Acute Lung Injury Patients Research Articles

Nasal Delivery of Hesperidin/Chitosan Nanoparticles Suppresses Cytokine Storm Syndrome in a Mouse Model of Acute Lung Injury.

The cytokine storm or cytokine storm syndrome (CSS) is associated with high mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), for example following sepsis or infectious diseases including COVID-19. However, there are no effective treatments for CSS-associated ALI or ALI/ARDS. Thus, there remains an urgent need to develop effective drugs and therapeutic strategies against CSS and ALI/ARDS. Nasal and inhaled drug delivery methods represent a promising strategy in the treatment of inflammatory lung disease as a result of their ability to improve drug delivery to lungs. Improving the nasal mucosa absorption of poorly water-soluble drugs with poor mucosa bioavailability to a therapeutically effective level is another promising strategy in the fight against ALI/ARDS. Here, chitosan nanoparticles loaded with hesperidin (HPD/NPs) were developed for nasal delivery of the anti-inflammatory HPD compound to inflammatory lungs. In vitro and in vivo, HPD/NPs exhibited enhanced cellular uptake in the inflammatory microenvironment compared with free HPD. In a mouse model of inflammatory lung disease, the HPD/NPs markedly inhibited lung injury as evidenced by reduced inflammatory cytokine levels and suppressed vascular permeability compared with free HPD. Collectively, our study demonstrates that nasal delivery of HPD/NPs suppresses CSS and ALI/ARDS in a murine model of inflammatory lung disease, and that nanoparticle-based treatment strategies with anti-inflammatory effects could be used to reduce CSS and ALI in patients with inflammatory lung injury.

Bilobalide, a bioactive compound on sepsis-induced acute lung injury through its anti-inflammatory and antioxidative activity

Background: Sepsis, one of the major life-threatening conditions and responsible for approximately 40% of clinical Acute Lung Injury (ALI) patients. Nevertheless, there are no specific medications available to reduce mortality. Bilobalide, a natural bioactive component present in Ginkgo biloba, has several medicinal properties. However, the effect of Bilobalide against ALI residues unknown. And so, the therapeutic property and underlying molecular mechanism of Bilobalide was investigated against sepsis-prompted ALI in the murine model. Materials and Methods: In C57BL/6J mice model, sepsis introduced by cecal ligation and puncture (CLP) to induce lung injury. Results: Our results showed that Bilobalide treatment increased the survival rate of CLP-induced sepsis mice. Pretreatment with Bilobalide substantially inhibits the sepsis-induced lung exudation, which is exposed by measuring the wet/dry weight of lung and lung permeability of the mice. Also, Bilobalide attenuated the histopathological alterations alike alveolar hemorrhage and infiltration of inflammatory cells are assessed by hematoxylin and eosin staining, tumor necrosis factor-α, interleukin (IL)-1 β, IL-6 and macrophage inflammatory protein-2 pro-inflammatory mediators and myeloperoxidase are measured by enzyme-linked immunosorbent assay. Molecular mechanism of Bilobalide in lung inflammation whereby cyclooxygenase-2 (COX-2), induced nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), and the activation of the nuclear factor-kappa B (kB) (p65)/IkB are determined by immunoblotting technique. Moreover, pretreatment of Bilobalide significantly downregulated the expression of COX-2, iNOS, and phosphorylation of p65 and induced the IkB activation in the lung. Further, Bilobalide prevented the oxidative stress by upregulating the expression of HO-1 in lung tissues, and gene expression of sepsis-induced anti-oxidative enzymes (catalase, MnSOD, CuZnSOD, and GPx-1) in the Bilobalide-treated mice were induced dose-dependently and it determined by a quantitative-real time-polymerase chain reaction. Conclusion: Hence, we suggested Bilobalide has the ability to act as a possible therapeutic candidate against sepsis caused ALI.

Clinical Analysis of Acute Lung Injury in 26 Cases of Diffuse Large B-Cell Lymphoma Treated with Rituximab Chemotherapy

To summarize and analyze the clinical characteristics, treatment and prognosis of acute lung injury in patients with diffuse large B-cell lymphoma (DLBCL) after chemotherapy with rituximab chemotherapy, so as to improve the understanding of the disease and guide the clinical treatment. Twenty-Six patients with DLBCL were treated with rituximab chemotherapy and developed to acute lung injury in Third Hospital of Peking University from January 2013 to September 2018 were selected. The clinical features, imaging findings, chemotherapy course, therapeutic effect and prognosis were analyzed. The main clinical symptoms of patients were fever, cough and chest tightness, among which 12 patients showed hypoxia and 3 patients showed respiratory failure type I. The mainly manifested chest CT was diffusive glass grinding in both lungs, and some patients were complicated with a small amount of pleural effusion. The onset chemotherapy time was mainly distributed in 2 to 4 courses, the time between the onset of symptoms and the infusion of rituximab was 8 to 49 days. 25 patients shows no obvious limitation in daily life after effective treatment, and 1 patient died of ineffective treatment. There are no typical clinical symptoms in the early stage of acute lung injury after rituximab chemotherapy in DLBCL. Early detection and early hormone therapy are very important to achieve good therapeutic effect.

Abstract 12651: Fine-Tuning of Lung Thrombosis is a Therapeutic Strategy Against Inflammatory Lung Injury

Introduction: Lung thrombosis (LT) and endothelial cell (EC) death are positively associated with mortality in sepsis-induced acute lung injury (ALI) patients, but anti-coagulants have failed in clinical trials of sepsis. Hypothesis: We hypothesized that different levels of LT mediate ALI by regulating lung EC viability. Methods: To assess the impact of different levels of LT on ALI, we used murine models of LT and ALI. To explore how LT level might alter lung EC viability and ALI, we assessed survival gene expression by RNA sequencing. To identify the mechanism(s) responsible for changes in ALI after varying levels of LT, we assessed lung EC viability and ALI in mice with cell-specific knockout of different survival genes. Results: In platelet-depleted mice, LT was reduced while ALI was increased. Intra-venous microbeads were then administered to induce LT in a dose-dependent manner, showing that restoration of LT to the level found in platelet-replete mice protected against thrombocytopenia-induced ALI. We next showed in wild type mice, that while excessive increases in LT worsened ALI, induction of a mild level of LT conversely protected against ALI. The opposing impact of diminished or excessive versus mild LT on ALI was associated with changes in lung EC apoptosis. Subsequent studies showed a panel of candidate survival factors were differentially expressed in the lungs of ALI mice with or without mild or excessive LT. Mechanistically, we found that the protective impact of mild LT on ALI is dependent upon hypoxia-inducible factor (HIF) 1α in Tie2-expressing cells. Remarkably, the same mild level of LT retained its protective impact in platelet-depleted and platelet-replete mice even when induced up to 8 hours after sepsis. Conclusions: ALI is enhanced by diminished or excessive LT but suppressed by mild LT through HIF1α. The control of LT represents a therapeutic strategy for the induction of a pro-survival response that protects against inflammatory lung injury.

Knockdown of lncRNA MALAT1 Alleviates LPS-Induced Acute Lung Injury via Inhibiting Apoptosis Through the miR-194-5p/FOXP2 Axis.

PurposeWe aimed to identify and verify the key genes and lncRNAs associated with acute lung injury (ALI) and explore the pathogenesis of ALI. Research showed that lower expression of the lncRNA metastasis-associated lung carcinoma transcript 1 (MALAT1) alleviates lung injury induced by lipopolysaccharide (LPS). Nevertheless, the mechanisms of MALAT1 on cellular apoptosis remain unclear in LPS-stimulated ALI. We investigated the mechanism of MALAT1 in modulating the apoptosis of LPS-induced human pulmonary alveolar epithelial cells (HPAEpiC).MethodsDifferentially expressed lncRNAs between the ALI samples and normal controls were identified using gene expression profiles. ALI-related genes were determined by the overlap of differentially expressed genes (DEGs), genes correlated with lung, genes correlated with key lncRNAs, and genes sharing significantly high proportions of microRNA targets with MALAT1. Quantitative real-time PCR (qPCR) was applied to detect the expression of MALAT1, microRNA (miR)-194-5p, and forkhead box P2 (FOXP2) mRNA in 1 μg/ml LPS-treated HPAEpiC. MALAT1 knockdown vectors, miR-194-5p inhibitors, and ov-FOXP2 were constructed and used to transfect HPAEpiC. The influence of MALAT1 knockdown on LPS-induced HPAEpiC proliferation and apoptosis via the miR-194-5p/FOXP2 axis was determined using Cell counting kit-8 (CCK-8) assay, flow cytometry, and Western blotting analysis, respectively. The interactions between MALAT1, miR-194-5p, and FOXP2 were verified using dual-luciferase reporter gene assay.ResultsWe identified a key lncRNA (MALAT1) and three key genes (EYA1, WNT5A, and FOXP2) that are closely correlated with the pathogenesis of ALI. LPS stimulation promoted MALAT1 expression and apoptosis and also inhibited HPAEpiC viability. MALAT1 knockdown significantly improved viability and suppressed the apoptosis of LPS-stimulated HPAEpiC. Moreover, MALAT1 directly targeted miR-194-5p, a downregulated miRNA in LPS-stimulated HPAEpiC, when FOXP2 was overexpressed. MALAT1 knockdown led to the overexpression of miR-194-5p and restrained FOXP2 expression. Furthermore, inhibition of miR-194-5p exerted a rescue effect on MALAT1 knockdown of FOXP2, whereas the overexpression of FOXP2 reversed the effect of MALAT1 knockdown on viability and apoptosis of LPS-stimulated HPAEpiC.ConclusionOur results demonstrated that MALAT1 knockdown alleviated HPAEpiC apoptosis by competitively binding to miR-194-5p and then elevating the inhibitory effect on its target FOXP2. These data provide a novel insight into the role of MALAT1 in the progression of ALI and potential diagnostic and therapeutic strategies for ALI patients.

Relationship between pulmonary vascular dysfunction and prognosis of patients with acute lung injury

To investigate the effect of pulmonary vascular dysfunction in the prognosis of patients with acute lung injury (ALI). Patients with ALI who underwent pulmonary artery catheterization in the department of critical care medicine of Wuhan NO.1 Hospital from June 2017 to June 2019 were enrolled. The general information, clinical and hemodynamic indexes [central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), pulmonary artery systolic pressure (sPAP), pulmonary artery diastolic pressure (dPAP), mean pulmonary artery pressure (mPAP), cardiac index (CI)], acute physiology and chronic health evaluation II (APACHE II) score, arterial blood gas parameters [pH, partial pressure of oxygen (PO2), partial pressure of carbon dioxide (PCO2), oxygenation index (PaO2/FiO2)], whether there was shock or not; ventilator parameters [platform pressure (Plat), positive end-expiratory pressure (PEEP)], etc. were recorded. Pulmonary artery oxygen saturation, pulmonary vascular function indexes [transpulmonary potential gradient (TPG) and pulmonary vascular resistance index (PVRi)] were calculated. The relationship between TPG, PVRi and mechanical ventilation time, the length of intensive care unit (ICU) stay, cardiovascular days and 60-day mortality were analyzed in patients with different prognosis of 60-day and whether the TPG increased (≥ 12 mmHg was defined as elevated TPG, 1 mmHg = 0.133 kPa). A total of 65 patients were included in the study, including 30 males and 35 females; aged (48.9±15.2) years old. Forty-eight cases survived in 60-days, 17 died, and the 60-day mortality was 26.2%. At the baseline, there were no significant differences in cardiopulmonary function measurements, such as CVP, sPAP, dPAP, PAWP, CI, etc. between the two groups of patients with different prognosis. The APACHE II score, shock ratio, TPG and PVRi of the death group were significant higher than those of the survival group [APACHE II: 34±9 vs. 28±11, shock: 52.9% vs. 25.0%, TPG (mmHg): 16.2±1.9 vs. 14.6±2.1, PVRi (kPa×s×L-1): 31.8±4.2 vs. 29.7±3.5, all P < 0.05]. The 60-day mortality of 47 patients with TPG ≥ 12 mmHg was significantly higher than that of 18 patients with TPG < 12 mmHg (34.0% vs. 5.6%), and the mechanical ventilation time and the length of ICU stay were also significantly longer (days: 17±9 vs. 11±8, 16±5 vs. 12±5), and the cardiovascular days also increased significantly (days: 23±7 vs. 18±6), and the differences were statistically significant (all P < 0.05). Pearson correlation analysis showed that PVRi was significantly correlated with mechanical ventilation time, the length of ICU stay and cardiovascular days (r1 = 0.317, P1 = 0.030; r2 = 0.277, P2 = 0.005; r3 = 0.285, P3 = 0.002). In the individual multivariate Logistic regression model, the highest PVRi was an independent risk factor for the 60-day mortality [odds ratio (OR) = 30.5, 95% confidence interval was 20.4-43.1, P = 0.023]. Pulmonary vascular dysfunction is common in ALI patients and is independently associated with adverse outcomes.

The effects and safety of omega-3 fatty for acute lung injury: a systematic review and meta-analysis

BackgroundSeveral randomized controlled trials (RCTs) have compared the treatment of acute lung injury (ALI) with omega-3 fatty, yet the results remained inconsistent. Therefore, we attempted this meta-analysis to analyze the role of omega-3 fatty in the treatment of ALI patients.MethodsWe searched PubMed databases from inception date to October 31, 2019, for RCTs that compared the treatment of ALI with or without omega-3 fatty. Two authors independently screened the studies and extracted data from the published articles. Summary mean differences (MD) with 95% confidence intervals (CI) were calculated for each outcome by fixed- or random-effects model.ResultsSix RCTs with a total of 277 patients were identified, of whom 142 patients with omega-3 fatty acid treatment and 135 patients without omega-3 fatty treatment. Omega-3 fatty treatments significantly improve the PaO2 (MD = 13.82, 95% CI 8.55–19.09), PaO2/FiO2 (MD = 33.47, 95% CI 24.22–42.72), total protein (MD = 2.02, 95% CI 0.43–3.62) in ALI patients, and omega-3 fatty acid treatments reduced the duration of mechanical ventilation (MD = − 1.72, 95% CI − 2.84 to − 0.60) and intensive care unit stay (MD = − 1.29, 95% CI − 2.14 to − 0.43) in ALI patients.ConclusionsOmega-3 fatty can effectively improve the respiratory function and promote the recovery of ALI patients. Future studies focused on the long-term efficacy and safety of omega-3 fatty use for ALI are needed.

Effects of chronic intermittent hypoxia caused by obstructive sleep apnea on lipopolysaccharide-induced acute lung injury

Aim of the study Obstructive sleep apnea (OSA) is a common disease associated with significant morbidity and mortality. Sleep quality is an important issue; some patients with acute lung injury (ALI) have underlying OSA. However, the potential influences of OSA on ALI have not been reported until now. In this study, we evaluated the impact of preceding intermittent hypoxia (IH), a typical characteristic of OSA, on lipopolysaccharide (LPS)-induced ALI in a mouse model. Methods C57BL/6J mice were randomly divided into four groups: room air-control (RA-CTL), intermittent hypoxia-control (IH-CTL), room air-lipopolysaccharide (RA-LPS), and intermittent hypoxia-lipopolysaccharide (IH-LPS) groups. The mice were exposed to RA or IH (20 cycles/h, FiO2 nadir 7 ± 0.5%, 8 h/day) for 30 days. The LPS groups received intratracheal LPS on day 28. Results The IH-LPS group tended to exhibit more severe inflammation, fibrosis, and oxidative stress compared to the other groups, including the RA-LPS group. Total cell, neutrophil, and eosinophil counts in bronchoalveolar lavage fluid increased significantly in the IH-LPS group compared to the RA-LPS group. Compared to the RA-LPS group, the hydroxyproline level increased significantly in the IH-LPS group. In addition, the IH-LPS group exhibited significantly more terminal deoxynucleotidyl transferase dUTP nick end labeled-positive cells compared to the RA-LPS group. Conclusions We found that prior IH may negatively impact LPS-induced ALI in a mouse model. This result suggests that ALI in patients with OSA may be more of a concern. Further research into the mechanisms underlying the effects of IH on ALI is needed.

The Monocyte-Derived Exosomal CLMAT3 Activates the CtBP2-p300-NF-κB Transcriptional Complex to Induce Proinflammatory Cytokines in ALI

Monocytes and macrophages are the two major cell types involved in innate immunity. Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing proteins, mRNAs, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs). However, it is still unclear whether monocyte-derived exosomes are involved in the communication between monocytes and macrophages. In this study, we analyzed the differentially expressed lncRNA profiles in monocytes isolated from blood samples of healthy controls and acute lung injury (ALI) patients. We focused our study on investigating the signaling downstream of CLMAT3 (colorectal liver metastasis-associated transcript 3), a lncRNA that regulated proinflammatory cytokine genes. We revealed that CLMAT3 specifically targeted CtBP2 (C-terminal binding protein 2) and repressed its expression. Elevated CtBP2 acted as a coactivator to assemble a transcriptional complex with histone acetyltransferase p300 and NF-κB (nuclear factor κB) subunits. In vitro coculture and in vivo injection of ALI monocyte-derived exosomes increased the production of proinflammatory cytokines. Importantly, the administration of two CtBP2 inhibitors, NSC95397 and MTOB, could significantly reverse CtBP2-mediated transactivation. Collectively, our results support a model in which monocyte-derived exosomal CLMAT3 activates the CtBP2-p300-NF-κB complex to induce proinflammatory cytokines, thus contributing to the pathogenesis of ALI.

Increased Th17andTh22Cell Percentages Predict Acute Lung Injury in Patients with Sepsis.

This study was conducted to investigate the percentages of Th22 and Th17 cells in the peripheral blood of septic patients with and without acute lung injury (ALI) and their clinical significance. A total of 479 patients were divided into non-ALI and ALI groups. The percentages of Th22 and Th17 cells and the levels of interleukin 22 (IL-22), 6 (IL-6), and 17 (IL-17) were determined. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of Th22 and Th17 cells to predict sepsis-induced ALI. The lunginjury prediction score (LIPS), IL-6, IL-17, and IL-22 levels and the percentages of Th17 and Th22 cells were significantly higher in the ALI group (P < 0.05). They were significant factors affecting sepsis-induced ALI (P < 0.05). Multivariate logistic regression analysis showed that the LIPS (OR = 1.130), IL-17 (OR = 1.982), IL-22 (OR = 2.612) and the percentages of Th17 (OR = 2.211) and Th22 (OR = 3.230) cells were independent risk factors for ALI. The area under the curve of Th22 cells was 0.844 to predict ALI with a cutoff value of 6.81%. The sensitivity and specificity for early diagnosis of sepsis-induced ALI by the Th22 cell percentage were 78.72% and 89.13%, respectively. Th22 and Th17 cells in peripheral blood are significantly increased in septic patients with ALI and they may be used as biomarkers for early diagnosis of sepsis-induced ALI.

Patients with acute respiratory distress syndrome exhibit increased stromelysin1 activity in the blood samples

Enzyme activity analyses in the blood are expected to be reliable, non-invasive diagnostic as well as prognostic markers to reflect disease progression in acute lung injury (ALI). The objective of the current study was to evaluate the enzymatic activity of stromelysin1 (matrix metalloprotease-3) in the plasma/serum samples collected from ALI patients compared to the samples collected from healthy controls. Gene expression omnibus (GEO) database analysis indicated a correlation between increased stromelysin1 gene expression and the incidence of ALI in various animal models. Our analysis of patient plasma/serum samples from healthy controls and ALI patients revealed a significant, 3-fold increase in stromelysin1 activity in ALI plasma/serum compared to healthy subjects with no difference in stromelysin1 activity between the serum and plasma samples. Interestingly, no significant difference in stromelysin1 activity between non-smoking and smoking subjects was observed. These findings provide fundamental information on the potential reliability of stromelysin1 activity analysis, combined with other biomarkers in development, in blood samples for the early detection of ALI.

Neutrophil Phenotypic Profiling and Acute Lung Injury in Patients After Cardiopulmonary Bypass (CPB)

Neutrophil Phenotypic Profiling and Acute Lung Injury in Patients After Cardiopulmonary Bypass (CPB)

Effect of Early Enteral Nutrition Guidelines on Occurrence of Gastrointestinal Complications Among Acute Lung Injury Patients

Proper nutrition found to be an essential in health maintenance and restoration in the critically ill patient. Aim of the study was to evaluate the effect of early enteral nutrition guidelines on occurrence of gastrointestinal complications among acute lung injury patients. Design A quasi-experimental research design was used to conduct this research. This study was carried out at Trauma Intensive Care Unit at Assiut University hospital. Sample: was consisted of 30 patients in each group. Tools: Tool I: Modified patient assessment questionnaire, Tool II: Gastrointestinal complications assessment related to enteral nutrition. Methods: data about 30 patients receiving enteral nutrition before enteral nutrition guidelines were retrospectively compared with data for 30 patients admitted after implementation of the guidelines. Results of the present study showed Patients in the after intervention group had a lower gastrointestinal complications than before intervention group. Conclusion: Implementing early enteral nutrition guidelines reduce occurrence of gastrointestinal complications among acute lung injury patient in ICU Recommendations: Provision an educational programs for nurses about enteral nutrition guideline.

Effect of implementing nursing care protocol about acute lung injury on patients’ outcomes

Acute lung injury in trauma patient associated with pernicious values. Cardiopulmonary, neurological, gastrointestinal, and urinary, complications can be potentially avoidable. Therefore, implementing nursing protocol for this patient help prevent complications, promote faster recovery. Aim: Identify the effect of implementing nursing care protocol on acute lung injury patients' outcomes. Method: Quasi experimental research design was used on 80 patients (study and control groups). This study was carried out in trauma intensive care unit at Assiut university hospital. Tools: Modified patient assessment sheet, Systemic Assessment Observation Check List and patients’ outcomes Assessment sheet. Results: Lower complications, length of stay and mechanical ventilator days and better respiratory mechanics among studied group subjects than control group. Conclusion: Nursing care protocol help in reducing length of stay and improving patient outcomes. Recommendations: Planning educational programs for the critical care nurses with manual booklet about nursing care protocol for acute lung injury patient is required

Acute lung injury in patients with COVID-19 infection.

During the 2020 Spring Festival in China, the outbreak of a novel coronavirus, named COVID‐19 by WHO, brought on a worldwide panic. According to the clinical data of infected patients, radiologic evidence of lung edema is common and deserves clinical attention. Lung edema is a manifestation of acute lung injury (ALI) and may progress to hypoxemia and potentially acute respiratory distress syndrome (ARDS). Patients diagnosed with ARDS have poorer prognosis and potentially higher mortality. Although no effective treatment is formally approved for COVID‐19 infection, support of ventilation with oxygen therapy and sometimes mechanical ventilation is often required. Treatment with systemic and/or local glucocorticoids might be helpful to alleviate the pulmonary inflammation and edema, which may decrease the development and/or consequences of ARDS. In this article, we focus on the lung edema and ALI of patients with this widely transmitted COVID‐19 infection in order to provide clinical indications and potential therapeutic targets for clinicians and researchers.

Ferrostatin-1 alleviates lipopolysaccharide-induced acute lung injury via inhibiting ferroptosis

BackgroundFerroptosis is a newly recognized type of cell death, which is different from traditional necrosis, apoptosis or autophagic cell death. However, the position of ferroptosis in lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored intensively so far. In this study, we mainly analyzed the relationship between ferroptosis and LPS-induced ALI.MethodsIn this study, a human bronchial epithelial cell line, BEAS-2B, was treated with LPS and ferrostatin-1 (Fer-1, ferroptosis inhibitor). The cell viability was measured using CCK-8. Additionally, the levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and iron, as well as the protein level of SLC7A11 and GPX4, were measured in different groups. To further confirm the in vitro results, an ALI model was induced by LPS in mice, and the therapeutic action of Fer-1 and ferroptosis level in lung tissues were evaluated.ResultsThe cell viability of BEAS-2B was down-regulated by LPS treatment, together with the ferroptosis markers SLC7A11 and GPX4, while the levels of MDA, 4-HNE and total iron were increased by LPS treatment in a dose-dependent manner, which could be rescued by Fer-1. The results of the in vivo experiment also indicated that Fer-1 exerted therapeutic action against LPS-induced ALI, and down-regulated the ferroptosis level in lung tissues.ConclusionsOur study indicated that ferroptosis has an important role in the progression of LPS-induced ALI, and ferroptosis may become a novel target in the treatment of ALI patients.

Lipid‐Embedded Molecular Dynamics Simulation Model for Exploring the Reverse Prostaglandin D2 Agonism of CT‐133 towards CRTH2 in the Treatment of Type‐2 Inflammation Dependent Diseases

Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) has been involved in several inflammation dependent diseases by mediating the chemotaxis of pro-inflammatory cells in response to allergy and other responses through PGD2 ligation. This CRTH2-PGD2 signaling pathway has become a target for treating allergic and type 2 inflammation dependent diseases, with many inhibitors developed to target the PGD2 binding pocket. One of such inhibitors is the ramatroban analog, CT-133, which exhibited therapeutic potency cigarette smoke-induced acute lung injury in patients. Nonetheless, the molecular mechanism and structural dynamics that accounts for its therapeutic prowess remain unclear. Employing computational tools, this study revealed that although the carboxylate moiety in CT-133 and the native agonist PGD2 aided in their stability within the CRTH2 binding pocket, the tetrahydrocarbazole group of CT-133 engaged in strong interactions with binding pocket residues which could have formed as the basis of the antagonistic advantage of CT-133. Tetrahydrocarbazole group interactions also enhanced the relative stability CT-133 within the binding pocket which consequently favored CT-133 binding affinity. CT-133 binding also induced an inactive or 'desensitized' state in the helix 8 of CRTH2 which could conversely favor the recruitment of arrestin. These revelations would aid in the speedy development of small molecule inhibitors of CRTH2 in the treatment of type 2 inflammation dependent diseases.

The Effect of Caloric Supplement in the Clinical Outcomes in Acute Lung Injury Patients

The Effect of Caloric Supplement in the Clinical Outcomes in Acute Lung Injury Patients

The methanol extract of Guettarda speciosa Linn. Ameliorates acute lung injury in mice

BackgroundGuettarda speciosa is mainly found in tropical areas in Asia. Although G. speciosa is traditionally used to treat some of the inflammatory disorders, the experimental evidence supporting the anti-inflammatory effect of G. speciosa is limited. Here, we sought to obtain evidence that G. speciosa has anti-inflammatory activity using an acute lung injury (ALI) mouse model and to explore possible underlying mechanisms for the activity.MethodsThe methanol extract of G. speciosa Linn. (MGS) was fingerprinted by HPLC. Cytotoxicity was determined by MTT and flow cytometer. As for an ALI mouse model, C57BL/6 mice received an intratracheal (i.t.) injection of lipopolysaccharide (LPS). The effects of MGS on lung inflammation in the ALI mice were assessed by differential cell counting and FACS of inflammatory cells and hematoxylin and eosin staining of lung tissue. Proteins were analyzed by immunoprecipitation and immunoblotting, and gene expression was by real-time qPCR. Neutrophil elastase activity was measured by ELISA.ResultsMGS did not cause metabolic disarray or produce reactive oxygen species that could induce cytotoxicity. Similar to ALI patients, C57BL/6 mice that received an i.t. LPS developed a high level of neutrophils, increased pro-inflammatory cytokines, and inflicted tissue damage in the lung, which was suppressed by i.t. MGS administered at 2 h after LPS. Mechanistically, MGS activated Nrf2, which was related to MGS interrupting the ubiquitin-dependent degradation of Nrf2. MGS suppressed the nuclear localization of NF-κB induced by LPS, suggesting the inhibition of NF-κB activity. Furthermore, MGS inhibited the enzymatic activity of neutrophil elastase.ConclusionMGS could suppress lung inflammation in an ALI mouse model, the effect of which could be attributed to multiple mechanisms, including the activation of Nrf2 and the suppression of NF-κB and neutrophil elastase enzymatic activity by MGS.

Semiparametric Inference for the Functional Cox Model

This article studies penalized semiparametric maximum partial likelihood estimation and hypothesis testing for the functional Cox model in analyzing right-censored data with both functional and scalar predictors. Deriving the asymptotic joint distribution of finite-dimensional and infinite-dimensional estimators is a very challenging theoretical problem due to the complexity of semiparametric models. For the problem, we construct the Sobolev space equipped with a special inner product and discover a new joint Bahadur representation of estimators of the unknown slope function and coefficients. Using this key tool, we establish the asymptotic joint normality of the proposed estimators and the weak convergence of the estimated slope function, and then construct local and global confidence intervals for an unknown slope function. Furthermore, we study a penalized partial likelihood ratio test, show that the test statistic enjoys the Wilks phenomenon, and also verify the optimality of the test. The theoretical results are examined through simulation studies, and a right-censored data example from the Improving Care of Acute Lung Injury Patients study is provided for illustration. Supplementary materials for this article are available online.