology* ; Inflammation/pathology* ; Protective Agents/therapeutic use*

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

To analyze clinical characteristics and risk factors of very low birth weight and extremely low birth weight infants with bronchopulmonary dysplasia (BPD). A retrospective epidemiological study was performed in 768 neonates (376 males) with birth weights<1 500 g and gestational age ≤ 34 weeks who survived ≥28 days. Clinical data were obtained from the multi-center clinical database of neonatal intensive care units (NICU) in 19 hospitals of Jiangsu Province between January 1, 2017 and December 31, 2017. These infants were divided into non-BPD group and BPD group according to BPD diagnositic criteria. Clinical features and potential risk factors were compared between groups with Chi-square test or nonparametric test. Risk factors for BPD were analyzed with Logistic regression analysis. Among the total of 768 eligible neonates, 577 without BPD, 191 with BPD (24.9%). Mild, moderate and severe BPD accounted for 73.3% (140/191), 23.6% (45/191) and 3.1% (6/191) of all BPD cases respectively. There were significant differences in the average gestational age (29 (28, 30) 30 (29, 31) weeks) or the average birth weight (1 170 (990, 1 300) 1 300 (1 160, 1 400) g) between BPD group and non-BPD group (-9.959,-7.202, both 0.000). The incidences of BPD in the infants with gestational age of<28 weeks, 28-31 weeks and 32-34 weeks were 51.7% (46/89), 24.8% (139/561), 5.1% (6/118) respectively. The incidences of BPD in infants with birth weigh1 000 g, 1 000- 1 249 g and 1 250-1 500 g were 62.3% (48/77), 25.9% (70/270) and 17.3% (73/421) respectively. Proportion of male (55.5% (106/191) 46.8% (270/577)), rate and length of conventional mechanical ventilation (48.7% (93/191) 14.9% (86/577), 120 (72, 259) 80 (29, 144)h), initial inhaled oxygen concentration and maximum inhaled oxygen concentration (0.35 (0.30, 0.40) 0.30(0.25, 0.40), 0.40 (0.30, 0.50) 0.30 (0.30, 0.40)) and volume of red blood cell transfusion (53(30, 90) .38(28, 55) ml) were higher in BPD group than in non-BPD group (χ(2)=4.350, 91.640, -3.557, -2.848, -3.776, -4.677, all 0.05). Rate of continuous positive airway pressure (12.6%(24/191) 19.4%(112/577)) during neonatal resuscitation in delivery room was lower in BPD group than that in non-BPD group (χ(2)=4.614, 0.032). The incidences of complications in BPD group including severe asphyxia, neonatal respiratory distress syndrome (NRDS), persistent pulmonary hypertension in newborns (PPHN), patent ductus arteriosus, anemia of prematurity, early onset sepsis, clinical sepsis and ventilator associated pneumonia were higher than that in non-BPD group (15.2%(29/191) 4.5% (26/577), 91.1% (174/191) 56.7% (327/577), 2.6% (5/191) 0.2% (1/577), 43.5% (83/191) 34.2% (197/577), 88.0% (168/191) 58.8% (339/577), 15.7% (30/191) 9.9% (57/577), 42.9% (82/191) 18.6% (107/577), 14.1% (27/191) 2.3% (13/577); χ(2)=24.605, 74.993, 9.167, 5.373, 61.866, 4.557, 43.149, 34.315, all 0.05). Multivariate logistic regression analysis showed that NRDS (4.651, 95: 1.860-11.625), clinical sepsis (1.989, 95: 1.067-3.708), ventilator associated pneumonia (3.155, 95: 1.060-9.388), conventional mechanical ventilation (2.298, 95: 1.152-4.586), and volume of red blood cell transfusion (1.013, 95: 1.002-1.024) were risk factors of BPD. BPD is more common in very low birth weight infants of male with gestational age less than 32 weeks. Using CPAP in the delivery room, active treatment of NRDS, preventing nosocomial infection, and reducing invasive ventilation and red blood cell transfusion may decrease the incidence of BPD.
Birth Weight ; Bronchopulmonary Dysplasia ; complications ; epidemiology ; pathology ; Gestational Age ; Humans ; Infant ; Infant, Extremely Low Birth Weight ; Infant, Newborn ; Infant, Very Low Birth Weight ; Male ; Respiratory Distress Syndrome, Newborn ; Retrospective Studies ; Risk Factors

Neonatal respiratory distress syndrome (RDS) is a disease that is unique to newborn infants. It is caused by a deficiency of pulmonary surfactant (PS), which is usually ready to be activated around the perinatal period. Until RDS was more clearly understood, it was not known why premature infants died from respiratory failure, although pathology revealed hyaline membranes in the alveoli. Surprisingly, the era of PS replacement therapy began only relatively recently. The first clinical trial investigating neonatal RDS was conducted in 1980. Since then, newborn survival has improved dramatically, which has led to significant advances in the field of neonatology. The present comprehensive review addresses PS, from its discovery to the application of artificial PS in newborns with RDS. It also reviews the history of PS in Korea, including its introduction, various commercial products, present and past research, newborn registries, and health insurance issues. Finally, it describes the inception of the Korean Society of Neonatology and future directions of research and treatment.
History of Medicine ; Humans ; Hyalin ; Infant, Newborn ; Infant, Premature ; Insurance, Health ; Korea ; Membranes ; Neonatology ; Pathology ; Pulmonary Surfactants ; Registries ; Respiratory Distress Syndrome, Newborn ; Respiratory Insufficiency

ObjectiveExposure to halogens, such as chlorine or bromine, results in environmental and occupational hazard to the lung and other organs. Chlorine is highly toxic by inhalation, leading to dyspnea, hypoxemia, airway obstruction, pneumonitis, pulmonary edema, and acute respiratory distress syndrome (ARDS). Although bromine is less reactive and oxidative than chlorine, inhalation also results in bronchospasm, airway hyperresponsiveness, ARDS, and even death. Both halogens have been shown to damage the systemic circulation and result in cardiac injury as well. There is no specific antidote for these injuries since the mechanisms are largely unknown.

Data SourcesThis review was based on articles published in PubMed databases up to January, 2018, with the following keywords: "chlorine," "bromine," "lung injury," and "ARDS."

Study SelectionThe original articles and reviews including the topics were the primary references.

ResultsBased on animal studies, it is found that inhaled chlorine will form chlorine-derived oxidative products that mediate postexposure toxicity; thus, potential treatments will target the oxidative stress and inflammation induced by chlorine. Antioxidants, cAMP-elevating agents, anti-inflammatory agents, nitric oxide-modulating agents, and high-molecular-weight hyaluronan have shown promising effects in treating acute chlorine injury. Elevated free heme level is involved in acute lung injury caused by bromine inhalation. Hemopexin, a heme-scavenging protein, when administered postexposure, decreases lung injury and improves survival.

ConclusionsAt present, there is an urgent need for additional research to develop specific therapies that target the basic mechanisms by which halogens damage the lungs and systemic organs.

Acute Lung Injury ; chemically induced ; Animals ; Chlorine ; toxicity ; Halogens ; toxicity ; Humans ; Lung ; drug effects ; pathology ; Respiratory Distress Syndrome, Adult ; drug therapy

BACKGROUND/AIMS: Diffuse alveolar damage (DAD) is the histopathologic hallmark of acute respiratory distress syndrome (ARDS). However, there are several non-DAD conditions mimicking ARDS. The purpose of this study was to investigate the histopathologic heterogeneity of ARDS revealed by surgical lung biopsy and its clinical relevance. METHODS: We retrospectively analyzed 84 patients with ARDS who met the criteria of the Berlin definition and underwent surgical lung biopsy between January 2004 and December 2013 in three academic hospitals in Korea. We evaluated their histopathologic findings and compared the clinical outcomes. Additionally, the impact of surgical lung biopsy on therapeutic alterations was examined. RESULTS: The histopathologic findings were highly heterogeneous. Of 84 patients undergoing surgical lung biopsy, DAD was observed in 31 patients (36.9%), while 53 patients (63.1%) did not have DAD. Among the non-DAD patients, diffuse interstitial lung diseases and infections were the most frequent histopathologic findings in 19 and 17 patients, respectively. Although the mortality rate was slightly higher in DAD (71.0%) than in non-DAD (62.3%), the difference was not significant. Overall, the biopsy results led to treatment alterations in 40 patients (47.6%). Patients with non-DAD were more likely to change the treatment than those with DAD (58.5% vs. 29.0%), but there were no significant improvements regarding the mortality rate. CONCLUSIONS: The histopathologic findings of ARDS were highly heterogeneous and classic DAD was observed in one third of the patients who underwent surgical lung biopsy. Although therapeutic alterations were more common in patients with non-DAD-ARDS, there were no significant improvements in the mortality rate.
Acute Lung Injury ; Berlin ; Biopsy* ; Humans ; Korea ; Lung Diseases, Interstitial ; Lung* ; Mortality ; Pathology ; Population Characteristics* ; Respiratory Distress Syndrome, Adult* ; Retrospective Studies

BACKGROUNDSepsis is one of the main causes of mortality in critically ill patients following progression to septic shock. To investigate the pathophysiologic changes of sepsis, we developed a novel porcine model of septic shock induced by acute respiratory distress syndrome (ARDS) due to methicillin-resistant Staphylococcus aureus(MRSA) pneumonia.

METHODSTwenty-six male Landraces (Lvyuanweiye, Beijing, China) weighing 30 ± 2 kg were divided into four groups: sham group (SH; n = 5); cotton smoke inhalation group (SM; n = 6); MRSA pneumonia group (MR; n = 6); and septic shock group with cotton smoke inhalation + MRSA pneumonia (SS; n = 9). Extensive hemodynamics, oxygen dynamics, and lung function were monitored for 24 h following the injury or until death. Tissues were collected, and histopathology evaluations were carried out.

RESULTSBlood cultures from 6 of 9 animals in the SS group were positive for MRSA. Two hours following the injury, decreased mean arterial blood pressure (60-70 mmHg) and cardiac index (<2 L.min-1.m-2) were observed in the animals in the SS group, while systemic vascular resistance index was increased. The hemodynamic characteristics of septic shock were only observed in the SS group but not significant in the other groups. The PO2/FiO2in the SM and SS groups decreased to 300 and 100, respectively. In the SS group, extravascular lung water index increased to 20 ml/kg, whereas thoracopulmonary compliance decreased to 10 ml/H2O after injury. Deterioration of pulmonary function in the SS group was more serious than the SM and MR groups. Severe lung injury in the SS group was confirmed by the histopathology evaluations. The lung injury confirmed by high-resolution thin-section computed tomography and histopathology in the SS group was more serious than those of other groups.

CONCLUSIONSIn the present study, we developed a novel porcine model of septic shock induced by ARDS due to severe MRSA pneumonia with characteristic hyperdynamic and hypodynamic phases in 24 h, which mimicked the hemodynamic changing of septic shock in human.

Animals ; Disease Models, Animal ; Hemodynamics ; physiology ; Male ; Methicillin-Resistant Staphylococcus aureus ; pathogenicity ; Pneumonia ; microbiology ; pathology ; Respiratory Distress Syndrome, Adult ; complications ; pathology ; Shock, Septic ; etiology ; pathology ; Swine

Recently, several prognostic scoring systems for patients with severe acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO) have been published. The aim of this study was to validate the established scoring systems for outcome prediction in Korean patients. We retrospectively reviewed the data of 50 patients on ECMO therapy in our center from 2012 to 2014. A calculation of outcome prediction scoring tools was performed and the comparison across various models was conducted. In our study, the overall hospital survival was 46% and successful weaning rate was 58%. The Predicting Death for Severe ARDS on V-V ECMO (PRESERVE) score showed good discrimination of mortality prediction for patients on ECMO with AUC of 0.80 (95% CI 0.66-0.90). The respiratory extracorporeal membrane oxygenation survival prediction (RESP) score and simplified acute physiology score (SAPS) II score also showed fair prediction ability with AUC of 0.79 (95% CI 0.65-0.89) and AUC of 0.78 (95% CI 0.64-0.88), respectively. However, the ECMOnet score failed to predict mortality with AUC of 0.51 (95% CI 0.37-0.66). When evaluating the predictive accuracy according to optimal cut-off point of each scoring system, RESP score had a best specificity of 91.3% and 66.7% of sensitivity, respectively. This study supports the clinical usefulness of the prognostic scoring tools for severe ARDS with ECMO therapy when applying to the Korean patients receiving ECMO.
Adult ; Aged ; Area Under Curve ; *Extracorporeal Membrane Oxygenation/classification ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Prognosis ; ROC Curve ; Republic of Korea ; Research Design/*standards ; Respiratory Distress Syndrome, Adult/mortality/pathology/*therapy ; Retrospective Studies ; Severity of Illness Index

Among the fire victims, respiratory tract injury resulted from smoke inhalation is the major cause of death. Particulate substances in smoke, toxic and harmful gas, and chemical substances act together would rapidly induce the occurrence of dramatic pathophysiologic reaction in the respiratory tract, resulting in acute injury to the respiratory tract, thus inducing serious injury to it and acute respiratory distress syndrome, leading to death of the victims. In recent years, the pathophysiologic mechanism of severe smoke inhalation injury has been gradually clarified, thus appreciable advances in its treatment have been achieved. This paper is a brief review of above-mentioned aspects.
Burns, Inhalation ; pathology ; physiopathology ; Fires ; Humans ; Respiratory Distress Syndrome, Adult ; physiopathology ; Smoke ; adverse effects ; Smoke Inhalation Injury ; pathology ; physiopathology

OBJECTIVEAcute respiratory distress syndrome (ARDS) is an acute and lethal clinical syndrome that is characterized by hypoxemic respiratory failure and diffuse alveolar inflammatory damage. This review aimed to search and discuss the mass spectrometry (MS)-based proteomic studies on different subsets of ARDS patients.

DATA SOURCESOriginal research articles were collected from the PubMed database published in English up to December 2015.

STUDY SELECTIONThe literature search was done using the term "(acute lung injury OR acute respiratory distress syndrome) AND (proteomics OR proteome OR mass spectrum OR differential in-gel electrophoresis OR two-dimensional polyacrylamide gel electrophoresis)". Related original research articles were included and were carefully analyzed.

RESULTSEight original proteomic researches on ARDS patients were found. The common proteomic modalities were two-dimensional (2D) high-performance liquid chromatography-based electronic spray ion-MS/MS and 2D-polyacrylamide gel electrophoresis/differential in-gel electrophoresis-based matrix-assisted laser desorption ionization-time of flight/MS. They compared the proteome between ARDS patients and normal controls and analyzed the dynamic changes of proteome at different ARDS stages or severity. The disturbed proteome in ARDS patients includes plasma acute-phase proteins, inflammatory/immune-associated proteins, and coagulation proteins.

CONCLUSIONSAlthough several previous studies have provided some useful information about the lung proteome in ARDS patients and gained several interesting disease-associated biomarkers, clinical proteomic studies in ARDS patients are still in the initial stage. An increased cooperation is still needed to establish a global and faithful database containing disease-specific proteome from the largest ARDS subsets.

Acute-Phase Proteins ; metabolism ; Humans ; Lung ; metabolism ; pathology ; Mass Spectrometry ; methods ; Precision Medicine ; methods ; Proteomics ; methods ; Respiratory Distress Syndrome, Adult ; metabolism