Changes in Expressions of HSP27, HSP70, and Soluble Glycoprotein in Heart Failure Rats Complicated with Pulmonary Edema and Correlations with Cardiopulmonary Functions.

The study is aimed at investigating the changes in expressions of heat shock protein 27 (HSP27), HSP70, and soluble glycoprotein (SGP) in heart failure (HF) rats complicated with pulmonary edema and exploring their potential correlations with cardiopulmonary functions. The rat model of HF was established, and the rats were divided into HF model group (model group, n = 15) and normal group (n = 15). After successful modeling, MRI and ECG were applied to detect the cardiac function indexes of the rats. The myocardial function indexes were determined, the injury of myocardial tissues was observed via hematoxylin and eosin (HE) staining, and the content of myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9), and tumor necrosis factor-alpha (TNF-α) in the blood was measured. The partial pressure of oxygen (PaO2) and oxygenation index (OI) were observed, and the airway resistance and lung compliance were examined. Moreover, quantitative polymerase chain reaction (qPCR) and Western blotting assay were performed to detect the gene and protein expression levels of HSP27, HSP70, and SGP130. The levels of serum creatine kinase (CK), creatine (Cr), and blood urea nitrogen (BUN) were increased markedly in model group (p < 0.05). Model group had notably decreased fractional shortening (FS) and ejection fraction (EF) compared with normal group (p < 0.05), while the opposite results of left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were detected. In model group, the content of serum MPO, MMP-9, and TNF-α was raised remarkably (p < 0.05), OI and PaO2 were reduced notably (p < 0.05), the airway resistance was increased (p < 0.05), and the lung compliance was decreased (p < 0.05). Obviously elevated gene and protein expression levels of HSP27, HSP70, and SGP130 were detected in model group (p < 0.05). The expressions of HSP27, HSP70, and SGP130 are increased in HF rats complicated with pulmonary edema, seriously affecting the cardiopulmonary functions of the rats.

Pulmonary and vascular effects of acute ozone exposure in diabetic rats fed an atherogenic diet.

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.

Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions.

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.

Innate inflammatory response to acute inhalation exposure of riot control agent oleoresin capsicum in female rats: An interplay between neutrophil mobilization and inflammatory markers.

Aim: The use of oleoresin capsicum (OC) sprays, due to their irreversible health effects has now grown into a matter of heated debate. In the present study, the early phase pulmonary events involving chemotactic and inflammatory mediators after short-exposure duration to OC have been presented.Materials and methods: Female Wistar rats used in the evaluation of respiratory parameters at 1 h, 3 h, and 24 h post-exposure, were sacrificed for the evaluation of blood cell counts, BALF cytokine estimation, lung capillary leakage, study of oxidative stress and histopathology of the lungs.Results: Results confirmed a dose-dependent effect of OC exposure on serum clinical chemistry and hematological parameters. Subsequent upregulation of IL-l and TNF-α indicated lung's responses to acute oxidant-induced injury and inflammation after OC exposure. Significant alterations in the pulmonary levels of reactive oxygen intermediates were seen following the inhalation of OC. Infiltration of polymorphonuclear leukocytes, mostly neutrophils, into the site of infection was evident in the cytocentrifuged samples of BALF. Histological samples of rat lung sections revealed the recruitment of inflammatory cells in the airways and around blood vessels in the subepithelium of conducting airways.Conclusion: Results of the present study demonstrated that, exposure to OC spray may mitigate inflammatory response and development of acute lung injury in rats. However, it can be concluded that although OC spray causes pulmonary hazards in the aforementioned concentrations, it can be used as a non-lethal riot control agent in minimal concentration. Understanding the in-depth mechanism of action in the molecular and receptor level will help in developing effective antagonist against OC.

Vascular Endothelial Growth Factor-121 Administration Mitigates Halogen Inhalation-Induced Pulmonary Injury and Fetal Growth Restriction in Pregnant Mice.

Background Circulating levels of sFLT-1 (soluble fms-like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non-pregnant female mice were exposed to air or to Br2 at 600 ppm for 30 minutes and were treated with vehicle or with VEGF-121 (100 µg/kg, subcutaneously) daily, starting 48 hours post-exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post-exposure. In Br2-exposed pregnant mice, there was a time-dependent and significant increase in plasma levels of sFLT-1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF-121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br2. Exogenous VEGF-121 administration had no effect in non-pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT-1 overexpression as a mechanism of pregnancy-specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.

The development of various forms of lung injury with increasing tidal volume in normal rats.

Sixty-three, open-chest normal rats were subjected to mechanical ventilation (MV) with tidal volumes (VT) ranging from 7.5-39.5ml kg-1 and PEEP 2.3 cmH2O. Arterial blood gasses and pressure, and lung mechanics were measured during baseline ventilation (VT = 7.5ml kg-1) before and after test ventilation, when cytokine, von Willebrand factor (vWF), and albumin concentration in serum and broncho-alveolar lavage fluid (BALF), wet-to-dry weight ratio (W/D), and histologic injury scores were assessed. Elevation of W/D and serum vWF and cytokine concentration occurred with VT > 25ml kg-1. With VT > 30ml kg-1 cytokine and albumin concentration increased also in BALF, arterial oxygen tension decreased, lung mechanics and histology deteriorated, while W/D and vWF and cytokine concentration increased further. Hence, the initial manifestation of injurious MV consists of damage of extra-alveolar vessels leading to interstitial edema, as shown by elevated vWF and cytokine levels in serum but not in BALF. Failure of the endothelial-epithelial barrier occurs at higher stress-strain levels, with alveolar edema, small airway injury, and mechanical alterations.

Carbohydrate antigen 125 predicts pulmonary congestion in patients with ST-segment elevation myocardial infarction.

Carbohydrate antigen 125 (CA125) has long been used as an ovarian cancer biomarker. However, because it is not specific for ovarian cells, CA125 could also be used to monitor congestion and inflammation in heart disease. Acute heart failure (HF) is used to identify patients with a worse prognosis in ST-segment elevation myocardial infarction (STEMI). We aimed to determine the association of CA125 with acute HF in STEMI and to compare CA125 with N-terminal pro brain natriuretic peptide (NTproBNP) with a cross-sectional study. At admission, patients were examined to define Killip class and then underwent coronary angioplasty. Blood samples, preferably taken in the hemodynamic ward, were centrifuged (1500 g for 15 min at ambient temperature) and stored at -80°C until biomarker assays were performed. Patients were divided into two groups according to the presence or absence of congestion. Patients in Killip class ≥II were in the congestion group and those with Killip

Minimal volume ventilation during robotically assisted mitral valve surgery.

INTRODUCTION: A minimal volume ventilation method for robotically assisted mitral valve surgery is described in this study. In an attempt to reduce postoperative pulmonary dysfunction, 40 of 174 patients undergoing robotically assisted mitral valve surgery were ventilated with a small tidal volume during cardiopulmonary bypass. METHODS: After propensity score matching, 31 patients with minimal volume ventilation were compared with 54 patients with no ventilation. Total ventilation time, PaO2/FiO2 ratio, arterial lactate concentration, and the rate of unilateral pulmonary edema in the matched minimal ventilation and standard treatment groups were evaluated. RESULTS: Patients in the minimal ventilation group had shorter ventilation times, 12.0 (interquartile range: 9.9-15.0) versus 14.0 (interquartile range: 12.0-16.3) hours (p = 0.036), and lower postoperative arterial lactate levels, 0.99 (interquartile range: 0.81-1.39) versus 1.28 (interquartile range: 0.99-1.86) mmol/L (p = 0.01), in comparison to patients in the standard treatment group. There was no difference in postoperative PaO2/FiO2 ratio levels or in the rate of unilateral pulmonary edema between the groups. CONCLUSION: Minimal ventilation appeared beneficial in terms of total ventilation time and blood lactatemia, while there was no improvement in arterial blood gas measurements or in the rate of unilateral pulmonary edema. The lower postoperative arterial lactate levels may suggest improved lung perfusion among patients in the minimal volume ventilation group. The differences in the ventilation times were in fact small, and further studies are required to confirm the possible advantages of the minimal volume ventilation method in robotically assisted cardiac surgery.

Hydrogen-Rich Saline Attenuates Acute Lung Injury Induced by Limb Ischemia/Reperfusion via Down-Regulating Chemerin and NLRP3 in Rats.

Limb ischemia/reperfusion (LI/R) injury is associated with high morbidity and mortality. The hypothesis of this study is that hydrogen-rich solution could attenuateacute lung injury and improve mortality via chemerin and NLRP3 after LI/R in rats. A rat model of LI/R was performed by clamping the bilateral femoral arteries for 3 h followed by reperfusion. Hydrogen-rich saline (HRS) was administered intraperitoneally (10 mL/kg or 2.5 mL/kg) when the atraumatic micro clips were released. The rats were euthanized at 2 h after reperfusion and then the arterial blood and lung specimens were harvested for further analyses. Meanwhile, survival rate was observed. The results showed that HRS improved the survival rate and attenuated pulmonary edema, injury, and apoptosis. HRS also decreased the levels of tumor necrosis factor-α, interleukin-6, myeloperoxidase and malondialdehyde, and increased the activity of superoxide dismutase in serum and lung after the LI/R event. HRS downregulated the expression of chemerin and NLRP3 in lung. The study demonstrated that chemerin and NLRP3 could serve as important response factors that were involved in the lung injury following LI/R. HRS could significantly attenuate LI/R-mediated acute lung injury, at least in part, by inhibiting the activated chemerin/NLRP3 signaling pathway.

Acute pulmonary effects of aerosolized nicotine.

Nicotine is a highly addictive principal component of both tobacco and electronic cigarette that is readily absorbed in blood. Nicotine-containing electronic cigarettes are promoted as a safe alternative to cigarette smoking. However, the isolated effects of inhaled nicotine are largely unknown. Here we report a novel rat model of aerosolized nicotine with a particle size (~1 µm) in the respirable diameter range. Acute nicotine inhalation caused increased pulmonary edema and lung injury as measured by enhanced bronchoalveolar lavage fluid protein, IgM, lung wet-to-dry weight ratio, and high-mobility group box 1 (HMGB1) protein and decreased lung E-cadherin protein. Immunohistochemical analysis revealed congested blood vessels and increased neutrophil infiltration. Lung myeloperoxidase mRNA and protein increased in the nicotine-exposed rats. Complete blood counts also showed an increase in neutrophils, white blood cells, eosinophils, and basophils. Arterial blood gas measurements showed an increase in lactate. Lungs of nicotine-inhaling animals revealed increased mRNA levels of IL-1A and CXCL1. There was also an increase in IL-1α protein. In in vitro air-liquid interface cultures of airway epithelial cells, there was a dose dependent increase in HMGB1 release with nicotine treatment. Air-liquid cultures exposed to nicotine also resulted in a dose-dependent loss of barrier as measured by transepithelial electrical resistance and a decrease in E-cadherin expression. Nicotine also caused a dose-dependent increase in epithelial cell death and an increase in caspase-3/7 activities. These results show that the nicotine content of electronic cigarettes may have adverse pulmonary and systemic effects.

Effects of Intraoperative Infusion of Esmolol on Systemic and Pulmonary Inflammation in a Porcine Experimental Model of Lung Resection Surgery.

BACKGROUND: Lung resection surgery (LRS) is associated with systemic and pulmonary inflammation, which can affect postoperative outcomes. Activation of ß-adrenergic receptors increases the expression of proinflammatory and anti-inflammatory mediators, and their blockade may attenuate the systemic inflammatory response. The aim of this study was to analyze the effect of a continuous perioperative intravenous perfusion of esmolol on postoperative pulmonary edema in an experimental model of LRS requiring periods of one-lung ventilation (OLV). METHODS: Twenty-four large white pigs were randomly assigned to 3 groups: control (CON), esmolol (ESM), and sham. The ESM group received an intravenous esmolol bolus (0.5 mg/kg) and then an esmolol infusion (0.05 mg·kg·minute) throughout the procedure. The CON group received the same volume of 0.9% saline solution as the ESM group plus a continual infusion of saline. The sham group underwent a left thoracotomy without LRS or OLV. At the end of the LRS, the animals were awakened, and after 24 hours, they underwent general anesthesia again. Lung biopsies and plasma samples were obtained to analyze the levels and expression of inflammatory mediators, and the animals also received a bronchoalveolar lavage. RESULTS: At 24 hours after the operation, the ESM group had less lung edema and lower expression of the proinflammatory biomarkers tumor necrosis factor (TNF) and interleukin (IL)-1 compared to the CON group for both lung lobes. For the mediastinal lobe biopsies, the mean difference and 95% confidence interval (CI) between the groups for edema, TNF, and IL-1 were 14.3 (95% CI, 5.6-23.1), P = .002; 0.19 (95% CI, 0.07-0.32), P = .002; and 0.13 (95% CI, 0.04-0.22), P = .006, respectively. In the left upper lobe, the mean differences for edema, TNF, and IL-1 were 12.4 (95% CI, 4.2-20.6), P = .003; 0.25 (95% CI, 0.12-0.37), P < .001; and 0.3 (95% CI, 0.08-0.53), P = .009. CONCLUSIONS: Our results suggest that esmolol reduces lung edema and inflammatory responses in the intraoperative and postoperative periods in animals that underwent LRS with OLV.

Carbohydrate antigen 125 predicts pulmonary congestion in patients with ST-segment elevation myocardial infarction

Carbohydrate antigen 125 (CA125) has long been used as an ovarian cancer biomarker. However, because it is not specific for ovarian cells, CA125 could also be used to monitor congestion and inflammation in heart disease. Acute heart failure (HF) is used to identify patients with a worse prognosis in ST-segment elevation myocardial infarction (STEMI). We aimed to determine the association of CA125 with acute HF in STEMI and to compare CA125 with N-terminal pro brain natriuretic peptide (NTproBNP) with a cross-sectional study. At admission, patients were examined to define Killip class and then underwent coronary angioplasty. Blood samples, preferably taken in the hemodynamic ward, were centrifuged (1500 g for 15 min at ambient temperature) and stored at −80°C until biomarker assays were performed. Patients were divided into two groups according to the presence or absence of congestion. Patients in Killip class ≥II were in the congestion group and those with Killip <II in the absence of congestion group. We evaluated 231 patients. The mean age was 63.3 years. HF at admission was identified in 17.7% of patients. CA125 and NTproBNP levels were higher in patients with Killip class ≥II than those with Killip class <II (8.03 vs 9.17, P=0.016 and 772.45 vs 1925, P=0.007, respectively). The area under the receiver operator characteristic curve was 0.60 (95%CI 0.53−0.66, P=0.024) for CA125 and 0.63 (95%CI 0.56−0.69, P=0.001) for NTproBNP. There was no statistical difference between the curves (P=0.69). CA125 has similar use to NTproBNP in identifying acute HF in patients presenting with STEMI.

The role of serum procalcitonin in the differential diagnosis of pneumonia from pulmonary edema among the patients with pulmonary infiltrates on chest radiography.

The aim of this study is to evaluate the usefulness of serum procalcitonin (PCT) as a diagnostic biomarker for distinguishing pneumonia from pulmonary edema in patients presenting with pulmonary infiltrates on chest radiography.A comparative study was performed retrospectively in a university-affiliated hospital, from May, 2013 to April, 2015. Adult patients (≥18 years) who showed pulmonary infiltrates on chest radiography and had blood tests with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), PCT, and N-terminal pro-b-type natriuretic peptide (NT-proBNP) on admission were included in the study. Clinical parameters collected on admission were compared between the case group (n = 143) with pneumonia and the control group (n = 88) with pulmonary edema alone.During the study period, a total of 1217 patients were identified. Of them, a total of 231 patients were included in analyses based on exclusion criteria. In the multivariate logistic regression analysis, PCT ≥0.25 ng/mL, ESR ≥35 mm/h, CRP ≥18 mg/L, NT-proBNP ≤200 pg/mL, underlying neurologic diseases, fever, sputum, absence of cardiomegaly, and a low Charlson comorbidity index were independently associated with pneumonia. For this model, the sensitivity, specificity, positive predictive value, and negative predictive value in distinguishing between the 2 groups were 90.2%, 79.6%, 87.8%, and 83.3%, respectively, with an area under the curve of 0.93.This study suggests that the practical use of PCT in conjunction with clinical data can be valuable in the differential diagnosis of pulmonary infiltrates and guidance for clinicians to prevent antibiotic misuse.

Correlation analysis on serum inflammatory cytokine level and neurogenic pulmonary edema for children with severe hand-foot-mouth disease.

OBJECTIVE: This study aims to discuss the correlation between serum inflammatory cytokines and neurogenic pulmonary edema (NPE) in children with severe hand-foot-mouth disease (HFMD). METHODS: A total of 89 patients with severe HFMD were enrolled into this study. These patients were divided into two groups, according to the presence of NPE: central nervous system disease (CNSD) group and NPE group. Serum IL-4, IL-10, IL-6, IL-17, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels were measured in patients by enzyme-linked immunosorbent assay at 1, 3, and 5 days after admission. Furthermore, risk factors for NPE were screened using multivariable logistic regression analysis. RESULTS: IL-6, TNF-α, IL-10, and interferon-γ (IFN-γ) levels in the NPE group were higher than in the CNSD group. TNF-α, IL-10, and IFN-γ levels reached a peak on the 3rd day of admission. Age, continuous fever, blood sugar, white blood cell count, and IL-10 were risk factors for the occurrence of NPE in severe HFMD. CONCLUSION: The dynamic unbalance of inflammatory cytokines is related to the occurrence and progress of NPE.

The plasma level changes of VEGF and soluble VEGF receptor-1 are associated with high-altitude pulmonary edema.

Hypoxia-induced plasma levels of VEGF and sFlt-1 are responsible for increased vascular permeability occurred in both brain and pulmonary edema. Currently, it remains unclear the exact roles of VEGF and sFlt-1 in High Altitude Pulmonary Edema (HAPE) pathogenesis. In this study, plasma levels of VEGF and sFlt-1 from 10 HAPE and 10 non-HAPE subjects were measured and compared. The results showed that plasma levels of both VEGF and sFlt-1 in HAPE patients were significantly increased as compared to the non-HAPE group. Interestingly, increased plasma levels of these two protein factors were markedly reduced after treatments. As compared to VEGF, sFlt-1 was much more affected by hypoxia and treatments, suggesting this factor was a key factor contributed to HAPE pathogenesis. Importantly, the ratio of sFlt-1 and VEGF in group of either non-HAPE or HAPE after recovery was significantly lower than the ratio in HAPE patients prior to treatments. Our findings suggested that sFlt-1 was a key factor that involved in HAPE pathogenesis and the sFlt-1/VEGF ratio could be used as a sensitive diagnostic marker for HAPE. J. Med. Invest. 65:64-68, February, 2018.

Protective Effects of Cucurbitacin B on Acute Lung Injury Induced by Sepsis in Rats.

BACKGROUND The aim of this study was to investigate the protective effects of cucurbitacin B (CuB) on sepsis-induced acute lung injury (ALI) in rats. MATERIAL AND METHODS An ALI model was made by cecal ligation and puncture (CLP) in SD rats. Rats were randomly divided into 5 groups (n=15 per group): animals undergoing a sham CLP (sham group); animals undergoing CLP (CLP control group); animals undergoing CLP and treated with CuB at 1 mg/kg of body weight (bw) (low-dose CuB [L-CuB] group), animals undergoing CuB at 2 mg/kg of bw (mid-dose CuB [M-CuB] group); and animals undergoing CuB at 5 mg/kg of bw (high-dose CuB [H-CuB] group). Samples of blood and lung tissue were harvested at different time points (6, 12, and 24 hour post-CLP surgery) for the detection of indicators which represented ALI. Five rats were respectively sacrificed at each time point. Pathological changes of lung tissue were observed by H&E staining. Another 50 rats were distributed into the same five groups to record the 72 hour survival rates. RESULTS Treatment with CuB significantly increased the blood gas PaO2 levels and decreased lung wet/dry (W/D) ratio (p<0.05). It significantly reduced protein concentration, accumulation of the inflammatory cells, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), (p<0.05), in the bronchoalveolar lavage fluid (BALF). Pulmonary pathological damage and survival rates at 72 hours were found to be effectively improved by CuB. In addition, CuB performed its pulmonary protection effects in a dose-depended manner. CONCLUSIONS CuB can effectively improve the pulmonary gas exchange function, reduce pulmonary edema, and inhibit the inflammatory response in the lung, revealing that CuB may serve as a potential therapeutic strategy for sepsis-induced ALI.

Increased Extravascular Lung Water and Plasma Biomarkers of Acute Lung Injury Precede Oxygenation Impairment in Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: After lung transplantation (LT), early prediction of grade 3 pulmonary graft dysfunction (PGD) remains a research gap for clinicians. We hypothesized that it could be improved using extravascular lung water (EVLWi) and plasma biomarkers of acute lung injury. METHODS: After institutional review board approval and informed consent, consecutive LT recipients were included. Transpulmonary thermodilution-based EVLWi, plasma concentrations of epithelial (soluble receptor for advanced glycation endproducts [sRAGE]) and endothelial biomarkers (soluble intercellular adhesion molecule-1 and endocan [full-length and cleaved p14 fragment]) were obtained before and after LT (0 [H0], 6, 12, 24, 48 and 72 hours after pulmonary artery unclamping). Grade 3 PGD was defined according to the International Society for Lung and Heart Transplantation definition, combining arterial oxygen partial pressure (PaO2)/inspired fraction of oxygen (FiO2) ratio and chest X-rays. Association of clinical risk factors, EVLWi and biomarkers with grade 3 PGD was analyzed under the Bayesian paradigm, using logistic model and areas under the receiver operating characteristic curves (AUCs). RESULTS: In 47 LT recipients, 10 developed grade 3 PGD, which was obvious at H6 in 8 cases. Clinical risk factors, soluble intercellular adhesion molecule-1 and endocan (both forms) were not associated with grade 3 PGD. Significant predictors of grade 3 PGD included (1) EVLWi (optimal cutoff, 13.7 mL/kg; AUC, 0.74; 95% confidence interval [CI], 0.48-0.99), (2) PaO2/FiO2 ratio (optimal cutoff, 236; AUC, 0.68; 95% CI, 0.52-0.84), and (3) sRAGE (optimal cutoff, 11 760 pg/mL; AUC, 0.66; 95% CI, 0.41-0.91) measured at H0. CONCLUSIONS: Immediate postreperfusion increases in EVLWi and sRAGE along with impaired PaO2/FiO2 ratios were early predictors of grade 3 PGD at or beyond 6 hours and may trigger early therapeutic interventions.

Tetrahydroberberrubine attenuates lipopolysaccharide-induced acute lung injury by down-regulating MAPK, AKT, and NF-κB signaling pathways.

Acute lung injury (ALI) is a life-threatening syndrome that is characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality worldwide. Here, we studied the protective effect of tetrahydroberberrubine (THBru), a berberine derivative, on a mouse model of lipopolysaccharide (LPS)-induced acute lung injury that was established in our previous studies. The results showed that a single oral administration of THBru significantly decreased the lung wet to dry weight (W/D) ratio at doses of 2, 10 and 50mg/kg administered 1h prior to LPS challenge (30mg/kg, intravenous injection). Histopathological changes, such as pulmonary edema, infiltration of inflammatory cells and coagulation, were also attenuated by THBru. In addition, THBru markedly decreased the total cell counts, total protein and nitrate/nitrite content in bronchoalveolar lavage fluid (BALF), significantly decreased tumor necrosis factor-α (TNF-α) and nitrate/nitrite content in the plasma, and reduced the myeloperoxidase (MPO) activity in the lung tissues. Additionally, THBru (10µM) significantly decreased the content of TNF-α and nitric oxide (NO) in LPS-induced THP-1 cells in vitro. Moreover, THBru significantly suppressed the activation of the MAPKs JNK and p38, AKT, and the NF-κB subunit p65 in LPS-induced THP-1 cells. These findings confirm that THBru attenuates LPS-induced acute lung injury by inhibiting the release of inflammatory cytokines and suppressing the activation of MAPKs, AKT, and NF-κB signaling pathways, which implicates it as a potential therapeutic agent for ALI or sepsis.