Positive regulation of TFEB and mitophagy by PGC-1α to alleviate LPS-induced acute lung injury in rats.

AIM OF THE STUDY: Acute lung injury (ALI) exhibits the features of noncardiogenic pulmonary edema and acute inflammatory process, and it also displays significant morbidity and mortality rates. This work focused on identifying how overexpression of PPARγ coactivator 1α (PGC-1α) positively regulated TFEB and mitophagy for resisting the lipopolysaccharide (LPS)-mediated ALI. MATERIALS AND METHODS: The levels of autophagic proteins and inflammatory factors in LPS-induced ALI rats and primary type II alveolar epithelial cells were measured, respectively. Lung wet/dry ratios were calculated. Protein co-immunoprecipitation of PGC-1α and TFEB was detected. To explore the interaction between TFEB and PGC-1α, a luciferase reporter assay was conducted. RESULTS: The results showed that overexpression of PGC-1α decreases IL-1 and IL-6 but increases IL-10 in LPS-mediated ALI rats and type II alveolar epithelial cells (P < 0.05). Overexpression of PGC-1α can reduce lung edema in LPS-mediated ALI rats (P < 0.05). Overexpression of PGC-1α upregulates mitophagy-related proteins, such as TFEB, LC3B, Beclin, and LAMP1, and improves mitophagy in LPS-induced ALI. Protein immunoprecipitation indicated that TFEB and PGC-1α are interacting proteins. The luciferase reporter assay demonstrated that PGC-1α positively regulated TFEB in the LPS-induced primary type II alveolar epithelial cells. CONCLUSION: PGC-1α protects LPS-induced ALI by decreasing inflammation and alleviating lung edema. The mechanism might be positive regulation of TFEB directly and then upregulation of mitophagy in LPS-induced ALI.

Application of Electrocautery Needle Knife Combined with Balloon Dilatation versus Balloon Dilatation in the Treatment of Tracheal Fibrotic Scar Stenosis.

BACKGROUND: Electrocautery needle knives can largely reduce scar and granulation tissue hyperplasia and play an important role in treating patients with benign stricture. OBJECTIVE: The aim of this retrospective study was to evaluate the efficacy and safety of electrocautery needle knife combined with balloon dilatation versus balloon dilatation alone in the treatment of tracheal stenosis caused by tracheal intubation or tracheotomy. METHODS: We retrospectively analysed the clinical data of 43 patients with tracheal stenosis caused by tracheotomy or tracheal intubation in our department from January 2013 to January 2016. Among these 43 patients, 23 had simple web-like stenosis and 20 had complex steno sis. All patients were treated under general anaesthesia, and the treatment methods were (1) balloon dilatation alone, (2) needle knife excision of fibrotic tissue combined with balloon dilatation, and (3) needle knife radial incision of fibrotic tissue combined with balloon dilatation. RESULTS: After treatment the symptoms, such as shortness of breath, were markedly improved immediately in all cases. The stenosis degree of patients who were treated with the elec-trocautery needle knife combined with balloon dilatation had better improvement compared with that of those treated with balloon dilatation treatment alone after 3 months (0.45 ± 0.04 vs. 0.67 ± 0.05, p < 0.01), and the proportion of restenosis occurrence that required further treatment was decreased at 6 months (46.9 vs. 81.8%), especially for the web-like stenosis patients, as most of their stenoses dilated with no obvious restenosis and achieved clinical cure. CONCLUSION: Electrocautery needle knife combined with balloon dilatation is an effective and safe treatment for tracheal fibrotic stenosis compared with balloon dilatation alone.

Losartan, a selective antagonist of AT1 receptor, attenuates seawater inhalation induced lung injury via modulating JAK2/STATs and apoptosis in rat.

Losartan is a selective antagonist of AngⅠ type (AT1) receptor of Angiotensin Ⅱ (Ang Ⅱ), which is widely used as a clinical medicine for the hypertension. Recent studies have shown that losartan was shown to protect from acute lung injury (ALI). However, the underlying mechanism remains unclear. The aim of this research was to clarify whether Ang Ⅱ participated in the inflammatory response of ALI induced by seawater inhalation, and whether losartan had the protective effects on ALI by blocking the combination of Ang Ⅱ and AT1 receptor. In the current study, the severity of lung injury and the inflammatory reactions during seawater drowning induced ALI were assessed. Besides, we also detected the activation of relative pathways such as NF-κB, JAK2/STATs and apoptosis. The results showed that seawater inhalation could up-regulate the expression of Ang Ⅱ and AT1. While pretreatment of losartan (especially 15 mg/kg and 30 mg/kg) alleviated lung injury by inhibiting Ang-Ⅱ and AT1 receptor combination and in turn decreased the expression of p-NF-κB and activation of JAK2/STATs pathway. We also confirmed that losartan could reduce the apoptotic ratio of cells in the lung by modulating the phosphorylation of JNK and leak of cytochrome C to cytosol. Taken together, these findings demonstrate that losartan might have a therapeutic potential as an anti-inflammatory agent for treating SWI-ALI.

Epigallocatechin-3-gallate ameliorates seawater aspiration-induced acute lung injury via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats.

Signal transducers and activators of transcriptions 1 (STAT1) play an important role in the inflammation process of acute lung injury (ALI). Epigallocatechin-3-gallate (EGCG) exhibits a specific and strong anti-STAT1 activity. Therefore, our study is to explore whether EGCG pretreatment can ameliorate seawater aspiration-induced ALI and its possible mechanisms. We detected the arterial partial pressure of oxygen, lung wet/dry weight ratios, protein content in bronchoalveolar lavage fluid, and the histopathologic and ultrastructure staining of the lung. The levels of IL-1, TNF-α, and IL-10 and the total and the phosphorylated protein level of STAT1, JAK1, and JAK2 were assessed in vitro and in vivo. The results showed that EGCG pretreatment significantly improved hypoxemia and histopathologic changes, alleviated pulmonary edema and lung vascular leak, reduced the production of TNF-α and IL-1, and increased the production of IL-10 in seawater aspiration-induced ALI rats. EGCG also prevented the seawater aspiration-induced increase of TNF-α and IL-1 and decrease of IL-10 in NR8383 cell line. Moreover, EGCG pretreatment reduced the total and the phosphorylated protein level of STAT1 in vivo and in vitro and reduced the phosphorylated protein level of JAK1 and JAK2. The present study demonstrates that EGCG ameliorates seawater aspiration-induced ALI via regulating inflammatory cytokines and inhibiting JAK/STAT1 pathway in rats.

The bleeding risk and safety of multiple treatments by bronchoscopy in patients with central airway stenosis.

BACKGROUND: Central airway obstruction (CAO) are common abnormality that usually needing interventional bronchoscopy, and sometimes multiple rounds of treatment. However, there were few studies explore the safety of it. RESEARCH DESIGN & METHODS: The records of patients who underwent interventional bronchoscopy because of CAO at Respiratory department between 1 January 2010, and 31 December 2020 were revised. The patients' clinical characteristics, information about bronchoscopy and incidence of complications were collected and analyzed. RESULTS: There were totally 1,482 bronchoscopy procedures conducted in the 733 CAO patients. And the incidence of major complications in the retreatment group was significantly lower than that in the first treatment group ((4.77% vs. 1.87%, χ2 = 9.78, df = 1, p < 0.01), so did the incidence of severe bleeding (2.46% vs. 0.40%, χ2 = 11.20, df = 1, p < 0.01). However, there was some variability between the two groups in age and anesthesia type. A short interval time, more treatment times, and general anesthesia were related to a lower incidence of hemorrhage. For patients who were previously bleeding, the incidence of hemorrhage was significantly higher than the incidence in the non-bleeding patients (42.93% vs. 16.33%, respectively; χ2 = 57.54, df = 1, p < 0.01). CONCLUSION: For the patients with CAO, repeated interventional bronchoscopy treatment was safe, and it should be treated with discretion when retreat the patients once bleeding during previous therapeutic bronchoscopy.

The bleeding risk and safety of repeated bronchoscopies with tissue sampling in patients with pulmonary lesions.

BACKGROUND: Many patients need repeated bronchoscopies with tissue sampling to obtain the final pathological results and guide the optimal subsequent treatment of pulmonary lesions. However, few studies have explored the safety of repeated biopsies. METHODS: The records of patients who underwent bronchoscopy-guided tissue sampling because of pulmonary lesions at the respiratory department between 1 January 2008 and 31 December 2019 were revised. The patients' clinical characteristics, information about bronchoscopy and incidence of complications were collected and analyzed. RESULTS: In total, 3899 bronchoscopy-guided tissue sampling procedures were conducted in the 1781 participants. There was no significant difference in the incidence of major complications between the initial bronchoscopies and repeated bronchoscopies (1.12% vs. 1.13%, χ2 < 0.01, df = 1, p = 0.98), as was the incidence of hemoptysis (χ2 = 2.18, df = 1, p = 0.14). However, the bleeding rate of patients who experienced bleeding during the first bronchoscopies was significantly higher than that of patients who did not experience bleeding (61.19% vs. 32.63%, χ2 = 253.00, df = 1, p < 0.01). CONCLUSIONS: For patients with pulmonary lesions, re-bronchoscopy with tissue sampling appears to infer the same risk of bleeding including severe bleeding as experienced during the initial bronchoscopy. However, it should be treated with discretion when performing repeated tissue sampling on patients who once bled.

Complications and safety analysis of diagnostic bronchoscopy in COPD: a systematic review and meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) often coexists with many diseases that require bronchoscopy. We conducted this systematic review and meta-analysis to assess the safety and complication rate of diagnostic bronchoscopy in patients with COPD. METHODS: We retrieved clinical trials that reporting the complications of conducting diagnostic bronchoscopy on patients with COPD through electronic databases. Analyses of the overall major complication rate of bronchoscopy and potential risk factors in patients with COPD were conducted. RESULTS: 18 trials/arms were evaluated. The overall major complication rate of bronchoscopy was 4.3% (95% CI, 2.2%-8.2%; 18 trials/arms, n = 2000). The major complication rate of the patients with an exacerbation of COPD was higher than that of the stable patients (7.8% vs. 4.5%, Q-value = 11.29, df (Q) = 1, p < 0.01); using of sedative medicine was also related with higher major complication rate (Q-value = 6.303, df (Q) = 2, p = 0.043). Patients with severe COPD who were GOLD stages III and IV (Q = 13.40, df = 1, p < 0.01; R2 = 0.66) or had a high BMI (Q = 30.83, df = 1, p < 0.01; R2 = 0.91) more easily encountered complications during bronchoscopy. CONCLUSIONS: The major complication rate of diagnostic bronchoscopy in patients with COPD was acceptable and low Exacerbations of COPD and using sedative medicine were related with higher major complication rate. EXPERT OPINION: COPD is a major risk factor for lung cancer and infection, so the patients with COPD often required bronchoscopy. Although our results showed diagnostic bronchoscopy might not be more fatal for patients with COPD, further studies are needed to explore the potential risk factors for major complications of bronchoscopy in patients with COPD.

Selective inhibition of JNK located on mitochondria protects against mitochondrial dysfunction and cell death caused by endoplasmic reticulum stress in mice with LPS­induced ALI/ARDS.

Few pharmacological interventions are able to improve the mortality rate of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). The aim of this research was to elucidate whether endoplasmic reticulum (ER) stress and c­Jun­N­terminal kinase (JNK)­mitochondria pathways serve important roles in ALI/ARDS and to determine whether the key component Sab is a potential treatment target. The current study investigated the activation of ER stress and the JNK pathway, the content of JNK located on the mitochondria during ER stress and lipopolysaccharide (LPS)­induced ALI/ARDS by western blot analysis. The treatment effects of Tat­SabKIM1, a selective inhibitor of JNK located on mitochondria were explored by multiple methods including histopathological evaluation, lung cell apoptosis tested by TUNEL assay, mitochondrial membrane permeability and survival analysis. The results verified that ER stress was enhanced during LPS­induced ALI/ARDS and could induce activation of the JNK pathway and JNK­mitochondrial localization as well as mitochondrial dysfunction and cell death. Tat­SabKIM1 alleviated LPS injection­induced lung injury and improved mouse survival rates by specifically inhibiting JNK localization to mitochondria and mito­JNK signal activation without affecting cytosolic/nuclear JNK activation. The protective effect of Tat­SabKIM1 against ALI/ARDS was partly caused by inhibition of the excessive activation of mitochondria­mediated apoptosis and autophagy. These results showed the important role of Sab as a treatment target of ALI/ARDS and the potential treatment effect of Tat­SabKIM1. In conclusion, abnormal activation of the JNK­mitochondrial pathway could significantly disrupt the normal physiological function of lung cells, resulting in the occurrence of ALI/ARDS and selective inhibit of JNK located on mitochondria by Tat­SabKIM1 had a protective effect against the mitochondrial dysfunction and cell death caused by endoplasmic reticulum stress in mice with LPS­induced ALI/ARDS.

Redox signaling and antioxidant therapies in acute respiratory distress syndrome: a systematic review and meta-analysis.

Objectives: No pharmacologic treatment that targets the pathophysiologic alterations of acute respiratory distress syndrome (ARDS) has proven effective. Previous studies have revealed overactive oxidative stress as a potential therapeutic target. Thus we conducted this systematic review to assess the efficacyof antioxidant therapy on the clinical outcomes of ARDS patients.Methods: We retrieved clinical trials from electronic databases. Articles and conference abstracts about antioxidant therapies for patients with ARDS were identified in which the overall effect of each antioxidant therapy on the mortality of ARDS patients was summarized.Results: We identified 18 relevant studies that met the inclusion criteria, including 899 patients in the experimental group and 870 patients in the control group. The pooled results indicated that most antioxidant therapies could not improve all-cause mortality and might even be harmful in ARDS patients at low risk of death.Conclusion: Unclassified patients could not benefit from the antioxidant therapies, and thus discretion must be exercised when using these therapies.Abbreviations ARDS: Acute respiratory distress syndrome; ICU: Intensive care unit; NAC: N-acetylcysteine; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; RR: Relative risk; CI: Confidence interval; OTC: L-2-oxothiazolidine-4-carboxylic acid; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; GLA: Gamma-linolenic acid; NA: Not applicable; PaO2/FiO2 ratio: The ratio of partial pressure arterial oxygen and fraction of inspired oxygen; ALI: Acute lung injury.

The hemorrhage risk of patients undergoing bronchoscopic examinations or treatments.

BACKGROUND: In recent years, bronchoscopic procedures have become more complex and sophisticated, as well as more extensively used. This study aimed to evaluate the safety, particularly the hemorrhage risk, of patients undergoing bronchoscopic examinations or treatments. METHODS: This retrospective study consisted of inpatients and outpatients who underwent bronchoscopic examinations or treatments in our respiratory department between January 1, 2008 and December 31, 2019. We collected and analyzed the patient and bronchoscopic data. RESULTS: Among the 45,734 patients who underwent diagnostic or therapeutic bronchoscopies, the severe complication rate was 0.85%, and the mortality was 0.01%. The severe complication rates varied significantly among the types of bronchoscopic procedures; the rate was higher with therapeutic bronchoscopies than with exploratory examination or biopsy bronchoscopies. Bleeding was the most common severe complication, and it occurred more frequently with biopsies in the left upper lobe and the bronchus intermedius, but its incidence decreased as the number of biopsies increased above one. CONCLUSIONS: Although bronchoscopic procedures have become more complex and sophisticated, bronchoscopies are still well tolerated. However, precautions should be taken because hemorrhaging and pneumothorax remain potential complications, and they can be fatal.

Selective inhibition of JNK mitochondrial location is protective against seawater inhalation­induced ALI/ARDS.

Localization of phosphorylated (p)­JNK to the mitochondria can lead to functional mitochondrial disorder, resulting in a decrease in energy supply and membrane potential, as well as an increase in reactive oxygen species production and apoptosis. JNK is involved in the occurrence of acute lung injury (ALI), and activation of the JNK pathway is one of the crucial factors resulting in injury. The aim of the present study was to investigate whether the JNK­mitochondria (mitoJNK) location participated in the occurrence of ALI and acute respiratory distress syndrome (ALI/ARDS). The present study examined the activation of the JNK pathway, the content of JNK located on the mitochondria and the treatment effects of a cell­permeable peptide Tat­SabKIM1, which can selectively inhibit the location of JNK on mitochondria. The expression levels of proteins were detected by western blot analysis. Lung injuries were evaluated by histological examination, wet­to­dry weight ratios, and H2O2 and malondialdehyde concentrations in the lung tissues. Lung cells apoptosis was evaluated using TUNEL assay. The results demonstrated that JNK was phosphorylated and activated during seawater inhalation­induced ALI/ARDS, not only in the routine JNK pathway but also in the mitoJNK pathway. It was also found that Tat­SabKIM1 could specifically inhibit JNK localization to mitochondria and the activation of mitoJNK signaling. Furthermore, Tat­SabKIM1 could inhibit Bcl­2­regulated autophagy and mitochondria­mediated apoptosis. In conclusion, mitoJNK localization disrupted the normal physiological functions of the mitochondria during ALI/ARDS, and selective inhibition of JNK and mitochondrial SH3BP5 (also known as Sab) binding with Tat­SabKIM1 can block deterioration from ALI/ARDS.

Comparison in efficacy and safety of forceps biopsy for peripheral lung lesions guided by endobronchial ultrasound-guided sheath (EBUS-GS) and electromagnetic navigation bronchoscopy combined with EBUS (ENB-EBUS).

Endobronchial ultrasound-guided sheath (EBUS-GS) and electromagnetic navigation bronchoscopy combined with EBUS (ENB-EBUS) are two diagnostic methods used to obtain lung tissue for biopsy of peripheral lung lesions. This study retrospectively summarized the case data of patients who underwent EBUS-GS or ENB-EBUS, both procedures performed at the respiratory endoscopy center of Tangdu Hospital, and the study compared the diagnostic efficacy and complications of the two methods. The study included 93 patients who underwent EBUS-GS and 26 who underwent ENB-EBUS. The diagnostic rates of EBUS-GS and ENB-EBUS were 71.1% and 65.4%, respectively, with no statistical difference (P=0.581). Furthermore, 89.2% of patients in the EBUS-GS group were diagnosed with malignant disease, which was significantly higher than 23.5% diagnosed with malignant disease in the ENB-EBUS group (P=0.00). An analysis of the factors influencing the diagnosis rate showed that the diagnosis rate of EBUS-GS in cases with bronchial signs was 82.5%, which was significantly higher than the 42.9% in the cases in the ENB-EBUS group with bronchial signs (P<0.05). An analysis of the complications showed that the incidence of complications in the EBUS-GS group was 8.4%, and the incidence of complications in the ENB-EBUS group was 3.8%, with no statistical difference (P>0.05). Both EBUS-GS and ENB-EBUS can be used for the diagnosis of peripheral pulmonary disease. However, the diagnostic rate of EBUS-GS is significantly higher than ENB-EBUS in cases with bronchial signs associated with the lesion, and the diagnostic rate of ENB-EBUS in cases with no bronchial signs was higher than that of EBUS-GS with no statistical difference.

Overexpression of transcription factor EB regulates mitochondrial autophagy to protect lipopolysaccharide-induced acute lung injury.

BACKGROUND: Acute lung injury (ALI) is characterized by an acute inflammatory process, and oxidative stress in the lung tissue leads to a lack of effective therapeutics. This study aimed to identify whether the overexpression of transcription factor EB (TFEB) regulates mitophagy to protect against lipopolysaccharide (LPS)-induced ALI. METHODS: We detected the expression of inflammatory factors, cytochrome c (Cyt.c) and nicotinamide adenine dinucleotide phosphate (NADPH), and autophagy-related proteins and observed the changes in lung histopathology induced by ALI in rats and the changes in the cell ultrastructure of primary alveolar type II epithelial cells induced by changing the expression of TFEB in the context of ALI. RESULTS: The overexpression of TFEB could reduce the expression of proinflammatory factors, such as IL-1 and IL-6, and increase the expression of anti-inflammatory factors, such as IL-10, both in vitro and in vivo. In addition, the overexpression of TFEB could reduce the Cyt.c and NADPH levels both in vivo and in vitro. The overexpression of TFEB could upregulate the expression of autophagy-related proteins, such as lysosomal-associated membrane protein 1 (LAMP1), microtubule-associated protein light chain 3B (LC3B), and Beclin both in vivo and in vitro, and promote mitochondrial autophagy. The overexpression of TFEB significantly improved the histopathologic changes induced by LPS-induced ALI in rats. However, low TFEB expression produced the opposite results. CONCLUSION: TFEB overexpression can decrease inflammation and mitochondrial damage in the lung tissue and alveolar epithelial cells through regulating mitochondrial autophagy to protect against LPS-induced ALI. Therefore, TFEB is likely a potential therapeutic target in LPS-induced ALI.

Diagnosing a solitary pulmonary nodule using multiple bronchoscopic guided technologies: A prospective randomized study.

BACKGROUND: The rate of detection of pulmonary nodules on computed radiography (CR) is approximately 0.09-0.2%, so rapid identification of the nature of solitary pulmonary nodules (SPNs) with a likelihood of malignancy is a critical challenge in the early diagnosis of lung cancer. OBJECTIVE: We conducted this study to compare the diagnostic yield and safety of endobronchial ultrasonography with a guide sheath (EBUS-GS), and the combination of EBUS-GS and virtual bronchoscopic navigation (VBN). METHODS: This was a prospective, multicenter, multi-arm, randomized controlled trial involving a total of 1010 subjects. All the patients recruited underwent a chest CT scan which found SPNs that needed to be diagnosed. The subjects were randomly divided into one of three groups: a traditional, non-guided, bronchoscopy biopsy group (NGB group), an EBUS-GS guided bronchoscopy biopsy group (EBUS group), and a guided bronchoscopy biopsy group that combined EBUS-GS with VBN (combined group). The primary endpoint was to investigate the differences between the diagnostic yields of the three groups. RESULTS: There was no significant difference in the diagnostic yield between the EBUS group (72.3%) and the combined group (74.3%), but the diagnostic yield for the NGB group was 41.2%. The time required to reach biopsy position was significantly less in the combined group (7.96 ± 1.18 min in the combined group versus 11.92 ± 5.37 min in the EBUS group, p < 0.05). However, the bronchoscope operation time was the same in the EBUS-GS and combined groups. The diagnostic yield for peripheral pulmonary lesions (PPLs) >20 mm in diameter was significantly higher than for those <20 mm in diameter. CONCLUSION: The results of our study suggest that guided bronchoscopy could increase the diagnostic yield in the context of peripheral lesions. There was no significant difference in the diagnostic yield between the EBUS and combined groups, but use of EBUS-GS with VBN could significantly shorten the bronchoscope arrival time.

Activation of TRPV1-dependent calcium oscillation exacerbates seawater inhalation-induced acute lung injury.

Calcium is an important second messenger and it is widely recognized that acute lung injury (ALI) is often caused by oscillations of cytosolic free Ca2+. Previous studies have indicated that the activation of transient receptor potential­vanilloid (TRPV) channels and subsequent Ca2+ entry initiates an acute calcium­dependent permeability increase during ALI. However, whether seawater exposure induces such an effect through the activation of TRPV channels remains unknown. In the current study, the effect of calcium, a component of seawater, on the inflammatory reactions that occur during seawater drowning­induced ALI, was examined. The results demonstrated that a high concentration of calcium ions in seawater increased lung tissue myeloperoxidase activity and the secretion of inflammatory mediators, such as tumor necrosis factor­α (TNF­α) and interleukin (IL)­1ß and IL­6. Further study demonstrated that the seawater challenge elevated cytosolic Ca2+ concentration, indicated by [Ca2+]c, by inducing calcium influx from the extracellular medium via TRPV1 channels. The elevated [Ca2+c] may have resulted in the increased release of TNF­α and IL­1ß via increased phosphorylation of nuclear factor­κB (NF­κB). It was concluded that a high concentration of calcium in seawater exacerbated lung injury, and TRPV1 channels were notable mediators of the calcium increase initiated by the seawater challenge. Calcium influx through TRPV1 may have led to greater phosphorylation of NF­κB and increased release of TNF­α and IL­1ß.

Identification of distinct genes associated with seawater aspiration­induced acute lung injury by gene expression profile analysis.

Seawater aspiration­induced acute lung injury (ALI) is a syndrome associated with a high mortality rate, which is characterized by severe hypoxemia, pulmonary edema and inflammation. The present study is the first, to the best of our knowledge, to analyze gene expression profiles from a rat model of seawater aspiration­induced ALI. Adult male Sprague­Dawley rats were instilled with seawater (4 ml/kg) in the seawater aspiration­induced ALI group (S group) or with distilled water (4 ml/kg) in the distilled water negative control group (D group). In the blank control group (C group) the rats' tracheae were exposed without instillation. Subsequently, lung samples were examined by histopathology; total protein concentration was detected in bronchoalveolar lavage fluid (BALF); lung wet/dry weight ratios were determined; and transcript expression was detected by gene sequencing analysis. The results demonstrated that histopathological alterations, pulmonary edema and total protein concentrations in BALF were increased in the S group compared with in the D group. Analysis of differential gene expression identified up and downregulated genes in the S group compared with in the D and C groups. A gene ontology analysis of the differential gene expression revealed enrichment of genes in the functional pathways associated with neutrophil chemotaxis, immune and defense responses, and cytokine activity. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the cytokine­cytokine receptor interaction pathway was one of the most important pathways involved in seawater aspiration­induced ALI. In conclusion, activation of the cytokine­cytokine receptor interaction pathway may have an essential role in the progression of seawater aspiration­induced ALI, and the downregulation of tumor necrosis factor superfamily member 10 may enhance inflammation. Furthermore, IL­6 may be considered a biomarker in seawater aspiration­induced ALI.

Epigallocatechin-3-gallate suppresses alveolar epithelial cell apoptosis in seawater aspiration-induced acute lung injury via inhibiting STAT1-caspase-3/p21 associated pathway.

The apoptosis of alveolar epithelial cells is important in seawater aspiration­induced acute lung injury (ALI). The present study aimed to investigate whether epigallocatechin-3-gallate (EGCG) is able to suppress apoptosis in alveolar epithelial cells in seawater aspiration­induced ALI in vivo and in vitro, and the possible mechanisms underlying it. The results indicated that seawater aspiration­induced ALI in rats is accompanied by increased apoptosis in lung tissue cells and the expression of apoptosis­associated proteins, caspase­3 and p21. EGCG pretreatment significantly ameliorated seawater aspiration­induced ALI. Furthermore, EGCG decreased seawater aspiration­induced apoptosis and the expression of caspase­3 and p21 in lung tissue cells. Seawater­challenged A549 cells experienced increased apoptosis and elevated levels of phosphorylated­signal transducer and activator of transcription 1 (P­STAT1). EGCG pretreatment of the cells resulted in significantly decreased seawater­induced apoptosis and lower levels of STAT1 and P­STAT1 in A549 cells. This suggests that EGCG suppresses alveolar epithelial cell apoptosis in seawater aspiration­induced ALI via inhibiting the STAT1-caspase-3/p21 associated pathway.

NFAT5 participates in seawater inhalation­induced acute lung injury via modulation of NF-κB activity.

Nuclear factor of activated T cells 5 (NFAT5) is a transcription factor that can be activated by extracellular tonicity. It has been reported that NFAT5 may increase the transcription of certain osmoprotective genes in the renal system, and the aim of the current study was to explore the role of NFAT5 in seawater inhalation­induced acute lung injury. Though establishing the model of seawater inhalation­induced acute lung injury, it was demonstrated that seawater inhalation enhanced the transcription and protein expression of NFAT5 (evaluated by reverse transcription­polymerase chain reaction, immunohistochemistry stain and western blotting) and activation of nuclear factor (NF)­κB (evaluated by western blotting and mRNA expression levels of three NF­κB­dependent genes) both in lung tissue and rat alveolar macrophage cells (NR8383 cells). When expression of NFAT5 was reduced in NR8383 cells using an siRNA targeted to NFAT5, the phosphorylation of NF­κB and transcription of NF­κB­dependent genes were significantly reduced. In addition, the elevated content of certain inflammatory cytokines [tumor necrosis factor α, interleukin (IL)­1 and IL­8] were markedly reduced. In conclusion, NFAT5 serves an important pathophysiological role in seawater inhalation­induced acute lung injury by modulating NF­κB activity, and these data suggest that NFAT5 may be a promising therapeutic target.

Thymosin alpha1 based immunomodulatory therapy for sepsis: a systematic review and meta-analysis.

OBJECTIVES: Thymosin alpha1 (Tα1) is considered a promising immunomodulatory drug. However, it is still unclear whether Tα1 should be recommended for the management of sepsis. Here we conducted a systematic review and meta-analysis to assess the efficacy of Tα1 based immunomodulatory therapy on the clinical outcomes of septic patients. METHODS: We searched for relevant clinical trials published before Dec. 12, 2014 through electronic databases. All articles about Tα1 based immunomodulatory therapy for sepsis were included regardless of language. Two authors independently selected studies, extracted data and assessed the quality of each included study. We polled the data related to all-cause mortality with Review Manager 5.1. RESULTS: Twelve controlled trials were evaluated in all. Tα1 based immunomodulatory therapy had a significant trend toward lower all-cause mortality among patients with sepsis (pooled risk ratio 0.68, 95%CI 0.59-0.78, p<0.00001, 12 trials, n=1480). CONCLUSIONS: Tα1 based immunomodulatory therapy was associated with a lower mortality in septic patients. Nevertheless, these findings should be interpreted cautiously because of the poor quality and small number of participants of the included trials. More well-designed worldwide multicenter clinical trials are needed to provide a conclusive guideline for clinical practice.

Enteral Immunomodulatory Diet (Omega-3 Fatty Acid, γ-Linolenic Acid and Antioxidant Supplementation) for Acute Lung Injury and Acute Respiratory Distress Syndrome: An Updated Systematic Review and Meta-Analysis.

UNLABELLED: Enteral immunomodulatory nutrition is considered as a promising therapy for the treatment of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, there are still some divergences, and it is unclear whether this treatment should be recommended for patients with ALI/ARDS. Therefore, we conducted this systematic review and meta-analysis to assess the efficacy and safety of an enteral immunomodulatory diet on the clinical outcomes of ALI/ARDS patients. METHODS: We retrieved potentially relevant clinical trials though electronic databases. All trials of enteral immunomodulatory diet for ALI/ARDS were included. Analyses of the overall all-cause mortality, 28-day ventilator-free days and 28-day intensive care unit (ICU) free days were conducted. RESULTS: In total six controlled trials were evaluated. The pooled results did not show a significant reduction in the risk of all-cause mortality (M-H RR (the overall Mantel-Haenszel relative risk), 0.81 (95% CI, 0.50-1.31); p = 0.38; 6 trials, n = 717) in ALI/ARDS patients treated with the immunomodulatory diet. This treatment also did not extend the ventilator-free days and ICU-free days. However, patients with high mortality might benefit from this treatment. CONCLUSIONS: The enteral immunomodulatory diet could not reduce the severity of the patients with ALI/ARDS. Whereas, for ALI/ARDS patients with high mortality, this treatment might reduce the all-cause mortality, but its use should be treated with discretion.