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Background Interstitial lung disease (ILD) is a common and potentially life-threatening complication for rheumatoid arthritis (RA) patients. However, there is a lack of clear prognostic factors in rheumatoid arthritis-associated interstitial lung disease (RA-ILD) patients. The purpose of this study was to complete a systematic review and meta-analysis of the factors associated with mortality in RA-ILD patients. Methods Medline, EMBASE and the Cochrane Library were searched up to September 1, 2020. The Newcastle–Ottawa Scale (NOS) was applied to assess the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, pooled hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) and pooled risk ratios (RRs) with 95% CIs were calculated to assess the factors associated with mortality in RA-ILD. Results Twenty-three of 3463 articles were eligible, and ten factors associated with mortality for RA-ILD were evaluated in the meta-analysis. Older age (HRs = 1.04, 95% CI 1.03–1.05), male sex (HRs = 1.44, 95% CI 1.21–1.73), having a smoking history (HRs = 1.42, 95% CI 1.03–1.96), lower diffusing capacity of the lung for carbon monoxide (DLCO)% predicted (HRs = 0.98, 95% CI 0.97–1.00), forced vital capacity (FVC)% predicted (HRs = 0.99, 95% CI 0.98–1.00), composite physiological index (CPI) (HRs = 1.04, 95% CI 1.02–1.06), usual interstitial pneumonia (UIP) pattern on HRCT (HRs = 1.88, 95% CI 1.14–3.10 and RRs = 1.90, 95% CI 1.50–2.39), emphysema presence (HRs = 2.31, 95% CI 1.58–3.39), and acute exacerbation of ILD (HRs = 2.70, 95% CI 1.67–4.36) were associated with increased mortality in RA-ILD, whereas rheumatoid factor (RF) positive status was not associated. Conclusions Through this systematic review and meta-analysis, we found that older age, male sex, smoking history, higher CPI, lower DLCO% predicted, lower FVC% predicted, UIP pattern on HRCT, emphysema presence and acute exacerbation of ILD were associated with an increased risk of mortality in RA-ILD.

Objective Interstitial lung disease (ILD) is a common and potentially life-threatening complication for individuals with systemic sclerosis (SSc). The purpose of this study was to complete a systematic review and meta-analysis on prevalence and risk factors of SSc-ILD in East Asia. Methods Medline, EMBASE, and Cochrane Library were searched up to January 22, 2021. The Reporting of Observational Studies in Epidemiology (STROBE) statement was applied to access the methodological quality of the eligible studies. Study characteristics and magnitude of effect sizes were extracted. Then, we calculated the pooled prevalence, weighted mean differences (WMDs), pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs), and performed subgroup analysis, sensitivity analysis, and publication bias with Egger's test. Results Twenty-seven of 1584 articles were eligible and a total of 5250 patients with SSc were selected in the meta-analysis. The pooled prevalence of SSc-ILD in East Asia was 56% (95% CI 49%-63%). The SSc-ILD prevalence was higher in China (72%) than in Japan (46%) and Korea (51%). Longer disease duration (WMD = 1.97, 95% CI 0.55-3.38), diffuse SSc (OR = 2.84, 95% CI 1.91-4.21), positive anti-topoisomerase I antibody (ATA) (OR = 4.92, 95% CI 2.74-8.84), positive anti-centromere body antibody (ACA) (OR = 0.14, 95% CI 0.08-0.25), positive anti-U3 ribonucleoprotein (RNP) antibody (OR = 0.17, 95% CI 0.04-0.66), and higher erythrocyte sedimentation rate (ESR) (WMD = 6.62, 95% CI 1.19-12.05) were associated with SSc-ILD in East Asia. Conclusion Through this systematic review and meta-analysis, we found that ILD occurs in up to approximately 56% of patients with SSc in East Asia. Longer disease duration, diffuse SSc, positive ATA, negative ACA, negative anti-U3 RNP antibody, and higher ESR were risk factors for SSc-ILD.

This study aimed to evaluate the role of human epididymis protein 4 (HE4) in the diagnosis and determination of the severity of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients.HE4 levels in peripheral blood (PB) and bronchoalveolar lavage fluid (BALF) samples were determined via electrochemiluminescence immunoassays in 102 RA patients (46 patients with ILD and 56 patients without ILD) and 51 healthy controls (HCs).Serum HE4 levels were significantly higher in RA-ILD patients (141.8±65.92 pmol/l) than those in the RA-no ILD patients (82.67±26.17 pmol/l) and healthy controls (35.72±7.6 pmol/l) (p0.0001). Consistent with serum HE4 levels, BALF HE4 levels were significantly higher in RA-ILD patients (637.6±154.9 pmol/l) than those in the RA-no ILD patients (427.3±111.2 pmol/l) and healthy controls (206.9±30.46 pmol/l) (p0.0001). In RA-ILD patients, HE4 levels were positively correlated with HRCT (high-resolution computed tomography) fibrosis scores, whereas a significant inverse relationship was found between HE4 levels and lung function parameters (such as, diffusion capacity of the lung for carbon monoxide (DLCO)). The logistic regression analysis showed that high levels of BALF HE4 (≥595 pmol/l) were associated with RA-ILD (odds ratio [OR] =8.09; 95% confidence interval [CI] =1.317-49.682; p=0.024).Serum and BALF HE4 levels were elevated in RA-ILD patients and strongly associated with the severity of ILD, thus supporting their potential clinical value as a new diagnostic aid for patients with RA-ILD.

Background Asbestosis and silicosis are characterized by diffuse or nodular interstitial lung fibrosis resulting from exposure to asbestos or silica dust, respectively. This study was designed to detect programmed cell death protein (PD-1)/programmed death ligands (PD-Ls) expression in patients with asbestosis and silicosis and to explore the possible clinical significance of PD-1/PD-Ls expression in patients with the two diseases. Methods Thirty patients with asbestosis, 23 patients with silicosis and 25 healthy controls were consecutively recruited and provided informed consent to participate in the study. Clinical data were collected from patients’ clinical charts. PD-1/PD-Ls expression in peripheral blood (PB) was detected using flow cytometry. Results PD-1 was expressed at significantly lower levels on CD4+ or CD8+ peripheral T cells from patients with asbestosis and silicosis than on cells from healthy controls. Similarly, significantly lower PD-L1 and PD-L2 expression was detected on CD14+ monocytes from patients with asbestosis and silicosis than on cells from healthy controls. In addition, no significant differences in PD-1, PD-L1 and PD-L2 expression were observed between the asbestosis and silicosis groups. Moreover, the proportions of PD-1+ CD4+ T cells and PD-1+ CD8+ T cells in patients with asbestosis were positively correlated with the percentage of forced vital capacity predicted. Conclusions Decreased PD-1 expression on CD4+ T or CD8+ T cells in PB was positively correlated with the asbestosis severity, implying that pulmonary fibrosis development in patients with asbestosis was positively correlated with the downregulation of the PD-1/PD-Ls pathway.

Background: Asbestosis and silicosis are characterized by diffuse or nodular interstitial lung fibrosis resulting from exposure to asbestos or silica dust, respectively. This study was designed to detect programmed cell death protein (PD-1)/programmed death-ligands (PD-Ls) expression in patients with asbestosis and silicosis and to explore the possible clinical significance of PD-1/PD-Ls expression in the two diseases.Methods: Thirty patients with asbestosis, 23 patients with silicosis and 25 healthy controls were consecutively recruited for and provided informed consent to participate in the study. Clinical data were collected from patient clinical charts. PD-1/PD-Ls expression in peripheral blood (PB) was detected by flow cytometry.Results: PD-1 expression on CD4+ or CD8+ peripheral T cells was significantly lower in patients with asbestosis and silicosis than in healthy controls. Similarly, PD-L1 and PD-L2 expression on CD14+ monocytes was significantly lower in patients with asbestosis and silicosis than in healthy controls. In addition, there was no significant difference in PD-1, PD-L1 or PD-L2 expression between the asbestosis and silicosis groups. Moreover, the proportions of PD-1+ CD4+T cells and PD-1+ CD8+T cells in patients with asbestosis were positively correlated with the percentage of forced vital capacity (FVC) predicted. Conclusion: Lower PD-1 expression on CD4+T or CD8+ T cells in PB was positively correlated with parameters representing disease severity, implying that pulmonary fibrosis development was positively correlated with PD-1/PD-Ls pathway down-regulation.

Background: Primary Sjogren syndrome (pSS) is a chronic inflammatory autoimmune disease that is characterized by lymphocytic infiltration of the exocrine glands and extraglandular organ systems. Interstitial lung disease (ILD) is common in pSS patients and is one of the independent risk factors for a poor prognosis. The previously reported characteristics and potential risks contributing to pSS-associated ILD have been controversial. Methods: A cohort of 201 newly diagnosed pSS patients were studied over a period of 3 years. Data were from clinical charts. The pSS patients were classified into two groups, namely pSS-ILD or pSS without ILD, according to the lung evaluation. Results: In total, the prevalence of pSS-associated ILD was 78.6%. The pSS patients associated ILD were more likely to be male, older and smokers in comparison to the pSS patients without ILD. There were no significant differences in multiorgan involvement between the two groups. Nonspecific interstitial pneumonia (NSIP) was the most common radiological pattern (45.5%). pSS with ILD was associated with increasing age [odds ratio (OR) =1.073], smoking (OR =8.544) and antinuclear antibody (ANA) positive (OR =3.286). Over a median follow-up period of 24 months (range, 18–30 months), no patients died, experienced acute exacerbation of ILD, or had newly diagnosed pSS-ILD. Conclusions: pSS associated ILD were more commonly in males, older patients and smokers. Aging, cigarette smoking, and ANA positivity may be potential risk factors contributing to ILD in pSS patients.

Background Regulatory T cells (Tregs) are crucial in maintaining immune tolerance and immune homeostasis, but their role in idiopathic pulmonary fibrosis (IPF) is unclear. This study was designed to explore the role of Tregs in IPF. Methods Percentages of Tregs and their subpopulations in peripheral blood (PB) and bronchoalveolar lavage (BAL) samples were determined by flow cytometry in 29 patients with IPF, 19 patients with primary Sjögren’s syndrome-related interstitial pneumonia (pSS-IP), and 23 healthy controls (HCs). Results In peripheral blood, no difference was found in CD4+CD25+Foxp3+ Treg percentages among patients with IPF, pSS-IP, or HCs. However, activated Treg (aTreg) fractions among CD4+ T cells increased significantly in IPF compared with pSS-IP or HCs. Being consistent with the result from the PB, aTreg fractions among CD4+ T cells in IPF also increased significantly compared with pSS-IP or HCs, accompanied by increased fraction III compared with HCs in BAL. IPF patients had lower levels of resting Tregs (rTregs) from the thymus than did HCs, whereas aTreg levels originating from the thymus did not significantly differ from HCs. Both rTregs and aTregs proliferated in IPF, with aTregs being more proliferative than rTregs. Both rTregs and aTregs significantly inhibited proliferation of CD4+ T lymphocytes in vitro. The percentage of aTregs was correlated negatively with predicted diffusing capacity values for carbon monoxide and positively with GAP index in IPF. Conclusions Our study showed the imbalance between subpopulations of Tregs in IPF. Increased aTregs proportion in the peripheral blood correlated inversely with disease severity.

Objectives: Asbestosis and silicosis are defined as diffuse or nodular interstitial fibrosis of the lungs as a consequence of exposure to asbestos or silica dust. Programmed death 1 (PD-1) combined with PD-Ls inhibits the activation of T cells in various diseases. We aimed to explore the expression of PD-1/PD-Ls in asbestosis and silicosis and the possible clinical meanings. Methods: Thirty asbestosis, 23 silicosis and 25 healthy controls (HCs) were recruited. The expression of PD-1 and PD-L1, PD-L2 in the peripheral blood was detected using flow cytometry. Results: The expression of PD-1 on CD4+T or CD8+ T cells in peripheral blood was significantly lower both in asbestosis and silicosis patients than in HCs. Similarly, the expression of PD-L1 and PD-L2 on CD14+ monocytes also significantly decreased in asbestosis and silicosis patients in comparison to in HCs, whereas there was no significant difference between asbestosis and silicosis. The varied effector T cells activation status were detected. The proportions of CD8+PD-1+T cells in peripheral blood of asbestosis or silicosis were positively correlated with the proportions of CD8+CD28+T cells. Moreover, the proportion of CD4+PD-1+ T cells and CD8+PD-1+T cells in asbestosis was positively correlated with the percentage of forced vital capacity predicted values. Conclusions: The lower PD-1 expression on CD4+T or CD8+ T cells in the peripheral blood correlated positively with the values of disease severity, implying a potential link between the development of pulmonary fibrosis and down-regulation of PD-1/PD-Ls pathway. (Supported by National Natural Science Foundation of China 81370159; National Science and Technology Major Project of China 2014ZX09J15104).

Background: Asbestosis and silicosis are the progressive pneumoconiosis characterized by interstitial fibrosis as a consequence of exposure to asbestos or silica dust. We aimed to evaluate the potential biomarkers for diagnosing the diseases. Methods: Serum Krebs von den Lungen (KL)-6, matrix metalloproteinases (MMP)-2,7,9 and surfactant protein (SP)-D were measured in 43 asbestosis, 45 silicosis and 45 healthy controls (HCs). Chest HRCT were reviewed by the experts blinded to clinical data. According to receiver operating characteristic (ROC) curve, the ideal level of each biomarker and the diagnostic sensitivity were obtained. Results: Serum KL-6 and MMP-2 were highest in asbestosis which was significantly different from those of HCs (P Conclusions: KL-6, SP-D and MMP-2 were available biomarkers in diagnosing asbestosis as well as silicosis. Combination of KL-6, SP-D and MMP-2 may improve the sensitivity for diagnosis. (National Science and Technology Major Project of China 2014ZX09J15104; National Natural Science Foundation of China 81370159).

Root exudates play important roles in root-soil microorganism interactions and can mediate tripartite interactions of beneficial microorganisms-plant-pathogen in the rhizosphere. However, the roles of organic acid components in this process have not been well studied. In this study the colonization of a plant growth-promoting rhizobacterium, Bacillus amyloliquefaciens SQR9, on cucumber root infected by Fusarium oxysporum f. sp. cucumerinum J. H. Owen (FOC) was investigated. Chemotaxis and biofilm formation response of SQR9 to root exudates and their organic acid components were analysed. Infection of FOC on cucumber had a positive effect (3.30-fold increase) on the root colonization of SQR9 compared with controls. Root secretion of citric acid (2.3 ± 0.2 μM) and fumaric acid (5.7 ± 0.5 μM) was enhanced in FOC-infected cucumber plants. Bacillus amyloliquefaciens SQR9 exhibited enhanced chemotaxis to root exudates of FOC-infected cucumber seedlings. Further experiments demonstrated that citric acid acts as a chemoattractant and fumaric acid as a stimulator of biofilm formation in this process. These results suggest that root exudates mediate the interaction of cucumber root and rhizosphere strain B. amyloliquefaciens SQR9 and enhance its root colonization.

It was hypothesized that disruption of the root–microbiome association creates empty rhizosphere niches that could be filled by both soilborne pathogens and beneficial microbes. The effect of de-coupling root–microbiome associations related to improve soil suppressiveness was investigated in cucumber using the pathogen Fusarium oxysporum f. sp. Cucumerinum (FOC) and its antagonist Bacillus amyloliquefaciens SQR9 (SQR9) system. The root–soil microbiome association of cucumber was disrupted by applying the fungicide carbendazim to the soil, and then FOC or/and its antagonist SQR9 were inoculated in the rhizosphere. In the fungicide treatment, the FOC wilt disease incidence was significantly increased by 13.3 % on average compared to the FOC treatment without fungicide. However, when the fungicide treatment was applied to the soil with SQR9 and FOC, the SQR9 effectively reduced the disease incidence, and improved cucumber plant growth compared to a no fungicide control. These results indicate that de-coupling of root–microbiome associations followed by antagonist inoculation can improve rhizosphere soil suppressiveness, which may help to develop strategies for efficient application of rhizosphere beneficial microbes in agriculture.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic disease limited to the lungs. The course of disease varies widely, with some patients experiencing acute respiratory deterioration, a condition called acute exacerbations of IPF (AE-IPF). The risk factors contributing to AE-IPF are unclear. This systematic review and meta-analysis investigated the risk factors for AE-IPF. Methods Studies of risk factors for AE-IPF were identified in Medline, EMBASE and Cochrane databases. Fixed effects models were used to calculate pooled relative risks and weighted mean differences (WMD).The meta-analysis included seven articles involving 14 risk factors for AE-IPF. Results Risk factors for AE included reductions in vital capacity (VC; WMD – 10.58, 95% confidence interval (CI) −17.17 to – 3.99), forced vital capacity (FVC; WMD −6.02, 95%CI – 8.58 to – 3.47), total lung capacity (TLC; WMD −4.88, 95%CI −7.59 to – 2.17), and PaO2 (WMD −4.19, 95%CI −7.66 to −0.71) and a higher alveolar-arterial oxygen difference (AaDO2; WMD 4.4, 95%CI 0.24 to 8.57). Mechanical procedures, higher serum KL-6 concentration and secondary pulmonary hypertension, might be risk factors for AE-IPF. In contrast, age, sex, body mass index (BMI), differences in diffusing lung capacity for carbon monoxide (DLCO), exposure to seasonal variations and air pollution, and virus infection might be unrelated to AE-IPF. Conclusions Poor pulmonary function, mechanical procedures, higher serum KL-6 and secondary pulmonary hypertension were associated with increased risks of AE-IPF.

Fusarium wilt, caused by Fusarium oxysporum f. sp. cucumerinum J. H. Owen, results in considerable yield losses for cucumber plants. A bio-organic fertilizer (BIO), which was a combination of manure composts with antagonistic microorganisms, and an organic fertilizer (OF) were evaluated for their efficiencies in controlling Fusarium wilt. Application of the BIO suppressed the disease incidence by 83% and reduced yield losses threefold compared with the application of OF. Analysis of microbial communities in rhizosphere soils by high-throughput pyrosequencing showed that more complex community structures were present in BIO than in OF treated soils. The dominant taxonomic phyla found in both samples were Proteobacteria, Firmicutes, Actinobacteria and Acidobacteria among bacteria and Ascomycota among fungi. Abundance of beneficial bacteria or fungi, such as Trichoderma, Hypoxylon, Tritirachium, Paenibacillus, Bacillus, Haliangium and Streptomyces, increased compared to the OF treatment, whereas the soil-borne pathogen, Fusarium, was markedly decreased. Overall, the results of this study demonstrate that the application of the BIO was a useful and effective approach to suppress Fusarium wilt and that the high-throughput 454 pyrosequencing was a suitable method for the characterization of microbial communities of rhizosphere soil of cucumber.

Bacillus Amyloliquefaciens SQR9 is a well-investigated plant growth-promoting rhizobacteria with strong root colonization capability. To identify the key proteins involved in in situ root colonization and biofilm formation, the proteomic profiles of planktonic and root colonized SQR9 cells were compared. A total of 755 proteins were identified, of which 78 and 95 proteins were significantly increased and deceased, respectively, when SQR9 was colonized on the root. The proteins that were closely affiliated with the root colonization belonged to the functional categories of biocontrol, detoxification, biofilm formation, cell motility and chemotaxis, transport, and degradation of plant polysaccharides. A two-component system protein ResE was increased 100-fold when compared to the planktonic status; impairment of the resE gene postponed the formation of cell biofilm and decreased the root colonization capability, which may be regulated through the spo0A-sinI-yqxM pathway. The SQR9 proteomic data provide valuable clues for screening key proteins in the plant-rhizobacteria interaction.

Here we report the complete genome sequence of a plant growth-promoting rhizobacterium (PGPR), Paenibacillus polymyxa SQR-21, which consists of one circular chromosome of 5,828,438 bp with 5,024 coding sequences (CDS). The data presented highlight multiple sets of functional genes associated with its plant-beneficial characteristics.

Bacillus amyloliquefaciens strain SQR9, isolated from the cucumber rhizosphere, suppresses the growth of Fusarium oxysporum in the cucumber rhizosphere and protects the host plant from pathogen invasion through efficient root colonization. In the Gram-positive bacterium Bacillus , the response regulator DegU regulates genetic competence, swarming motility, biofilm formation, complex colony architecture, and protease production. In this study, we report that stepwise phosphorylation of DegU in B. amyloliquefaciens SQR9 can influence biocontrol activity by coordinating multicellular behavior and regulating the synthesis of antibiotics. Results from in vitro and in situ experiments and quantitative PCR (qPCR) studies demonstrate the following: (i) that the lowest level of phosphorylated DegU (DegU∼P) (the degQ mutation) impairs complex colony architecture, biofilm formation, colonization activities, and biocontrol efficiency of Fusarium wilt disease but increases the production of macrolactin and bacillaene, and (ii) that increasing the level of DegU∼P by degQ and degSU overexpression significantly improves complex colony architecture, biofilm formation, colonization activities, production of the antibiotics bacillomycin D and difficidin, and efficiency of biocontrol of Fusarium wilt disease. The results offer a new strategy to enhance the biocontrol efficacy of Bacillus amyloliquefaciens SQR9.

Fusaricidins produced by Paenibacillus polymyxa are lipopeptide antibiotics with outstanding antifungal activity. In this study, the whole gene cluster responsible for fusaricidin biosynthesis (fusA) was isolated and identified from the cDNA library of one biocontrol agent P. polymyxa SQR-21 (SQR-21). MALDI-TOF MS analysis confirmed that SQR-21 could produce four kinds of fusaricidins: A, B, C, and D. A central promoter that drove the transcription of fusGFEDCBA was revealed by mapping of the fus promoter region by 5' deletions. The disruption of fusA in SQR-21 led to the abolishment of fusaricidin production and antifungal activity. The direct interaction between a potential regulator, AbrB, and the promoter region of fus gene cluster was confirmed by electrophoretic mobility shift assays. One abrB disruption mutant showed significantly higher antifungal activity compared with the wild type. These results revealed a pathway for the transcriptional regulation of the fus gene cluster in P. polymyxa.

The effects of storage temperature (20, 30 and 40 °C), inoculum type (pure spores, an equal mix of spores and vegetative cells and pure vegetative cells) and water content (20%, 30% and 40%) on the survival and spore formation of the biocontrol agent, Paenibacillus polymyxa SQR-21, in a bioorganic fertilizer were modeled in a 3 × 3 × 3 factorial design. Bacterial and spore populations were monitored by plate count and fluorescence in situ hybridization (FISH). Temperature significantly affected survival of inoculants after storage for 60 days. Populations were 1.48 (plate counting) or 1.71 (FISH) times greater when stored at 20 °C compared to 40 °C. Inoculation of the fertilizer with pure spores led to the highest spore formation percentage (67.6% for plate counting, 94.2% for FISH). This study provides useful information for preservation of bioorganic fertilizer.

To alleviate the stress of continuous cropping for cucumber continuous cropping (CCC) system, a beneficial fungus Trichoderma harzianum SQR-T037 (SQR-T037) was isolated and applied to soil to degrade allelochemicals exuded from cucumber plants in a Rhizobox experiment. The following phenolic acids (PAs), classified as allelochemicals, were isolated and identified from cucumber rhizospheres: 4-hydroxybenzoic acid, vanillic acid, ferulic acid, benzoic acid, 3-phenylpropionic acid, and cinnamic acid. Mixed PAs added in potato dextrose broth, each with 0.2 gram per liter, were completely degraded by SQR-T037 after 170 h of incubation. In Rhizobox experiments, inoculation of SQR-T037 in the CCC soil also degraded the PAs exuded from cucumber plant roots. This degradation was 88.8% for 4-hydroxybenzoic acid, 90% for vanillic acid, 95% for benzoic acid, and 100% for ferulic acid, 3-phenylpropionic acid, and cinnamic acid at 45 days after plantation. Simultaneously, a significant (p ≥ 0.05) decrease in the disease index of Fusarium wilt and an increase in dry weights of cucumber plants were obtained in pot experiments by application of SQR-T037. This was mostly attributed to degradation of PAs exuded from cucumber roots in CCC soil by SQR-T037 and alleviation of the allelopathic stress. Application of beneficial microorganisms, such as SQR-T037 that biodegrades allelochemicals, is a highly efficient way to resolve the problems associated with continuous cropping system.