Epithelial-mesenchymal transition (EMT) is essential in asthma airway remodeling. IL-33 from epithelial cells is involved in pulmonary fibrosis. CD146 has been extensively explored in ...cancer-associated EMT. Whether IL-33 regulates CD146 in the EMT process associated with asthma airway remodeling is still largely unknown. We hypothesized that EMT in airway remodeling was regulated by the IL-33/CD146 axis. House dust mite (HDM) extract increased the expression of IL-33 and CD146 in epithelial cells. Increased expression of CD146 in HDM-treated epithelial cells could be blocked with an ST2-neutralizing antibody. Moreover, HDM-induced EMT was dependent on the CD146 and TGF-β/SMAD-3 signaling pathways. IL-33 deficiency decreased CD146 expression and alleviated asthma severity. Similarly, CD146 deficiency mitigated EMT and airway remodeling in a murine model of chronic allergic airway inflammation. Furthermore, CD146 expression was significantly elevated in asthma patients. We concluded that IL-33 from HDM extract-treated alveolar epithelial cells stimulated CD146 expression, promoting EMT in airway remodeling in chronic allergic inflammation.
Deficiency of TOM5, a mitochondrial protein, causes organizing pneumonia (OP) in mice. The clinical significance and mechanisms of TOM5 in the pathogenesis of OP remain elusive. We demonstrated that ...TOM5 was significantly increased in the lung tissues of OP patients, which was positively correlated with the collagen deposition. In a bleomycin-induced murine model of chronic OP, increased TOM5 was in line with lung fibrosis. In vitro, TOM5 regulated the mitochondrial membrane potential in alveolar epithelial cells. TOM5 reduced the proportion of early apoptotic cells and promoted cell proliferation. Our study shed light on the roles of TOM5 in OP.
Post-COVID-19 syndrome may be associated with the abnormal immune status. Compared with the unexposed age-matched elder group, PD-1 in the CD8
T cells from recovered COVID-19 patients was ...significantly lower. IFN-γ in the plasma of COVID-19 convalescent patients was increased, which inhibited PD-1 expression in CD8
T cells from COVID-19 convalescent patients. scRNA-seq bioinformatics analysis revealed that AKT/GSK3β may regulate the INF-γ/PD-1 axis in CD8
T cells from COVID-19 convalescent patients. In parallel, an IFN-γ neutralizing antibody reduced AKT and increased GSK3β in PBMCs. An AKT agonist (SC79) significantly decreased p-GSK3β. Moreover, AKT decreased PD-1 on CD8
T cells, and GSK3β increased PD-1 on CD8
T cells according to flow cytometry analysis. Collectively, we demonstrated that recovered COVID-19 patients may develop long COVID. Increased IFN-γ in the plasma of recovered Wuhan COVID-19 patients contributed to PD-1 downregulation on CD8
T cells by regulating the AKT/GSK3β signaling pathway.
It has been reported that IL-33 receptor ST2 deficiency mitigates
Cryptococcus neoformans
(
C. neoformans
) pulmonary infection in BALB/c mice. IL-33 may modulate immune responses in ST2-dependent ...and ST2-independent manners. The host genetic background (i.e., BALB/c, C57BL/6 J) influences immune responses against
C. neoformans
. In the present study, we aimed to explore the roles of IL-33 and ST2 in pulmonary
C. neoformans
-infected mice on a C57BL/6 J genetic background.
C. neoformans
infection increased IL-33 expression in lung tissues. IL-33 deficiency but not ST2 deficiency significantly extended the survival time of
C. neoformans
-infected mice. In contrast, either IL-33 or ST2 deficiency reduced fungal burdens in lung, spleen and brain tissues from the mice following
C. neoformans
intratracheal inoculation. Similarly, inflammatory responses in the lung tissues were more pronounced in both the IL-33
−/−
and ST2
−/−
infected mice. However, mucus production was decreased in IL-33
−/−
infected mice alone, and the level of IL-5 in bronchoalveolar lavage fluid (BALF) was substantially decreased in the IL-33
−/−
infected mice but not ST2
−/−
infected mice. Moreover, IL-33 deficiency but not ST2 deficiency increased iNOS-positive macrophages. At the early stage of infection, the reduced pulmonary fungal burden in the IL-33
−/−
and ST2
−/−
mice was accompanied by increased neutrophil infiltration. Collectively, IL-33 regulated pulmonary
C. neoformans
infection in an ST2-dependent and ST2-independent manner in C57BL/6 J mice.
China launched its new round of health care reform to develop primary care in 2009, establishing 954,390 primary care institutions that employed over 10 million staff by 2019. However, some studies ...have shown that the prevention and management of respiratory diseases is inadequate in these institutions.
We conducted a cross-sectional survey of grassroots institutions throughout China between September and December 2020 based on the standardized Prevention and Treatment System and Capacity Building Project of Respiratory Diseases in primary care settings. The operation of the respiratory department in primary health care institutions was evaluated in terms of facilities, drugs, personnel and management of chronic diseases by means of questionnaires. Descriptive analyses were performed to calculate percentages and frequencies of key parameters.
A total of 144 primary health care institutions were surveyed, including 51 in the east, 82 in the west, 9 in the central and 2 in the northeast. Approximately 60% of institutions had spirometers and pulse oximeters. The majority had short-acting bronchodilators, theophylline, systemic corticosteroids, antibiotics, and traditional Chinese medicine. More than half had at least one respiratory physician and operator for spirometry. Half of the institutions carried out screening of chronic obstructive pulmonary disease within the jurisdiction. The institutions in the east were superior to those in the west regarding the equipment, common drugs, medical staff, and management of respiratory diseases.
The study reveals that the overall operation of the respiratory department in primary care settings needs to be further strengthened. It is crucial to provide adequate essential equipment, medical professionals, and medicines for proper diagnosis and treatment of chronic respiratory diseases, as well as improving the management of diseases.
Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of the tuberous sclerosis complex (TSC) with distinctive histological characteristics. Most case reports of ...MMPH associated with TSC usually have a history and typical clinical features (seizures, mental retardation, and skin lesions) of TSC. We present a peculiar asymptomatic MMPH case that lacked the history and typical clinical features of TSC.
A 56-year-old man was referred to our hospital with bilateral ground-glass opacities (GGOs) on chest computed tomography (CT) lasting 8 months, with no complaint of any discomfort. Because of the lack of clinical manifestations, the diagnosis of MMPH and TSC was confirmed by lung biopsy histopathology and gene sequencing of nonsense mutations in the TSC1 gene. Considering the relevant literature review and that the prognosis of most patients with MMPH is generally stable, no special treatment was given. We followed up with the patient for three years after discharge, and the clinical manifestations and imaging features of the patient were stable.
To our best knowledge, this is the first case of MMPH lacking typical clinical manifestations of TSC confirmed by histopathology combined with gene sequencing. MMPH should be considered as one of the differential diagnoses of multiple GGOs in the lung even when the findings of TSC are not recognized.
This study examined the levels of soluble CD146 (sCD146) in plasma samples from patients with chronic obstructive pulmonary disease (COPD) and assessed the relationship between sCD146 and the ...severity of COPD. A total of 97 COPD patients were recruited from 20 medical centers in Jiangsu, China, including 13 stable subjects and 84 exacerbated subjects. The plasma sCD146 level in exacerbated subjects (28.77 ± 10.80 ng/mL) was significantly lower than that in stable subjects (38.84 ± 15.00 ng/mL). In the high sCD146 group, the proportion of subjects with modified Medical Research Council (mMRC) scores of 0–1 was higher, the proportion of subjects with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 was lower, and the proportion of subjects with ≥1 hospitalizations in the past year was lower. The plasma sCD146 level was negatively correlated with the COPD Assessment Test (CAT) score (r = −0.2664, p = 0.0087). Logistic regression analysis showed that sCD146 was an independent risk factor for acute exacerbation of COPD (AECOPD). Receiver operating characteristic (ROC) analysis suggested that sCD146 combined with sex, age, pulmonary function, and acute exacerbations in the past year had clinical value for the accurate identification of AECOPD, with an area under the ROC curve (AUC) of 0.908 (95% CI: 0.810–1.000, p < 0.001). In addition, there was a significant negative correlation between plasma sCD146 and S100A9 (r = −0.3939, p < 0.001).
•TCRαβ+CD56− DNT cells were increased in malignant pleural effusions (MPE) from lung cancer patients.•MPE-derived DNT cells expressed much higher levels of PD-1 and TRAIL.•Exosomes from MPE ...supernatant impaired the cytotoxicity of DNT cells via the PD-1/PD-L1 and CEACAM1/TIM3 pathways.
CD3+CD4−CD8− double-negative T (DNT) cells are new weapons in cancer immunotherapy. Here, we explored DNT cells in malignant pleural effusions (MPEs) from lung cancer patients. DNT cells, especially TCRαβ+CD56− DNT cells, were increased in MPE from lung cancer patients. DNT cells highly expressed PD-1, TRAIL, NKG2D and DNAM-1. In contrast, FasL was barely detected in DNT cells. Compared with non-MPE cells, MPE-derived DNT cells expressed much higher levels of PD-1 and TRAIL. DNT cells from healthy peripheral blood donors potentially killed lung cancers, which was decreased by MPE supernatant. Exosomes from MPE supernatant expressed PD-1 and CEACAM1 and impaired the cytotoxicity of DNT cells. Blocking PD-1 and TIM3 rescued the cytotoxicity of DNT cells treated with MPE-derived exosomes. Overall, we demonstrated that the frequency of DNT cells in MPE from lung cancer patients was increased and that MPE-derived exosomes impaired the cytotoxicity of DNT cells via the PD-1/PD-L1 and CEACAM1/TIM3 pathways.
Exosomes in malignant pleural effusions (MPEs) from lung cancer patients expressed PD-L1 and CECAM1. In MPE, exosomes compromised the cytotoxicity of double negative T (DNT) cells. Anti-TIM3 and anti-PD1 rescued the inhibitory effects of MPE-derived exomes on DNT cells.
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The roles and mechanisms of long noncoding RNAs (lncRNAs) in T helper 2 (Th2) differentiation from allergic asthma are poorly understood. We aimed to explore a novel lncRNA, LincR-protein phosphatase ...2 regulatory subunit B' gamma (PPP2R5C), in Th2 differentiation in a mouse model of asthma.
LincR-PPP2R5C from RNA-seq data of CD4
T cells of asthma-like mice were validated and confirmed by quantitative reverse transcription polymerase chain reaction, northern blotting, nuclear and cytoplasmic separation, and fluorescence
hybridization (FISH). Lentiviruses encoding LincR-PPP2R5C or shRNA were used to overexpress or silence LincR-PPP2R5C in CD4
T cells. The interactions between LincR-PPP2R5C and PPP2R5C were explored with western blotting, chromatin isolation by RNA purification assay, and fluorescence resonance energy transfer. An ovalbumin-induced acute asthma model in knockout (KO) mice (LincR-PPP2R5C KO, CD4 conditional LincR-PPP2R5C KO) was established to explore the roles of LincR-PPP2R5C in Th2 differentiation.
LncR-PPP2R5C was significantly higher in CD4
T cells from asthmatic mice
and Th2 cells
. The lentivirus encoding LincR-PPP2R5C suppressed Th1 differentiation; in contrast, the short hairpin RNA (shRNA) lentivirus decreased LincR-PPP2R5C and Th2 differentiation. Mechanistically, LincR-PPP2R5C deficiency suppressed the phosphatase activity of the protein phosphatase 2A (PP2A) holocomplex, resulting in a decline in Th2 differentiation. The formation of an RNA-DNA triplex between LincR-PPP2R5C and the PPP2R5C promoter enhanced PPP2R5C expression and activated PP2A. LincR-PPP2R5C KO and CD4 conditional KO decreased Th2 differentiation, airway hyperresponsiveness and inflammatory responses.
LincR-PPP2R5C regulated PPP2R5C expression and PP2A activity by forming an RNA-DNA triplex with the PPP2R5C promoter, leading to Th2 polarization in a mouse model of acute asthma. Our data presented the first definitive evidence of lncRNAs in the regulation of Th2 cells in asthma.
Although long non-coding RNAs (lncRNAs) have been linked to many diseases including asthma, little is known about lncRNA transcriptomes of CD4
T cells in asthma. The present study aimed to explore ...the lncRNAs profile in the CD4
T cells from the mouse model of acute asthma.
Next generation sequencing for lncRNAs and mRNAs was performed on CD4+ T cells from asthma and control mice. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were performed to predict the functions and signal pathways for the aberrant lncRNAs. The selected lncRNAs were further measured using quantitative real-time PCR (polymerase chain reaction) and observed in the fluorescence
hybridization (FISH). The lncRNA-mRNA co-expression network was constructed via Pearson's correlation coefficient and Cytoscape 3.6.
Next generation sequencing revealed 36 up-regulated lncRNAs and 98 down-regulated lncRNAs in acute asthma compared with controls. KEGG pathway analysis showed that cytokine-cytokine receptor interaction had the highest enrichment scores. A co-expression network was constructed in which 23 lncRNAs and 301 mRNAs altered formed a total of 12424 lncRNA and mRNA pairs. To validate the RNA sequencing results, we measured the 4 different lncRNAs using qPCR. The lncRNA fantom3_9230106C11 was significantly reduced in CD4+ T cells of asthma. Bioinformatics analysis showed that lncRNA fantom3_9230106C11 had the potential to interact with many miRNAs and transcription factors related to Th2 differentiation.
This study provided the first evidence for different expression of lncRNAs of CD4+T cells in asthma and may serve as a template for further, larger functional in-depth analyses regarding asthma molecular lncRNAs.
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