Ac2-26 Reduced Lung Injury After Cardiopulmonary Bypass via the AKT1/GSK3ß/eNOS Pathway.

INTRODUCTION: Cardiopulmonary bypass (CPB) leads to severe inflammation and lung injury. Our previous study showed that Ac2-26 (an active n-terminal peptide of Annexin A1) can reduce acute lung injury. The aim of this study was to evaluate the effect of Ac2-26 on lung injury in CPB rats. METHODS: Forty rats were randomly divided into the sham, CPB, Ac, Ac/serine/threonine kinase 1 (AKT1), and Ac/ glycogen synthase kinase (GSK)-3ß groups. The rats in the sham group only received anesthesia, intubation, and cannulation. The rats in the other 4 groups received the standard CPB procedure. The rats in the CPB, Ac, Ac/AKT1, and Ac/GSK3ß groups were immediately injected with saline, Ac2-26 (1 mg/kg), Ac2-26 combined with short hairpin RNA (AKT1), or Ac2-26 combined with a GSK3ß inhibitor after CPB. At 12 h after the end of CPB, the PaO2/ fraction of inspired oxygen ratio, wet/dry weight ratio and protein content in the bronchoalveolar lavage fluid (BALF) were recorded. The numbers of macrophages and neutrophils in the BALF and blood were determined. Cytokine levels in the blood and BALF were investigated. Lung tissue histology and apoptosis were estimated. The expression of nuclear factor kappa- B, AKT1, GSK3ß, endothelial nitric oxide synthase and apoptosis-related proteins was analyzed. The survival of all the rats was recorded. RESULTS: Compared with the rats in the sham group, all the parameters examined worsened in the rats that received CPB. Compared with those in the CPB group, Ac2-26 significantly improved pulmonary capillary permeability, reduced cytokine levels, and decreased histological scores and apoptosis. The protective effect of Ac2-26 on lung injury was significantly reversed by AKT1 short hairpin RNA or a GSK3ß inhibitor. CONCLUSIONS: Ac2-26 significantly reduced lung injury and inflammation after CPB. The protective effect of Ac2-26 mainly depended on the AKT1/GSK3ß/endothelial nitric oxide synthase pathway.

Ac2-26 activated the AKT1/GSK3ß pathway to reduce cerebral neurons pyroptosis and improve cerebral function in rats after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) results in brain injury, which is primarily caused by inflammation. Ac2-26 protects against ischemic or hemorrhage brain injury. The present study was to explore the effect and mechanism of Ac2-26 on brain injury in CPB rats. METHODS: Forty-eight rats were randomized into sham, CPB, Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups. Rats in sham group only received anesthesia and in the other groups received standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups were injected with shRNA, inhibitor and agonist of GSK3ß respectively. The neurological function score, brain edema and histological score were evaluated. The neuronal survival and hippocampal pyroptosis were assessed. The cytokines, activity of NF-κB, S100 calcium-binding protein ß(S100ß) and neuron-specific enolase (NSE), and oxidative were tested. The NLRP3, cleaved-caspase-1 and cleaved-gadermin D (GSDMD) in the brain were also detected. RESULTS: Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury. Ac2-26 reduced the local and systemic inflammation, oxidative stress response and promoted neuronal survival. Ac2-26 reduced hippocampal pyroptosis and decreased pyroptotic proteins in brain tissue. The protection of Ac2-26 was notably lessened by shRNA and inhibitor of GSK3ß. The agonist of GSK3ß recovered the protection of Ac2-26 in presence of shRNA. CONCLUSIONS: Ac2-26 significantly improved neurological function, reduced brain injury via regulating inflammation, oxidative stress response and pyroptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1/ GSK3ß pathway.

Identification of distinct clinical phenotypes of acute respiratory distress syndrome with differential responses to treatment.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome, and the identification of homogeneous subgroups and phenotypes is the first step toward precision critical care. We aimed to explore whether ARDS phenotypes can be identified using clinical data, are reproducible and are associated with clinical outcomes and treatment response. METHODS: This study is based on a retrospective analysis of data from the telehealth intensive care unit (eICU) collaborative research database and three ARDS randomized controlled trials (RCTs) (ALVEOLI, FACTT and SAILS trials). We derived phenotypes in the eICU by cluster analysis based on clinical data and compared the clinical characteristics and outcomes of each phenotype. The reproducibility of the derived phenotypes was tested using the data from three RCTs, and treatment effects were evaluated. RESULTS: Three clinical phenotypes were identified in the training cohort of 3875 ARDS patients. Of the three phenotypes identified, phenotype I (n = 1565; 40%) was associated with fewer laboratory abnormalities, less organ dysfunction and the lowest in-hospital mortality rate (8%). Phenotype II (n = 1232; 32%) was correlated with more inflammation and shock and had a higher mortality rate (18%). Phenotype III (n = 1078; 28%) was strongly correlated with renal dysfunction and acidosis and had the highest mortality rate (22%). These results were validated using the data from the validation cohort (n = 3670) and three RCTs (n = 2289) and had reproducibility. Patients with these ARDS phenotypes had different treatment responses to randomized interventions. Specifically, in the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on ventilator-free days differed by phenotype (p = 0.001); in the FACTT cohort, there was a significant interaction between phenotype and fluid-management strategy for 60-day mortality (p = 0.01). The fluid-conservative strategy was associated with improved mortality in phenotype II but had the opposite effect in phenotype III. CONCLUSION: Three clinical phenotypes of ARDS were identified and had different clinical characteristics and outcomes. The analysis shows evidence of a phenotype-specific treatment benefit in the ALVEOLI and FACTT trials. These findings may improve the identification of distinct subsets of ARDS patients for exploration in future RCTs.

Diannexin Can Ameliorate Acute Respiratory Distress Syndrome in Rats by Promoting Heme Oxygenase-1 Expression.

BACKGROUND: The recombinant protein diannexin can inhibit platelet-mediated events, which contribute to acute respiratory distress syndrome (ARDS). Here, we investigated the effect of diannexin and its effect on heme oxygenase-1 (HO-1) in ARDS. METHODS: A total of 32 rats were randomized into sham, ARDS, diannexin (D), and diannexin+HO-1 inhibitor (DH) groups. Alveolar-capillary permeability was evaluated by testing the partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio, lung wet/dry weight ratio, and protein levels in the lung. Inflammation was assessed by measuring cytokine levels in the bronchial alveolar lavage fluid (BALF) and serum and nuclear factor-κB (NF-κB) in the lung tissue. Inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and myeloperoxidase (MPO) were measured to evaluate the oxidative stress response. Lung tissue pathology and apoptosis were also evaluated. We measured HO-1 expression in the lung tissue to investigate the effect of diannexin on HO-1 in ARDS. RESULTS: Compared with the ARDS group, diannexin improved PaO2/FiO2, lung wet/dry weight ratio, and protein levels in the BALF and decreased levels of cytokines and NF-κB in the lung and serum. Diannexin inhibited the oxidative stress response and significantly ameliorated pathological lung injury and apoptosis. The partial reversal of diannexin effects by a HO-1 inhibitor suggests that diannexin may promote HO-1 expression to ameliorate ARDS. CONCLUSIONS: We showed that diannexin can improve alveolar-capillary permeability, inhibit the oxidative stress response and inflammation, and protect against ARDS-induced lung injury and apoptosis.

Budesonide ameliorates lung injury induced by large volume ventilation.

BACKGROUND: Ventilation-induced lung injury (VILI) is a health problem for patients with acute respiratory dysfunction syndrome. The aim of this study was to investigate the effectiveness of budesonide in treating VILI. METHODS: Twenty-four rats were randomized to three groups: a ventilation group, ventilation/budesonide group, and sham group were ventilated with 30 ml/kg tidal volume or only anesthesia for 4 hor saline or budesonide airway instillation immediately after ventilation. The PaO2/FiO2and wet-to-dry weight ratios, protein concentration, neutrophil count, and neutrophil elastase levels in bronchoalveolar lavage fluid (BALF) and the levels of inflammation-related factors were examined. Histological evaluation of and apoptosis measurement inthe lung were conducted. RESULTS: Compared with that in the ventilation group, the PaO2/FiO2 ratio was significantly increased by treatment with budesonide. The lung wet-to-dry weight ratio, total protein, neutrophil elastase level, and neutrophilcount in BALF were decreased in the budesonide group. The BALF and plasma tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, intercellular adhesion molecule (ICAM)-1, and macrophage inflammatory protein (MIP)-2 levels were decreased, whereas the IL-10 level was increased in the budesonide group. The phosphorylated nuclear factor (NF)-kBlevels in lung tissue were inhibited by budesonide. The histological changes in the lung and apoptosis were reduced by budesonide treatment. Bax, caspase-3, and cleaved caspase-3 were down-regulated, and Bcl-2 was up-regulated by budesonide. CONCLUSIONS: Budesonide ameliorated lung injury induced by large volume ventilation, likely by improving epithelial permeability, decreasing edema, inhibiting local and systemic inflammation, and reducing apoptosis in VILI.

Tranexamic acid for the prevention of postpartum hemorrhage after cesarean section: a double-blind randomization trial.

OBJECT: Our purpose in conducting this study was to determine the efficacy of tranexamic acid (TXA) in reducing blood loss in patients after cesarean section (CS). METHOD: A randomized, double-blind, case-controlled study was conducted on 174 primipara undergoing CS. 88 of them given 10 mg/kg TXA immediately before CS were compared with 86 others to whom TXA was not given. Blood loss was calculated from blood collected and measured during two periods: the first period was from placental delivery to end of CS and the second from the end of CS to 2 h postpartum. Vital signs such as BP, HR, RP, hemoglobin, platelet count, postoperative PT and PPT were tested in the two groups. RESULTS: Blood loss in the period between the end of CS and 2 h postpartum was significantly lower (p < 0.01) in the TXA group (46.6 ± 42.7) than in the control group (84.7 ± 80.2). The quantity of total blood from placental delivery to 2 h postpartum was also significantly reduced (p = 0.02) in the TXA group (379.2 ± 160.1) than in the control group (441.7 ± 189.5). However, the amount of blood loss in the period from placental delivery to the end of CS did not differ between the TXA and control groups (p = 0.17). PPH stopped in 65 women (75.6 %) in the control group and in 81 (92.0 %) in the TXA group (p < 0.01). No significant abnormal vital signs were observed after TXA administration. Mild, transient side effects occurred more often in the TXA group than in the control group. CONCLUSION: Treatment with TXA is effective in reducing blood loss in patients undergoing CS. Although the study was not adequately powered to address safety issues, the observed side effects were mild and transient.

Annexin A1 peptide Ac2-26 mitigates ventilator-induced lung injury in acute respiratory distress syndrome rats and partly depended on the endothelial nitric oxide synthase pathway.

PURPOSE: Although mechanical ventilation is an essential support for acute respiratory distress syndrome (ARDS), ventilation also leads to ventilator-induced lung injury (VILI). This study aimed to estimate the effect and mechanism of Annexin A1 peptide (Ac2-26) on VILI in ARDS rats. METHODS: Thirty-two rats were randomized into the sham (S), mechanical ventilation (V), mechanical ventilation/Ac2-26 (VA), and mechanical ventilation/Ac2-26/L-NIO (VAL) groups. The S group only received anesthesia, and the other three groups received endotoxin and then ventilation for 4 h. Rats in the V, VA and VAL groups received saline, Ac2-26, and A c2-26/N5-(1-iminoethyl)-l-ornithine (L-NIO), respectively. RESULTS: All indexes deteriorated in the V, VA and VAL groups compared with the S group. Compared with V group, the PaO2/FiO2 ratio was increased, but the wet-to-dry weight ratio and protein levels in bronchoalveolar lavage fluid were decreased in the VA group. The inflammatory cells and proinflammatory factors were reduced by Ac2-26. The oxidative stress response, lung injury and apoptosis were also decreased by Ac2-26 compared to V group. All improvements of Ac2-26 were partly reversed by L-NIO. CONCLUSIONS: Ac2-26 mitigates VILI in ARDS rats and partly depended on the endothelial nitric oxide synthase pathway.

Inhibition of DNA methylation attenuates lung ischemia-reperfusion injury after lung transplantation.

OBJECTIVE: DNA methylation plays an important role in inflammation and oxidative stress. This study aimed to investigate the effect of inhibiting DNA methylation on lung ischemia-reperfusion injury (LIRI). METHODS: We adopted a completely random design for our study. Thirty-two rats were randomized into the sham, LIRI, azathioprine (AZA), and pluripotin (SC1) groups. The rats in the LIRI, AZA, and SC1 groups received left lung transplantation and intravenous injection of saline, AZA, and SC1, respectively. After 24 hours of reperfusion, histological injury, the arterial oxygen partial pressure to fractional inspired oxygen ratio, the wet/dry weight ratio, protein and cytokine concentrations in lung tissue, and DNA methylation in lung tissue were evaluated. The pulmonary endothelium that underwent hypoxemia and reoxygenation was treated with AZA or SC1. Endothelial apoptosis, chemokines, reactive oxygen species, nuclear factor-κB, and apoptotic proteins in the endothelium were studied. RESULTS: Inhibition of DNA methylation by AZA attenuated lung injury, inflammation, and the oxidative stress response, but SC1 aggravated LIRI injury. AZA significantly improved endothelial function, suppressed apoptosis and necrosis, reduced chemokines, and inhibited nuclear factor-κB. CONCLUSIONS: Inhibition of DNA methylation ameliorates LIRI and apoptosis and improves pulmonary function via the regulation of inflammation and oxidative stress.

Segmentation of human functional tissue units in support of a Human Reference Atlas.

The Human BioMolecular Atlas Program (HuBMAP) aims to compile a Human Reference Atlas (HRA) for the healthy adult body at the cellular level. Functional tissue units (FTUs), relevant for HRA construction, are of pathobiological significance. Manual segmentation of FTUs does not scale; highly accurate and performant, open-source machine-learning algorithms are needed. We designed and hosted a Kaggle competition that focused on development of such algorithms and 1200 teams from 60 countries participated. We present the competition outcomes and an expanded analysis of the winning algorithms on additional kidney and colon tissue data, and conduct a pilot study to understand spatial location and density of FTUs across the kidney. The top algorithm from the competition, Tom, outperforms other algorithms in the expanded study, while using fewer computational resources. Tom was added to the HuBMAP infrastructure to run kidney FTU segmentation at scale-showcasing the value of Kaggle competitions for advancing research.

3D reconstruction of skin and spatial mapping of immune cell density, vascular distance and effects of sun exposure and aging.

Mapping the human body at single cell resolution in three dimensions (3D) is important for understanding cellular interactions in context of tissue and organ organization. 2D spatial cell analysis in a single tissue section may be limited by cell numbers and histology. Here we show a workflow for 3D reconstruction of multiplexed sequential tissue sections: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis). We demonstrate MATRICS-A in 26 serial sections of fixed skin (stained with 18 biomarkers) from 12 donors aged between 32-72 years. Comparing the 3D reconstructed cellular data with the 2D data, we show significantly shorter distances between immune cells and vascular endothelial cells (56 µm in 3D vs 108 µm in 2D). We also show 10-70% more T cells (total) within 30 µm of a neighboring T helper cell in 3D vs 2D. Distances of p53, DDB2 and Ki67 positive cells to the skin surface were consistent across all ages/sun exposure and largely localized to the lower stratum basale layer of the epidermis. MATRICS-A provides a framework for analysis of 3D spatial cell relationships in healthy and aging organs and could be further extended to diseased organs.

Leveraging online shopping behaviors as a proxy for personal lifestyle choices: New insights into chronic disease prevention literacy.

Objective: Ubiquitous internet access is reshaping the way we live, but it is accompanied by unprecedented challenges in preventing chronic diseases that are usually planted by long exposure to unhealthy lifestyles. This paper proposes leveraging online shopping behaviors as a proxy for personal lifestyle choices to improve chronic disease prevention literacy, targeted for times when e-commerce user experience has been assimilated into most people's everyday lives. Methods: Longitudinal query logs and purchase records from 15 million online shoppers were accessed, constructing a broad spectrum of lifestyle features covering various product categories and buyer personas. Using the lifestyle-related information preceding online shoppers' first purchases of specific prescription drugs, we could determine associations between their past lifestyle choices and whether they suffered from a particular chronic disease. Results: Novel lifestyle risk factors were discovered in two exemplars-depression and type 2 diabetes, most of which showed reasonable consistency with existing healthcare knowledge. Further, such empirical findings could be adopted to locate online shoppers at higher risk of these chronic diseases with decent accuracy [i.e. (area under the receiver operating characteristic curve) AUC=0.68 for depression and AUC=0.70 for type 2 diabetes], closely matching the performance of screening surveys benchmarked against medical diagnosis. Conclusions: Mining online shopping behaviors can point medical experts to a series of lifestyle issues associated with chronic diseases that are less explored to date. Hopefully, unobtrusive chronic disease surveillance via e-commerce sites can grant consenting individuals a privilege to be connected more readily with the medical profession and sophistication.

Tissue registration and exploration user interfaces in support of a human reference atlas.

Seventeen international consortia are collaborating on a human reference atlas (HRA), a comprehensive, high-resolution, three-dimensional atlas of all the cells in the healthy human body. Laboratories around the world are collecting tissue specimens from donors varying in sex, age, ethnicity, and body mass index. However, harmonizing tissue data across 25 organs and more than 15 bulk and spatial single-cell assay types poses challenges. Here, we present software tools and user interfaces developed to spatially and semantically annotate ("register") and explore the tissue data and the evolving HRA. A key part of these tools is a common coordinate framework, providing standard terminologies and data structures for describing specimen, biological structure, and spatial data linked to existing ontologies. As of April 22, 2022, the "registration" user interface has been used to harmonize and publish data on 5,909 tissue blocks collected by the Human Biomolecular Atlas Program (HuBMAP), the Stimulating Peripheral Activity to Relieve Conditions program (SPARC), the Human Cell Atlas (HCA), the Kidney Precision Medicine Project (KPMP), and the Genotype Tissue Expression project (GTEx). Further, 5,856 tissue sections were derived from 506 HuBMAP tissue blocks. The second "exploration" user interface enables consortia to evaluate data quality, explore tissue data spatially within the context of the HRA, and guide data acquisition. A companion website is at https://cns-iu.github.io/HRA-supporting-information/ .

Ac2-26 mitigated acute respiratory distress syndrome rats via formyl peptide receptor pathway.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by severe local and systemic inflammation. Ac2-26, an Annexin A1 Peptide, can reduce the lung injury induced by reperfusion via the inhibition of inflammation. The present study aims to evaluate the effect and mechanism of Ac2-26 in ARDS. METHODS: Thirty-two rats were anaesthetized and randomized into four groups: sham (S), ARDS (A), ARDS/Ac2-26 (AA), and ARDS/Ac2-26/BOC-2 (AAB) groups. Rats in the S group received saline for intratracheal instillation, while rats in the other three groups received endotoxin for intratracheal instillation, in order to prepare the ARDS and inject the saline, Ac2-26, and Ac2-26 combined with BOC-2. After 24 h, the PaO2/FiO2 ratio was calculated. The lung tissue wet-to-dry weight ratio and the protein level in bronchoalveolar lavage fluid (BALF) were tested. Then, the cytokines in BALF and serum, and the inflammatory cells in BALF were investigated. Afterwards, the oxidative stress response and histological injury was evaluated. Subsequently, the epithelium was cultured and analyzed to estimate the effect of Ac2-26 on apoptosis. RESULTS: Compared to the S group, all indexes worsened in the A, AA, and AAB groups. Furthermore, compared to the S group, Ac2-26 significantly improved the lung injury and alveolar-capillary permeability, and inhibited the oxidative stress response. In addition, Ac2-26 reduced the local and systemic inflammation through the regulation of pro- and anti-inflammatory cytokines, and the decrease in inflammatory cells in BALF. Moreover, Ac2-26 inhibited the epithelium apoptosis induced by LPS through the modulation of apoptosis-regulated proteins. The protective effect of Ac2-26 on ARDS was partially reversed by the FPR inhibitor, BOC-2. CONCLUSION: Ac2-26 reduced the lung injury induced by LPS, promoted alveolar-capillary permeability, ameliorated the local and systemic inflammation, and inhibited the oxidative stress response and apoptosis. The protection of Ac2-26 on ARDS was mainly dependent on the FPR pathway.

Corrigendum to "Desflurane Attenuates Ventilator-Induced Lung Injury in Rats with Acute Respiratory Distress Syndrome".

[This corrects the article DOI: 10.1155/2018/7507314.].

Considerations for Using the Vasculature as a Coordinate System to Map All the Cells in the Human Body.

Several ongoing international efforts are developing methods of localizing single cells within organs or mapping the entire human body at the single cell level, including the Chan Zuckerberg Initiative's Human Cell Atlas (HCA), and the Knut and Allice Wallenberg Foundation's Human Protein Atlas (HPA), and the National Institutes of Health's Human BioMolecular Atlas Program (HuBMAP). Their goals are to understand cell specialization, interactions, spatial organization in their natural context, and ultimately the function of every cell within the body. In the same way that the Human Genome Project had to assemble sequence data from different people to construct a complete sequence, multiple centers around the world are collecting tissue specimens from diverse populations that vary in age, race, sex, and body size. A challenge will be combining these heterogeneous tissue samples into a 3D reference map that will enable multiscale, multidimensional Google Maps-like exploration of the human body. Key to making alignment of tissue samples work is identifying and using a coordinate system called a Common Coordinate Framework (CCF), which defines the positions, or "addresses," in a reference body, from whole organs down to functional tissue units and individual cells. In this perspective, we examine the concept of a CCF based on the vasculature and describe why it would be an attractive choice for mapping the human body.

Endothelial colony-forming cells reduced the lung injury induced by cardiopulmonary bypass in rats.

BACKGROUND: Cardiopulmonary bypass (CPB) results in severe lung injury via inflammation and endothelial injury. The aim of this study was to evaluate the effect of endothelial colony-forming cells (ECFCs) on lung injury in rats subjected to CPB. METHODS: Thirty-two rats were randomized into the sham, CPB, CPB/ECFC and CPB/ECFC/L-NIO groups. The rats in the sham group received anaesthesia, and the rats in the other groups received CPB. The rats also received PBS, ECFCs and L-NIO-pre-treated ECFCs. After 24 h of CPB, pulmonary capillary permeability, including the PaO2/FiO2 ratio, protein levels in bronchoalveolar lavage fluid (BALF) and lung tissue wet/dry weight were evaluated. The cell numbers and cytokines in BALF and peripheral blood were tested. Endothelial injury, lung histological injury and apoptosis were assessed. The oxidative stress response and apoptosis-related proteins were analysed. RESULTS: After CPB, all the data deteriorated compared with those obtained in the S group (sham vs CPB vs CPB/ECFC vs CPB/ECFC/L-NIO: histological score 1.62 ± 0.51 vs 5.37 ± 0.91 vs 3.37 ± 0.89 vs 4.37 ± 0.74; PaO2/FiO2 389 ± 12 vs 233 ± 36 vs 338 ± 28 vs 287 ± 30; wet/dry weight 3.11 ± 0.32 vs 6.71 ± 0.73 vs 4.66 ± 0.55 vs 5.52 ± 0.57; protein levels in BALF: 134 ± 22 vs 442 ± 99 vs 225 ± 41 vs 337 ± 53, all P < 0.05). Compared to the CPB treatment, ECFCs significantly improved pulmonary capillary permeability and PaO2/FiO2. Similarly, ECFCs also decreased the inflammatory cell number and pro-inflammatory factors in BALF and peripheral blood, as well as the oxidative stress response in the lung tissue. ECFCs reduced the lung histological injury score and apoptosis and regulated apoptosis-related proteins in the lung tissue. Compared with the CPB/ECFC group, all the indicators were partly reversed by the L-NIO. CONCLUSIONS: ECFCs significantly reduced lung injury induced by inflammation after CPB.

Endothelial Progenitor Cells Attenuate Ventilator-Induced Lung Injury with Large-Volume Ventilation.

Ventilator-induced lung injury (VILI) is a common complication that results from treatment with mechanical ventilation (MV) in acute respiratory distress syndrome (ARDS) patients. The present study investigated the effect of endothelial progenitor cell (EPC) transplantation on VILI. Wistar rats were divided into three groups (n = 8): sham (S), VILI model (V) induced by tidal volume ventilation (17 mL/kg), and VILI plus EPC transplantation (VE) groups. The lung PaO2/FiO2 ratio, pulmonary wet-to-dry (W/D) weight ratio, number of neutrophils, total protein, neutrophil elastase level, and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were examined. Furthermore, the histological and apoptotic analysis, and lung tissue protein expression analysis of Bax, Bcl-2, cleaved caspase-3, matrix metalloproteinase (MMP)-9, total nuclear factor kappa B (total-NF-κB), phosphorylated NF-κB (phospho-NF-κB) and myosin light chain (MLC) were performed. The ventilation-induced decrease in PaO2/FiO2 ratio, and the increase in W/D ratio and total protein concentration were prevented by the EPC transplantation. The EPC transplantation (VE group) significantly attenuated the VILI-induced increased expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-8, MMP-9, phospho-NF-κB and MLC, neutrophil elastase levels and neutrophil counts in BALF. In addition, the anti-inflammatory factor IL-10 increased in the VE group. Furthermore, pulmonary histological injury and apoptosis (TUNEL-positive cells, increase in Bax and cleaved caspase-3) were considerably diminished by the EPC transplantation. The EPC transplantation ameliorated the VILI. The mechanism may be primarily through the improvement of epithelial permeability, inhibition of local and systemic inflammation, and reduction in apoptosis.

Ac2-26 ameliorates lung ischemia-reperfusion injury via the eNOS pathway.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a major complication after lung transplantation. Annexin A1 (AnxA1) ameliorates inflammation in various injured organs. This study aimed to determine the effects and mechanism of AnxA1 on LIRI after lung transplantation. METHODS: Thirty-two rats were randomized into sham, saline, Ac2-26 and Ac2-26/L groups. Rats in the saline, Ac2-26 and Ac2-26/L groups underwent left lung transplantation and received saline, Ac2-26, and Ac2-26/L-NIO, respectively. After 24 h of reperfusion, serum and transplanted lung tissues were examined. RESULTS: The partial pressure of oxygen (PaO2) was increased in the Ac2-26 group compared to that in the saline group but was decreased by L-NIO treatment. In the Ac2-26 group, the wet-to-dry (W/D) weight ratios, total protein concentrations, proinflammatory factors and inducible nitric oxide synthase levels were notably decreased, but the concentrations of anti-inflammatory factors and endothelial nitric oxide synthase levels were significantly increased. Ac2-26 attenuated histological injury and cell apoptosis, and this improvement was reversed by L-NIO. CONCLUSIONS: Ac2-26 reduced LIRI and improved alveoli-capillary permeability by inhibiting oxygen stress, inflammation and apoptosis. The protective effect of Ac2-26 on LIRI largely depended on the endothelial nitric oxide synthase pathway.

Endothelial Colony-forming Cells Attenuate Ventilator-induced Lung Injury in Rats with Acute Respiratory Distress Syndrome.

BACKGROUND: Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). AIM OF THE STUDY: This study investigated whether endothelial colony-forming cells (ECFC) could inhibit VILI in a rat model of acute respiratory distress syndrome (ARDS). METHODS: Male Wistar rats received the femoral artery and venous cannulation (sham group) or were injected intravenously with 500 µg/kg lipopolysaccharide to induce ARDS. The ARDS rats were subjected to MV. Immediately after the MV, the rats were randomized and injected intravenously with vehicle (ARDS group) or ECFC (ECFC group, n = 8 per group). The oxygen index, lung wet-to-dry weight (W/D) ratios, cytokine protein levels in serum or bronchoalveolar lavage fluid (BALF), neutrophil counts, neutrophil elastase and total protein levels in BALF, histology and cell apoptosis in the lung were detected. The protein levels of endothelin-1, inducible nitric oxide synthase (iNOS), endothelial NOS, matrix metalloproteinase (MMP)-9, Bax, Bcl-2, gelsolin, cleaved caspase-3, phosphorylated NF-κBp65 and myosin light chain (MLC) in the lung were analyzed. RESULTS: Compared with the ARDS group, treatment with ECFC significantly increased the oxygen index, and decreased the lung W/D ratios and injury, and the numbers of apoptotic cells in the lungs, neutrophils counts, total protein and elastase concentrations in BALF of rats. ECFC treatment significantly minimized the protein levels of pro-inflammatory cytokines in BALF and serum, but increased interleukin 10 in rats. Furthermore, ECFC treatment significantly reduced the protein levels of endothelin-1, iNOS, Bax, Gelsolin, MMP-9, cleaved caspase-3, phosphorylated NF-κBp65 and MLC, but enhanced eNOS and Bcl-2 in the lungs of rats. CONCLUSIONS: Therefore, ECFC attenuated inflammation, cell apoptosis and VILI in ARDS rats.

Desflurane Attenuates Ventilator-Induced Lung Injury in Rats with Acute Respiratory Distress Syndrome.

Ventilator-induced lung injury aggravates the existing lung injury. This study investigated the effect of desflurane on VILI in a rat model of acute respiratory distress syndrome. Forty-eight rats were randomized into a sham (S) group, control (C) group, lipopolysaccharide/ventilation (LV) group, lipopolysaccharide/ventilation/desflurane (LVD) group, or lipopolysaccharide/low ventilation with and without desflurane (LLV and LLVD) groups. Rats in the S group received anesthesia only. Rats in the LV and LVD groups received lipopolysaccharide and were ventilated with a high tidal volume. Rats in LLV and LLVD groups were treated as the LV and LVD groups and ventilated with a low tidal volume. PaO2/FiO2, lung wet-to-dry weight ratios, concentrations of inflammatory factors in serum and BALF, histopathologic analysis of lung tissue, and levels of nuclear factor- (NF-) κB protein in lung tissue were investigated. PaO2/FiO2 was significantly increased by desflurane. Total cell count, macrophages, and neutrophils in BALF and proinflammatory factors in BALF and serum were significantly decreased by desflurane, while IL-10 was increased. The histopathological changes and levels of NF-κB protein in lung tissue were decreased by desflurane. The results indicated that desflurane ameliorated VILI in a rat model of acute respiratory distress syndrome.