The efficacy of hydrogen/oxygen therapy favored the recovery of omicron SARS-CoV-2 variant infection: results of a multicenter, randomized, controlled trial.

Clinical studies had found that hydrogen/oxygen mixed inhalation was beneficial to ameliorate the respiratory symptoms in the adjuvant treatment of patients with COVID-19. We aimed to explore the efficacy of hydrogen/oxygen therapy in favoring the recovery of Omicron SARS-CoV-2 variant infection. There were 64 patients who randomly assigned to receive hydrogen/oxygen inhalation (32 patients) and oxygen inhalation (32 patients). The average shedding duration of Omicron in hydrogen/oxygen group was shorter than oxygen group. The trend of cumulative negative conversion rate of Omicron increased gradually after the third day. The IL-6 levels in hydrogen/oxygen group decreased by 22.8% compared with the baseline. After hydrogen/oxygen mixed gas inhalation, the lymphocyte count increased to 61.1% of the baseline on the 3rd day in the hydrogen/oxygen group. More patients in the hydrogen/oxygen group had resolution of pulmonary lesions. Our study showed the beneficial trends of molecular hydrogen in treating patients with COVID-19, which may offer a prospective solution to adjuvant therapy for COVID-19 Patients.

Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice.

It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.

[Research progress of non-coding RNA in regulating the function of T cells in asthma].

Bronchial asthma (i.e. asthma) is a chronic inflammatory disease characterized by airway inflammatory response, hyperresponsiveness and airway remodeling, in which T cells play a vital role, especially T helper cells (Th cells). Non-coding RNAs (ncRNAs) are the RNAs that do not encode proteins, mainly including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are widely found in eukaryotic genomes and participate in the regulation of various biological processes. Previous studies have shown that ncRNAs play an important role in the activation and transformation of T cells and other biological processes in asthma. The specific molecular mechanism and clinical application are worth in-depth discussion. This article reviewed the research progress in regulation of miRNAs, lncRNAs and circRNAs on T cells in asthma in recent years.

Establishment of surfactant-associated protein A suicide gene system and analysis of its activity.

Alveolar epithelial type II (AT II) cells are essential for lung development and remodeling, as they are precursors for type I cells and also produce other non-repair cells (fibroblasts). Progenitor cells are believed to possess capability of multi-potent transdifferentiation, which is closely related to the niche, suggesting the importance of establishment of a lung progenitor cell niche model. We hypothesized that pulmonary surfactant-associated protein A (SPA) suicide gene system would cause AT II cell to kill itself through apoptosis and leave its niche. In vitro, the recombinant adeno-associated virus vectors-SPA-thymidine kinase (rAAV-SPA-TK) system was established to get targeted apoptotic AT II cells. The apoptosis of AT II cells was detected by using MTT. The results showed that cloned SPA gene promoter had specific transcriptional activity in SPA high expression cells, and SPA high expression cells (H441) transfected with TK gene had higher sensitivity to ganciclovir (GCV) than SPA low expression cells (A549). In vivo, increased apoptosis of AT II cells induced by GCV in rAAV-SPA-TK system was observed by TUNEL. Finally, the successful packaging and application of rAAV-SPA-TK system provide experimental basis to get specific lung progenitor cell (AT II) niche in vitro and in vivo.

Mannose-binding lectin two gene polymorphisms and tuberculosis susceptibility in Chinese population: a meta-analysis.

Numerous studies have been done to explore the association between mannose-binding lectin two (MBL2) gene polymorphisms and the risk of tuberculosis (TB). However, the results are inconsistent. We performed a meta-analysis to investigate whether polymorphisms in the MBL2 gene were associated with TB risk. Databases including PubMed, Medline, Chinese Biomedicine Database, China National Knowledge Infrastructure, Wanfang Database, and Weipu Database were searched to find relevant articles published up to 2 October, 2012. Odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of association. All statistical tests were performed by using Revman 5.1 software and STATA 11.0 software. Six case-control studies including 1106 cases and 1190 controls were accepted in the meta-analysis. The results indicated that individuals carrying the MBL2 codon 54 B allele may have an increased risk of TB as compared with AA homozygotes (BB+AB vs. AA: OR=1.52, 95% CI: 1.22-1.88), whereas MBL2 +4 P/Q was possibly not associated with TB susceptibility in Chinese population.

Inhibitory effect of dexamethasone on expression of cysteine-rich 61 protein in airway epithelial cells of allergic mouse models.

In order to study whether cysteine-rich 61 protein (cyr61) is involved in the pathogenesis of asthma and its relation to airway inflammation, the effect of dexamethasone (Dxm) on the expression of cyr61 in the lung tissues of asthmatic mice was investigated. Forty BALB/c mice were divided into asthma group (n=15), control group (n=10) and Dxm group (n=15). The asthma group was sensitized and challenged by ovalbumin (OVA). The mice in Dxm group were intraperitoneally administered with Dxm after OVA challenge. The expression of cyr61 in the lung tissues was detected by using immunohistochemistry, and that of eotaxin protein in the bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). The number of inflammatory cells in BALF was also analyzed. The results showed that the cyr61 expression was highest in asthma group (P<0.05), followed by Dxm group (P<0.05) and control group. The cyr61 had a positive correlation with the total nucleated cells (r=0.867, P<0.05), especially eosinophils (r=0.856, P<0.05), and eotaxin level (r=0.983, P<0.05) in the BALF. Our findings suggested that cyr61 is expressed in airway epithelial cells and has a positive correlation with eotaxin and number of airway infiltrating eosinophils.

Effect of dexamethasone on expression of AGR2 protein in asthmatic mice.

This study examined the expression of the anterior gradient-2 (AGR2) protein and Muc5ac protein in the lung tissues of asthmatic mice and the effect of dexamethasone, with an attempt to explore the role of AGR2 in the over-secretion of mucus in the airway. Eighteen BALB/c mice were divided into asthma group, control group and dexamethasone group. In dexamethasone group, dexamethasone was intraperitoneally administered. Expression of AGR2 protein and Muc5ac protein in the murine lung tissues was immunohistochemically detected. IL-13 level was determined in the bronchoalveolar lavage fluid (BALF) by ELISA. The results exhibited that the expression of AGR2 protein in asthma group (0.522±0.041) was significantly higher than that in normal controls (0.361±0.047) (P<0.01) and bore a positive linear relationship to the expression of Muc5ac protein (r=0.873, P<0.05) and IL-13 level (r=0.828, P<0.05). Expression of AGR2 protein in the dexamethasone group (0.456±0.049) was significantly lower than that in the asthma group. It was concluded that: (1) the expression of AGR2 protein was significantly higher in asthmatic mice as compared with their normal counterparts; (2) the expression was obviously related to the expression of Muc5ac protein and IL-13; (3) dexamethasone could down-regulate the expression of AGR2 protein. Our findings suggested that AGR2 might be involved in the over-secretion of mucus in the airway in asthma.

An Investigation of the Effects of B7-H4 Gene rs10754339 and miR-125a Gene rs12976445 on Cancer Susceptibility.

Objective: To investigate the effects of the B7-H4 gene rs10754339 and miR-125a gene rs12976445 on cancer susceptibility through a case-control study and meta-analysis. Methods: A total of 1,490 cancer patients (lung/gastric/liver/: 550/460/480) and 800 controls were recruited in this case-control study. The meta-analysis was performed by pooling the data from previous related studies and the present study. Results: The results of this study showed that in the Hubei Han Chinese population, the rs10754339 gene was significantly associated with the risk of lung and gastric cancer but not liver cancer, and the rs12976445 gene was significantly associated with the risk of lung cancer but not liver or gastric cancer. The meta-analysis results indicated that rs10754339 and rs12976445 contributed to cancer susceptibility in the Chinese population and also revealed a significant association between rs10754339 and breast cancer risk, as well as between rs12976445 and lung cancer risk. Conclusion: The B7-H4 gene rs10754339 and miR-125a gene rs12976445 may be the potential genetic markers for cancer susceptibility in the Chinese population, which should be validated in future studies with larger sample sizes in other ethnic populations.

Stem cell therapy for chronic obstructive pulmonary disease.

ABSTRACT: Chronic obstructive pulmonary disease (COPD), characterized by persistent and not fully reversible airflow restrictions, is currently one of the most widespread chronic lung diseases in the world. The most common symptoms of COPD are cough, expectoration, and exertional dyspnea. Although various strategies have been developed during the last few decades, current medical treatment for COPD only focuses on the relief of symptoms, and the reversal of lung function deterioration and improvement in patient's quality of life are very limited. Consequently, development of novel effective therapeutic strategies for COPD is urgently needed. Stem cells were known to differentiate into a variety of cell types and used to regenerate lung parenchyma and airway structures. Stem cell therapy is a promising therapeutic strategy that has the potential to restore the lung function and improve the quality of life in patients with COPD. This review summarizes the current state of knowledge regarding the clinical research on the treatment of COPD with mesenchymal stem cells (MSCs) and aims to update the understanding of the role of MSCs in COPD treatment, which may be helpful for developing effective therapeutic strategies in clinical settings.

Plasmid-based short hairpin RNA against cyclin D1 attenuated pulmonary vascular remodeling in smoking rats.

Accumulating evidence indicated that smoking might directly induce pulmonary vascular remodeling at the initial stage of chronic obstructive pulmonary disease (COPD). However, the molecular mechanism underlying this process remains poorly understood. To investigate the role of cyclin D1 in pulmonary vascular remodeling, we constructed a plasmid-based short hairpin RNA (shRNA) to knock down the expression of cyclin D1 in smoking rats. Specific shRNA against cyclin D1 significantly prevented the cyclin D1 expression and the cell proliferation in rat pulmonary artery smooth muscle cells (rPASMCs). Furthermore, the plasmid-based shRNA successfully decreased the cyclin D1 protein in intra-pulmonary arteries of smoking rats and subsequently decreased the wall thickness of pulmonary vessels and the percentage of muscularized vessels. We conclude that the plasmid-based shRNA against cyclin D1 gene attenuated pulmonary vascular remodeling in smoking rats. Cyclin D1 might play a critical role in cigarette smoke-induced pulmonary vascular remodeling via regulating rPASMCs proliferation.

Primary pulmonary coccidioidomycosis in China.

Coccidioidomycosis is a fungal infection endemic to south-west USA, north Mexico and parts of Central and South America. We report here a case of primary pulmonary coccidioidomycosis in a previously healthy 14-year-old boy in China, which is considered a non-endemic country. The patient had non-specific symptoms of pulmonary infection, including fever, non-productive cough and night sweats. Both spherules and endospores of Coccidioides immitis were seen histologically following transbronchial biopsy of a cavitary lesion. The patient was treated with amphotericin B and fluconazole. Follow up 6 months post discharge found that the patient made a good recovery.

Expression of the Th1-specific cell-surface protein Tim-3 increases in a murine model of atopic asthma.

T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is preferentially expressed on Th1-helper type T-cells and functions to repress the Th1-mediated immune response. However, the role of Tim-3 during the inflammatory pathogenesis of asthma remains unclear. This study determines the expression level of Tim-3 in CD4+ T-cells within the peripheral blood and bronchoalveolar lavage fluid (BALF) isolated from a murine model of atopic asthma and explores the potential role of Tim-3 during the inflammatory response. Mice were randomly divided into normal control, asthma day 1, and asthma day 7 groups, and peripheral blood T lymphocytes and BALF cells were collected. The ratio of Tim-3+/CD4+ cells among the total CD4+cell populations from peripheral blood and BALF was determined by flow cytometry, and the expression of the Tim-3 mRNA was determined by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). In contrast with the normal control group, the ratio of Tim-3+/CD4+:CD4+ cells and the level of Tim-3 mRNA in both the peripheral blood T lymphocytes and BALF cells among the asthma day 1 and asthma day 7 groups were significantly increased (p < 0.01), and those in the asthma day 7 group were higher than the asthma day 1 group (p < 0.05). There was also a positive correlation between the ratio of Tim-3+/CD4+:CD4+ detected in BALF and that the ratio detected in peripheral blood T lymphocytes (r = 0.84, p < 0.01). Therefore, the expression of Tim-3 is increased in CD4+ T-cells following airway challenge and likely affects asthma-induced inflammation by repressing the Th1-mediated immune response.

Retraction Note: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

The authors have retracted the article [Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma, Cell Death & Disease volume 7, page e2388 (2016), doi 10.1038/cddis.2016.260] because it has recently come to their attention that the A549 cells used in this research were contaminated with Hela cells, which may have altered the outcome of their experiment. The conclusions of this article are therefore unreliable. All authors agree to this retraction.

Correction to: Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Following publication of their article, the authors noticed that there were minor errors in Figs. 3, 7 and S5. The errors had no effect on the scientific content or conclusions. The rectified figures are given below.

Effect of intramuscular injection of hepatocyte growth factor plasmid DNA with electroporation on bleomycin-induced lung fibrosis in rats.

BACKGROUND: So far, there is no efficient treatment for pulmonary fibrosis. The objective of this study was to determine whether intramuscular injection of the hepatocyte growth factor (HGF) plasmid DNA by in vivo electroporation could prevent bleomycin-induced pulmonary fibrosis in rats, and to investigate the possible mechanisms. METHODS: Twenty male Wistar rats were randomly divided into four groups: control group (group C), model group (group M), early intervention group (group I) and late intervention group (group II). Groups M, I and II were intratracheally infused with bleomycin, then injected the plasmid pcDNA3.1-hHGF to group I on day 7, 14 and 21. Group II received the same treatment like Group I on day 14 and 21. All the rats were killed on day 28 after bleomycin injection. We detected Homo HGF expression in the rats with ELISA method and estimated the pathological fibrosis score of lung tissue using hematoxylin eosin (HE) and Massion staining. The mRNA expression of transforming growth factor-beta1 (TGF-beta1), cycloxygenase-2 (COX-2), and rat HGF in rat pulmonary parenchyma were evaluated by RT-PCR. Immunohistochemistry and Western blotting were performed to determine the protein expression of transforming TGF-beta1 and COX-2 in lung parenchyma. RESULTS: The plasmid pcDNA3.1-hHGF could express hHGF in NIH3T3 cells and the hHGF protein is secreted into the culture medium. The expression of hHGF protein could be monitored in quadriceps muscle, plasma and lung in Groups I and II. Pulmonary fibrosis levels of Groups I and II were obviously lower than that of group M (P < 0.05). Expression of TGF-beta1 protein and mRNA in lung tissue was markedly decreased in Groups I and II compared with Group M (P < 0.05). The level of expression of HGF and COX-2 mRNA was higher in Groups I and II than in Group M (P < 0.05). CONCLUSIONS: Injection of the plasmid pcDNA3.1-hHGF into skeletal muscle with electroporation has a potential role in the treatment of bleomycin-induced lung fibrosis. Exogenous HGF may inhibit the expression of TGF-beta1 and regulate the crosstalk between AECs and mesenchymal fibroblasts.

[Liposarcoma of the pleura: clinical characteristics].

OBJECTIVE: Primary liposarcoma of the pleura is extremely rare. The first case report in China was described. METHODS: The clinical data of a case of primary liposarcoma of the pleura diagnosed in this hospital were reported, and the pertinent literature was reviewed. RESULTS: A total of 17 cases of primary liposarcomas of the pleura, including the case reported herein, had been described in international literature. Primary pleural liposarcomas occur predominantly in males and older patients, and the myxoid histological subtype is common. The most common symptoms are chest pain and shortness of breath. Radiographic and surgical evaluation are important for its diagnosis. Surgical resection with adjuvant radiation therapy is recommended for the disease. CONCLUSION: More data are required for the treatment and prognostic evaluation of the primary liposarcoma of the pleura.

[Losartan inhibited angiotensin induced human lung fibroblast transformation and collagen synthesis].

OBJECTIVE: To observe the induction of cell transdifferentiation, connective tissue growth factor (CTGF) expression and collagen production of human lung fibroblast (HLF) by angiotensin II (Ang II), and to investigate the inhibitory effect of Ang II receptor antagonist-losartan on this process. METHODS: HLF cells were cultured and divided into a control group, an Ang II treated group, an Ang II + losartan co-incubated group and a losartan group. The marker of myofibroblast-alpha-smooth muscle actin (alpha-SMA) was detected by immunofluorescence and Western blot respectively, and the expression of CTGF mRNA and protein level were measured by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry respectively. Groups of Ang II and Ang II + losartan incubated with CTGF phosphothioate antisense, sense and random oligonucleotides transfected HLFs respectively, and collagen I (Col) I mRNA and alpha-SMA expression level were compared. The amount of hydroxyproline in the cell culture was measured by colorimetric assay. RESULTS: In the Ang II group, CTGF mRNA level (0.82 +/- 0.07) was significantly higher than the control group (0.29 +/- 0.05), the Ang II + Losartan group (0.51 +/- 0.04) and the Losartan group (0.26 +/- 0.04). The CTGF protein level in the Ang II group (0.24 +/- 0.05) was increased as compared to the other groups. In the Ang II group, Col I mRNA (1.03 +/- 0.12) and amount of hydroxyproline (0.62 +/- 0.01 ng/ml) were significantly different as compared with the other three groups. The alpha-SMA expression level (1.14 +/- 0.15) and Col I mRNA (0.30 +/- 0.04) of HLF cells transfected with antisense oligonucleotide incubated with Ang II decreased significantly as compared to those of sense and random oligonucleotide transfected cells. Alpha-SMA expression level (0.85 +/- 0.09) and Col I mRNA (0.20 +/- 0.02) of Losartan + Ang II co-incubated antisense oligonucleotide transfected HLF cells decreased significantly as compared to Ang II treated alone. CONCLUSION: Ang II promoted HLF cell transdifferentiation into myofibroblasts and increased collagen production through induction of CTGF expression. Blocking CTGF expression decreased Ang II induced transdifferentiation. Losartan blocked Ang II induced HLF cell transdifferentiation and collagen production.

Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

This corrects the article DOI: 10.1038/cddis.2016.260.

[Effects of recombinant adeno-virus vector carrying interleukin-5 antisense on the expression of interleukin-5 mRNA and protein in CD4+ T lymphocytes of asthmatic rats].

OBJECTIVE: To construct recombinant adeno-associated virus vector carrying antisense interleukin-5 (IL-5) gene (rAAV-asIL-5), and to explore the effects of this virus transfection on IL-5 mRNA and protein in CD(4)(+) T lymphocytes of asthmatic rats. METHODS: The eukaryotic antisense IL-5 expressing vector plasmid of recombinant adeno-associated virus (pasIL-5/rAAV) was constructed by gene recombination technique. The rAAV-asIL-5 particles were produced by co-transfection of pasIL-5/rAAV, pXX2, and pXX6 in package cell 293 through phosphate calcium deposit, and the titers of rAAV-asIL-5 were measured by Southern blot. The rAAV-asIL-5 particles were transfected into CD(4)(+) T lymphocytes obtained by gradient of Ficoll and immunomagnetic beads from the peripheral blood of asthmatic rats. Then IL-5 mRNA in T lymphocytes and IL-5 protein in supernatant of cell culture were determined with semi-quantitative RT-PCR and ELISA respectively. RESULTS: (1) The rAAV-asIL-5 was constructed and identified, and the titer of rAAV-asIL-5 was 1.3 x 10(11) virus particles/ml. (2) The relative ratio A of absorbance (IL-5/beta-actin) of rAAV group was 1.0515 +/- 0.1477, which was significantly lower than that of the control group (1.4271 +/- 0.1655) (n = 6, P < 0.01). (3) The protein level of IL-5 in supernatant of culture of rAAV group was (12.0840 +/- 1.4769) ng/L, significantly lower than that of the control group [(15.3590 +/- 1.2685) ng/L, n = 6, P < 0.01]. CONCLUSION: Construction of rAAV-asIL-5 was successful, and transfection of this virus was capable of inhibiting the expression of IL-5 mRNA and protein in CD(4)(+) T lymphocytes of asthmatic rats. The results of this study provide experimental data for further study of gene therapy for asthma.

Hsa-miR-623 suppresses tumor progression in human lung adenocarcinoma.

Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation. Downregulation of hsa-miR-623 was associated with poor clinical outcomes of lung adenocarcinoma patients. Hsa-miR-623 suppressed lung adenocarcinoma cell proliferation, clonogenicity, migration and invasion in vitro. Hsa-miR-623 inhibited xenografts growth and metastasis of lung adenocarcinoma in vivo. Ku80 knockdown in lung adenocarcinoma cells suppressed tumor properties in vitro and in vivo similar to hsa-miR-623 overexpression. Further, hsa-miR-623 overexpression decreased matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels, with decreased ERK/JNK phosphorylation. Inhibition of hsa-miR-623 or overexpression of Ku80 promoted lung adenocarcinoma cell invasion, activated ERK/JNK phosphorylation and increased MMP-2/9 expressions, which could be reversed by ERK kinase inhibitor or JNK kinase inhibitor. In summary, our results showed that hsa-miR-623 was downregulated in lung adenocarcinoma and suppressed the invasion and metastasis targeting Ku80 through ERK/JNK inactivation mediated downregulation of MMP-2/9. These findings reveal that hsa-miR-623 may serve as an important therapeutic target in lung cancer therapy.