Small diameter vascular grafts: progress on electrospinning matrix/stem cell blending approach.

The exploration of the next-generation small diameter vascular grafts (SDVGs) will never stop until they possess high biocompatibility and patency comparable to autologous native blood vessels. Integrating biocompatible electrospinning (ES) matrices with highly bioactive stem cells (SCs) provides a rational and promising solution. ES is a simple, fast, flexible and universal technology to prepare extracellular matrix-like fibrous scaffolds in large scale, while SCs are valuable, multifunctional and favorable seed cells with special characteristics for the emerging field of cell therapy and regenerative medicine. Both ES matrices and SCs are advanced resources with medical application prospects, and the combination may share their advantages to drive the overcoming of the long-lasting hurdles in SDVG field. In this review, the advances on SDVGs based on ES matrices and SCs (including pluripotent SCs, multipotent SCs, and unipotent SCs) are sorted out, and current challenges and future prospects are discussed.

FeNO, a potential biomarker for evaluating glucocorticoids treatment and prognosis in ABPA.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by enhanced Th2 inflammatory response. Fractional exhaled nitric oxide (FeNO) measurement has been utilized as a valuable tool in predicting the development and management of asthma, another typical Th2 inflammation. However, the clinical significance of FeNO in ABPA remains unclear. OBJECTIVE: To investigate the association between FeNO and the prognosis of ABPA patients, so as to provide a basis for the use of FeNO in evaluating the efficacy of glucocorticoids in ABPA treatment. METHODS: This study consists of two parts. 58 patients were enrolled in the retrospective study. Clinical indexes between patients with different prognoses were compared and ROC curve analysis were employed to determine the threshold value. The prospective observational study involved 61 patients who were regularly followed up at 4-6 weeks and 6 months since the initial treatment. Patients were grouped based on baseline FeNO values, correlation analysis were performed between clinical data. RESULTS: Different prognoses were observed between patients with High- and Low- baseline FeNO values, with a threshold value of 57 ppb. The percentage of A. fumigatus-specific IgE, percentage of positive A. fumigatus-specific IgG, and relapse/exacerbation rate differed significantly between the H/L-FeNO groups. Patients with higher FeNO needed longer treatment duration and showed shorter interval between glucocorticoid withdrawal and the next relapse/exacerbation. CONCLUSION: Our findings indicate that the level of FeNO is associated with the prognosis of ABPA. It can serve as an independent and valuable biomarker for evaluating the effectiveness of glucocorticoid treatment.

Th2-skewed peripheral T-helper cells drive B-cells in allergic bronchopulmonary aspergillosis.

INTRODUCTION: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. The involvement of T-cell subsets remains unclear. METHODS: We enrolled ABPA patients, asthma patients and healthy controls. T-helper type 1 (Th1), 2 (Th2) and 17 (Th17) cells, regulatory T-cells (Treg) and interleukin (IL)-21+CD4+T-cells in total or sorted subsets of peripheral blood mononuclear cells and ABPA bronchoalveolar lavage fluid (BALF) were analysed using flow cytometry. RNA sequencing of subsets of CD4+T-cells was done in exacerbated ABPA patients and healthy controls. Antibodies of T-/B-cell co-cultures in vitro were measured. RESULTS: ABPA patients had increased Th2 cells, similar numbers of Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T-cells were rarely detected in healthy controls, but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T-cells were mainly peripheral T-helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph cells were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T-helper cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B-cells into plasmablasts and significantly enhanced the production of IgE. CONCLUSION: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.

Nanomaterials for small diameter vascular grafts: overview and outlook.

Small-diameter vascular grafts (SDVGs) cannot meet current clinical demands owing to their suboptimal long-term patency rate. Various materials have been employed to address this issue, including nanomaterials (NMs), which have demonstrated exceptional capabilities and promising application potentials. In this review, the utilization of NMs in different forms, including nanoparticles, nanofibers, and nanofilms, in the SDVG field is discussed, and future perspectives for the development of NM-loading SDVGs are highlighted. It is expected that this review will provide helpful information to scholars in the innovative interdiscipline of cardiovascular disease treatment and NM.

Tourism development influence on environmental quality: how renewable energy use and income matter?

Tourism is a significant economic growth and development source, but it relies heavily on the energy sector and contributes to carbon dioxide (CO2) emissions. This study examines how tourism growth, renewable energy, and real GDP affect CO2 emissions in the BRICS countries. The researchers used panel unit root, Pedroni, and Kao methods to test for a long-run equilibrium relationship among the variables. The results reveal that tourism growth harms CO2 emissions in the long run, with a 1% increase in tourism growth leading to a 0.05% decrease in CO2 emissions. Renewable energy usage also harms CO2 emissions, with a 1% increase in renewable energy leading to a 0.15% decrease in CO2 emissions in the long run. CO2 emissions and real GDP show a U-shaped relationship in the long run, supporting the environmental Kuznets curve hypothesis. This hypothesis suggests that CO2 emissions increase with economic growth at low-income levels but decrease with economic growth at high-income levels. Therefore, the study implies that tourism growth can significantly lower CO2 emissions by promoting renewable energy usage and economic development.

Pseudomonas aeruginosa Induces Interferon-ß Production to Promote Intracellular Survival.

Pseudomonas aeruginosa (PA) is known as one kind of extracellular pathogens. However, more evidence showed that PA encounters the intracellular environment in different mammalian cell types. Little is known of innate immune factors modulating intracellular PA survival. In the present study, we proposed that interferon-ß (IFN-ß) is beneficial to the survival of PA in the cytoplasm of macrophages. Furthermore, we found that interleukin-1ß (IL-1ß) induced by PA suppresses IFN-ß response driven by the cGAS-STING-TBK1 pathway. Mechanistically, IL-1ß decreased the production of cyclic GMP-AMP (cGAMP) by activating AKT kinase. cGAMP is necessarily sufficient to stimulate the transcription of IFN-ß via the STING adaptor-TBK1 kinase-IRF3 transcription factor axis. Thus, our findings uncovered a novel module for PA intracellular survival involving IFN-ß production restricted by IL-1ß and provided a strong rationale for a potential clinical strategy against pulmonary PA infection patients. IMPORTANCE The link between innate immunity and intracellular Pseudomonas aeruginosa is unclear. Our studies illuminated the role of interferon-ß (IFN-ß) in remote intracellular PA infection. Furthermore, our experimental evidence also indicated that IL-1ß is a negative regulator of IFN-ß production and, in particular, P. aeruginosa infection. The inhibition of IFN-ß may be used as a potential therapeutic method against pulmonary PA infection.

Airway acidification impaired host defense against Pseudomonas aeruginosa infection by promoting type 1 interferon ß response.

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonß (IFN-ß) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-ß signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.

Idiopathic Pulmonary Fibrosis Mortality Risk Prediction Based on Artificial Intelligence: The CTPF Model.

Background: Idiopathic pulmonary fibrosis (IPF) needs a precise prediction method for its prognosis. This study took advantage of artificial intelligence (AI) deep learning to develop a new mortality risk prediction model for IPF patients. Methods: We established an artificial intelligence honeycomb segmentation system that segmented the honeycomb tissue area automatically from 102 manually labeled (by radiologists) cases of IPF patients' CT images. The percentage of honeycomb in the lung was calculated as the CT fibrosis score (CTS). The severity of the patients was evaluated by pulmonary function and physiological feature (PF) parameters (including FVC%pred, DLco%pred, SpO2%, age, and gender). Another 206 IPF cases were randomly divided into a training set (n = 165) and a verification set (n = 41) to calculate the fibrosis percentage in each case by the AI system mentioned previously. Then, using a competing risk (Fine-Gray) proportional hazards model, a risk score model was created according to the training set's patient data and used the validation data set to validate this model. Result: The final risk prediction model (CTPF) was established, and it included the CT stages and the PF (pulmonary function and physiological features) grades. The CT stages were defined into three stages: stage I (CTS≤5), stage II (5 < CTS<25), and stage III (≥25). The PF grades were classified into mild (a, 0-3 points), moderate (b, 4-6 points), and severe (c, 7-10 points). The AUC index and Briers scores at 1, 2, and 3 years in the training set were as follows: 74.3 [63.2,85.4], 8.6 [2.4,14.8]; 78 [70.2,85.9], 16.0 [10.1,22.0]; and 72.8 [58.3,87.3], 18.2 [11.9,24.6]. The results of the validation sets were similar and suggested that high-risk patients had significantly higher mortality rates. Conclusion: This CTPF model with AI technology can predict mortality risk in IPF precisely.

The role of pirfenidone in the treatment of interstitial pneumonia with autoimmune features.

OBJECTIVES: No approved pharmacotherapies are available for patients with interstitial pneumonia with autoimmune features (IPAF). In the present work, we aimed to evaluate the efficacy and safety of pirfenidone for the treatment of IPAF. METHODS: A retrospective cohort study consisting of patients who met diagnostic criteria for IPAF was performed after a multidisciplinary review, and the patients receiving pirfenidone were compared with those in the non-pirfenidone group. The baseline data and diagnostic characteristics of patients were assessed. Pulmonary function and prednisone dose were analysed by a mix-effects model. RESULTS: A total of 184 patients, who met the diagnostic criteria of IPAF, were divided into two groups: pirfenidone group (n=81) and non-pirfenidone group (n=103). Patients in the pirfenidone group had a lower forced vital capacity (FVC%, p<0.001) and a lower diffusion capacity for carbon monoxide (DLCO%, p=0.003). The pirfenidone group exhibited a greater increase of FVC% at 6 (p=0.003), 12 (p=0.013), and 24 (p=0.003) months. After adjustment for sex, age, UIP pattern, baseline FVC% and DLCO%, patients in the pirfenidone group continued to show a greater improvement in FVC% (χ2(1)=4.59, p=0.032). Subgroup analysis identified superior therapeutic effects of pirfenidone in patients with dosage >600 mg/day (p=0.010) and medication course >12 months (p=0.007). Besides, the pirfenidone group had a lower prednisone dose than the non-pirfenidone group after 12 months of treatment (p=0.002). Moreover, 17 patients (19.32%) experienced side effects after taking pirfenidone, including one case of anaphylactic shock. CONCLUSIONS: Pirfenidone (600-1,800 mg/day) might help improve FVC, with an acceptable safety and tolerability profile in IPAF patients.

New pulmonary rehabilitation exercise for pulmonary fibrosis to improve the pulmonary function and quality of life of patients with idiopathic pulmonary fibrosis: a randomized control trial.

BACKGROUND: The aim of our study is to investigate the impact of the simple breathing exercises (LHP's respiratory rehabilitation for pulmonary fibrosis, LHP's RRPF) on patients with idiopathic pulmonary fibrosis (IPF). METHODS: (I) The safety and effectiveness of LHP's RRPF were first verified in 20 healthy individuals. (II) A total of 101 patients with IPF administrated in Shanghai Pulmonary Hospital between January 2015 and May 2017 were screened, and 82 cases were randomly assigned to receive a 12-month LHP's RRPF program (exercise group) or usual medical care (control group). Lung function, chest X-ray, 6-minute walk distance (6MWD), quality of life (St. George's Respiratory Questionnaire, SGRQ), and EKG were measured at the 6th and 12th month during the trial. RESULTS: At the 6th month visit, the exercise group showed improved SGRQ score and lung function parameters (FVC, FEV1, and DLCO). At the 12th months visit, the exercise group had significantly improved SGRQ score, 6MWD, and lung function (FVC, FEV1, and DLCO) compared to the control group (P<0.05). No obvious adverse events occurred in the exercise group. The incidence of acute exacerbation and one-year mortality were 7.69% and 2.56%, respectively in the exercise group, which were lower than those (20.9% and 9.3%, respectively) in the control group. CONCLUSIONS: LHP's RRPF can delay the pulmonary function decline of patients with IPF and improve their quality of life. This breathing exercise may be an adjunct to pulmonary rehabilitation for IPF.

Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

Ion therapy of pulmonary fibrosis by inhalation of ionic solution derived from silicate bioceramics.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an "ion therapy" approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis.

Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6-p-STAT3-p63-JAG2 pathway.

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute respiratory failure with extremely high mortality and few effective treatments. Mesenchymal stem cells (MSCs) may reportedly contribute to tissue repair in ALI and ARDS. However, applications of MSCs have been restricted due to safety considerations and limitations in terms of large-scale production and industrial delivery. Alternatively, the MSC secretome has been considered promising for use in therapeutic approaches and has been advanced in pre-clinical and clinical trials. Furthermore, the MSC secretome can be freeze-dried into a stable and ready-to-use supernatant lyophilized powder (SLP) form. Currently, there are no studies on the role of MSC SLP in ALI. METHODS: Intratracheal bleomycin was used to induce ALI in mice, and intratracheal MSC SLP was administered as a treatment. Histopathological assessment was performed by hematoxylin and eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis, inflammatory infiltration, immunological cell counts, cytokine levels, and mRNA- and protein-expression levels of relevant targets were measured by performing terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, determining total cell and protein levels in bronchoalveolar lavage fluids, flow cytometry, multiple cytokine-detection techniques, and reverse transcriptase-quantitative polymerase chain reaction and western blot analysis, respectively. RESULTS: We found that intratracheal MSC SLP considerably promoted cell survival, inhibited epithelial cell apoptosis, attenuated inflammatory cell recruitment, and reversed immunological imbalances induced by bleomycin. MSC SLP inhibited the interleukin 6-phosphorylated signal transducer and activator of transcription signaling pathway to activate tumor protein 63-jagged 2 signaling in basal cells, suppress T helper 17 cell differentiation, promote p63+ cell proliferation and lung damage repair, and attenuate inflammatory responses. CONCLUSIONS: MSC SLP ameliorated ALI by activating p63 and promoting p63+ cell proliferation and the repair of damaged epithelial cells. The findings of this study also shed insight into ALI pathogenesis and imply that MSC SLP shows considerable therapeutic promise for treating ALI and ARDS.

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.

Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis.

OBJECTIVE: To observe the efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for pulmonary alveolar proteinosis (PAP). MATERIALS AND METHODS: A total of 55 patients with PAP were screened at Shanghai Pulmonary Hospital between May 2014 and May 2018. Among these, 42 were diagnosed with idiopathic PAP, 24 were included in this study, 20 were treated for 6 months, and 17 were followed up for additional 6 months. All patients received a subcutaneous injection of 75µg/d GM-CSF qd for 1 month. The therapeutic dose was adjusted according to the changes in the lesions of chest CT. If the lesions were absorbed, subcutaneous injections of 75µg/d GM- CSF qd and 75µg/d GM-CSF qod were given for 2 and 3 months, otherwise, the dose was increased to 150µg/d GM-CSF qd and 150µg/d qod for 2 and 3 months, respectively. All cases were treated once a day in the first 3 months and once every other day in the last 3 months. The total course of treatment was 6 months. After withdrawal, the patients were followed up for another 6 months. The deadline of follow up was September 30, 2019. RESULTS: Twenty patients completed the treatment and efficacy evaluation. One patient was completely cured, 16 cases improved, three cases were noneffective. After 1-month evaluation, 12 patients received an increased dose (150µg) from the second month of treatment. Seventeen patients completed the 12-month follow-up, among which fourteen improved. CT showed the lesions were slightly increased in three cases. Economic burden was the following: RMB 7324-15,190 Yuan were required for the 6-month treatment course, which is significantly lower compared to other treatment methods. CONCLUSION: Subcutaneous injection of rhGM-CSF at low dose (75µg-150µg /d) is effective treatment for patients with idiopathic PAP. TRIAL REGISTRATION: NCT01983657. Registered 16 April 2013.

IL-17A Can Promote Propionibacterium acnes-Induced Sarcoidosis-Like Granulomatosis in Mice.

The etiology of sarcoidosis is unknown. In this study, Propionibacterium acnes (PA) was used to induce sarcoidosis-like granulomatous inflammation in a mouse model. Wild-Type (WT) C57BL/6 mice were divided into three groups: (1) WT-PA group; (2) WT-PA + Incomplete Freund's Adjuvant (IFA) group; and (3) WT-PBS group. Loose granuloma formation was observed in the lungs on day 56 in the WT-PA and WT-PA + IFA groups. The proportions of peripheral Th17 cells in the WT-PA (p = 0.0004) and WT-PA + IFA groups (p = 0.0005) were significantly higher than that in the WT-PBS group. The proportions of peripheral Treg cells in the WT-PA (p < 0.0001) and WT-PA + IFA groups (p < 0.0001) were lower than that in the WT-PBS group. Then, to explore the mechanism of IL-17, Wild-Type (WT) C57BL/6 mice were divided into three groups: (1) WT-PBS group (2) WT-PA group; (3) WT-PA + mouse IL-17A neutralizing antibody (IL-17Ab) group. IL-17A gene knockout mice (KO) were divided into two groups: (1) KO -PA group; (2) KO-PBS group. The KO-PA and WT-PA + IL-17Ab groups showed reduced inflammation and no loose granuloma formation on day 56. As compared to the WT-PA group, the ratio of peripheral Th17 in the KO-PA (p < 0.0001) and WT-PA + IL-17Ab groups (p < 0.0001) decreased, while the ratio of peripheral Treg in the KO-PA (p < 0.0001) and WT-PA + IL-17Ab (p = 0.0069) groups increased on day 56. Hence, PA can be used to establish a mouse model of sarcoidosis-like granuloma. IL-17A plays an important role in experimental sarcoidosis-like granuloma formation.

Dioscin Alleviates Crystalline Silica-Induced Pulmonary Inflammation and Fibrosis through Promoting Alveolar Macrophage Autophagy.

Occupational exposure to crystalline silica (CS) particles leads to silicosis, which is characterized by chronic inflammation and abnormal tissue repair. Alveolar macrophages (AMs) play a crucial role in the process of silicosis. Previously, we demonstrated positive effect of dioscin on silicosis through modulating macrophage-elicited innate immune response. However, the concrete molecular mechanism remains to be discovered. Methods: We established experimental model of silicosis with wildtype and Atg5flox/floxDppa3Cre/+ mice and oral administrated dioscin daily to explore the effects of dioscin on macrophages and pulmonary fibrosis. AM cell line MH-S with Atg5 silence was used to explore specific function of dioscin on macrophage-derived inflammation and the underlying molecular mechanism. Results: Dioscin could promote autophagy in macrophages. Dioscin-triggered AMs autophagy limited mitochondrial reactive oxygen species (mtROS) mass stimulated by CS, reduced mitochondria-dependent apoptosis pathway activation and facilitated cell survival. Relieved oxidative stress resulted in decreased secretion of inflammatory factors and chemokines. Dioscin treatment alleviated macrophage-derived inflammation and subsequent abnormal collagen repair. All the dioscin's protective effects were diminished in Atg5flox/floxDppa3Cre/+ mice. Conclusion: Dioscin promoting autophagy leads to reduced CS-induced mitochondria-dependent apoptosis and cytokine production in AMs, which may provide concrete molecular mechanism for the therapy of silicosis.

The Role of Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

BACKGROUND: Acute exacerbation of IPF (AE-IPF) is associated with high mortality. We studied changes in pathogen involvement during AE-IPF and explored a possible role of infection in AE-IPF. OBJECTIVES: Our purpose is to investigate the role of infection in AE-IPF. METHODS: Overall, we recruited 170 IPF patients (48 AE-IPF, 122 stable) and 70 controls at Shanghai Pulmonary Hospital. Specific IgM against microbial pathogens and pathogens in sputum were assessed. RNA sequences of pathogens in nasopharyngeal swab of IPF patients were detected by PathChip. A panel of serum parameters reflecting immune function were assessed. RESULTS: Antiviral/bacterial IgM was higher in IPF vs. controls and in AE-IPF vs. stable IPF. Thirty-eight different bacterial strains were detected in IPF patient sputum. Bacteria-positive results were found in 9/48 (18.8%) of AE-IPF and in 26/122 (21.3%) stable IPF. Fifty-seven different viruses were detected in nasopharyngeal swabs of IPF patients. Virus-positive nasopharyngeal swabs were found in 18/30 (60%) of tested AE-IPF and in 13/30 (43.3%) of stable IPF. AE-IPF showed increased inflammatory cytokines (IL-6, IFN-γ, MIG, IL-17, and IL-9) vs. stable IPF and controls. Mortality of AE-IPF in one year (39.5%) was higher compared to stable IPF (28.7%).Conclusions. IPF patients had different colonization with pathogens in sputum and nasopharyngeal swabs; they also displayed abnormally activated immune response, which was exacerbated during AE-IPF.

Diagnosis and endovascular treatment of iliac venous compression syndrome.

OBJECTIVES: To report *The first two authors contributed equally to this work. our clinical experience on diagnostic criteria and endovascular management in patients with iliac venous compression syndrome. METHOD: Between July 2013 and May 2015, 85 consecutive patients with suspected iliac venous compression syndrome were evaluated by transfemoral venography and intravascular ultrasonography. Venographic evidence of iliac venous occlusion, stenosis, or pelvic collateral vessels, and the degree of stenosis as examined with intravascular ultrasonography were recorded. The endovascular procedure, complications, clinical outcome, and the Venous Clinical Severity Score were evaluated before and after the intervention. RESULTS: Of the 85 limbs, 66 cases of iliac venous compression syndrome were confirmed and 19 cases were excluded. In all of the 66 patients, we successfully performed endovascular intervention (22 balloon dilations, 44 balloon dilations + stenting). Two patients with stent implantation developed acute lower extremity deep vein thrombosis, resulted in successful lysis of the thrombus with catheter-directed thrombolysis. CONCLUSIONS: The presence of intraluminal spurs and pelvic collateral vessels represents not only pathological and anatomical changes by long-term mechanical compression, but also indicators of the severity of iliac venous compression syndrome. The degree of stenosis cannot accurately represent the severity and treatment of iliac venous compression syndrome, especially in the right iliac vein. Endovascular intervention is a safe and effective treatment that reduces lower extremity symptoms. Full and intentional dilation of the intraluminal spurs is an important technical aspect, which is often ignored.

IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.