Xiaorong Wang

Extracellular matrix (ECM) disorder was considered as the result of fibrosis, but it is recently recognized that fibrotic ECM initiates a self-reinforcing circuit and contributes to development of fibrosis. Versican, an ECM component, participates in cell-ECM interaction and ECM regeneration. In pleura, versican is primarily derived from pleural mesothelial cells (PMCs). However, the role and mechanism of versican in pleural fibrosis remained unknown. In this study, versican and versican-mediated pleural viscoelasticity was found elevated in both human and murine pleural fibrotic tissues. Versican knockdown by shRNA prevented increases of viscoelasticity as well as pleural fibrosis. High level of versican and viscoelasticity promoted mesothelial to mesenchymal transition (MesoMT) in PMCs. Mechanistically, increased viscoelasticity induced pleural fibrosis through CD44/USP10/Smad4 mechanotransduction pathway. In conclusion, these results revealed that excessive versican in fibrotic pleural ECM enhanced ECM viscoelasticity, and consequently promoted progression of pleural fibrosis.

Tuberculosis infection (TBI) is a significant cause of bronchiectasis (BE). Identifying risk factors for radiological BE (RBE) could enhance the early detection of high-risk individuals following TB infection. This study aimed to develop and validate a novel Inflammation-Nutrition Risk Score (INRS) and a corresponding nomogram model to predict the risk of RBE after TBI. We enrolled 2,210 post-TBI patients from two medical centres. Data from 1,825 patients at Wuhan Jinyintan Hospital were used to develop the INRS and the RBE nomogram. An independent cohort of 385 patients from Wuhan Union Hospital served as an external validation set. The INRS was derived from four parameters: PNI, HALP score, Lg(SII) and CAR. Multivariate analysis identified the following independent risk factors for RBE: age ≥60 years (OR = 1.19, p = 0.030), current smoking (OR = 1.71, p = 0.009), COPD (OR = 3.13, p < 0.001), RDW-CV ≥12.8% (OR = 1.09, p = 0.005), ALB p = 0.003) and INRS ≥1.86 (OR = 5.04, p < 0.001). The RBE nomogram model demonstrated strong discriminatory power, accuracy and clinical utility across the development, internal validation and external validation cohorts. In post-TBI patients, the INRS represents a novel predictive biomarker for RBE. The INRS-based nomogram is a clinically applicable and efficient tool for risk stratification and guiding follow-up management to prevent RBE progression.

Background: High-resolution computed tomography reveals a marked radiological heterogeneity in bronchiectasis; however, the clinical characteristics have not been clearly elucidated. Method: We conducted a prospective observational cohort of 334 bronchiectasis patients at Wuhan Union Hospital. Patients were classified into distal airway (DA) and proximal–intermediate airway (PIA) phenotypes and followed every six months for exacerbations. Clinical, inflammatory, microbial, and metabolic features were compared between groups. Results: Among 334 patients, 206 were classified as DA and 128 as PIA. Most allergic bronchopulmonary aspergillosis cases belonged to the PIA group (p < 0.001). The DA group showed a lower FEV₁%pred (p = 0.010) and Bhalla scores (p < 0.001), higher BSI (p = 0.003) and FACED scores (p < 0.001), more frequent exacerbations (p = 0.002), and a greater prevalence of Pseudomonas aeruginosa (PA) colonization (p < 0.001). Radiologically, the DA group exhibited more extensive structural lung damage (all p < 0.05). Inflammatory profiling showed higher neutrophil counts (p = 0.047) and elevated CRP levels (p = 0.006) in DA, whereas the PIA group was characterized by eosinophilic inflammation (p = 0.026); no significant differences were observed in inflammatory cytokine levels. Microbial interaction network analysis revealed distinct ecological structures between phenotypes. The PIA group showed strong negative correlations with Streptococcus, Rothia, and other commensal taxa, whereas the DA group exhibited no significant associations between Pseudomonas aeruginosa and other species. Furthermore, metabolomic analyses revealed elevated 4-hydroxynonenal levels in the DA group, which also experienced a higher rate of acute exacerbations during follow-up (p = 0.003). Conclusions: Distinct radiological phenotypes based on airway generation in bronchiectasis are associated with different clinical severity, inflammatory profiles, and microbiome features which enable personalized bronchiectasis management.

Background: Under persistent inflammation, asymptomatic radiological bronchiectasis (ARB) may develop into clinical bronchiectasis (CB). Although CB has been extensively studied, the potential for ARB to evolve into CB remains largely unexplored. Whether the ARB could progress to CB and the risk factors to speed up the process are poorly understood. Methods: This was an observational cohort study. 370 patients with radiological bronchiectasis were included in Wuhan Union Hospital in 2018. 296 ARB patients were followed up in 2022 to verify if they progressed to CB and divided the development and validation of clinical prediction models into a training set (n=207) and a validation set (n=89) by the ratio of 7:3. LASSO algorithm and multivariable logistic regression analysis were performed to construct a new nomogram model. ROC, a calibration and decision curve were used to assess the predictive performance of our new prediction model. Results: 370 patients (74, 20% with CB) were finally included. Compared with ARB, CB had lower BMI, Bhalla score, FEV1% predicted, greater extent and degree of bronchodilation, more lobes with mucus plugs, greater thickness of bronchodilation, greater likelihood of pulmonary heart disease and chronic obstructive pulmonary disease (COPD), and lower likelihood of hypertension and coronary artery disease (P< 0.05). In 2022, 60 out of 296 ARB patients progressed to CB. Age, FEV1% predicted, COPD, heart failure (HF), degree of bronchiectasis, number of lobes with bronchiectasis and number of lung segments with mucus plugs were risk factors. The AUCs of the prediction model were 0.866 (95% CI, 0.802– 0.931) in the training set and 0.860 (95% CI, 0.770– 0.949) in the validation set. Conclusion: ARB may progress to CB under the risk factors, including age, FEV1% predicted, COPD, HF and CT images including degree of bronchiectasis, number of lobes with bronchiectasis and number of lung segments with mucus plugs), based on which the nomogram model is a convenient and efficient tool for follow-up management and preventing CB in patients with ARB.

Th1/Th2 balances may play a vital role in the processes of inflammation and fibrosis. The Th1/Th2 paradigm can be evaluated by representing IFN-γ for Th1 and IL-4 for Th2. OM-85 BV encouraged preferential development of the Th1-type immunity characterized by amplified IFN-γ and decreased IL-4 production. This study aimed to evaluate the inhibitory effect of OM85 on bleomycin (BLM)-induced pulmonary fibrosis in C57 and its possible mechanisms. In vitro experiments demonstrated that OM85 exhibited no significant toxicity to HELF cells. OM-85 inhibited the TGF-β1-induced protein expression of Notch1 and Hes1 and reduced the fibrosis-related marker profiles, such as collagen I, collagen III, fibronectin, P21, and α-SMA, following TGF-β1 treatment of these cells. Immunofluorescence also revealed that OM-85 decreased the expression of α-SMA induced by TGF-β1 in HELF cells. In the vivo experiments, a pulmonary fibrosis model was established by administering three intratracheal doses of BLM (1 mg/kg). The BLM-OM85 group was exposed to an aerosol containing 10.5 mg of OM-85 dissolved in 10 mL of sterile PBS on days 42, 44, 46, 49, 51, and 53. BLM-induced pulmonary fibrosis, leading to increased levels of lung hydroxyproline, total cell count, macrophages, neutrophils, lymphocytes, and the expression of TGF-β1 as well as Notch1 and Hes1 in lung tissue, along with fibrosis-associated proteins such as collagen I, collagen III, fibronectin, P21, and α-SMA. Additionally, the Th1 response was suppressed, as evidenced by decreased IFN-γ in the bronchoalveolar lavage fluid (BALF), while the Th2 response was amplified, marked by increased IL-4 levels in BALF. Moreover, morphological assessments showed that BLM caused increased Ashcroft scores, relative collagen content, and an expanded damaged area, as well as an increased optical density (OD) of collagen I. The administration of OM-85 significantly mitigated these effects. These findings suggest that OM-85 holds therapeutic potential for BLM-induced pulmonary fibrosis in female C57 mice, partly due to the inhibition of Notch1 and Hes1 expression and the modulation of the IFN-γ/IL-4 ratio.

Purpose: To investigate the molecular epidemiology and risk factors of carbapenem-resistant Klebsiella pneumoniae (CRKP) infection. Patients and Methods: Patient’s clinical data and CRKP strains were collected from November 2017 to December 2018 at a tertiary hospital in Wuhan, China. The antimicrobial susceptibilities, carbapenem-resistant genes, multi-locus sequence typing (MLST), homologous analysis, and risk factors for CRKP were determined. Results: A total of 203 CRKP strains were isolated, and 98.5% (200/203) of patients were nosocomially infected. The mortality rate was 17.7% (36/203). All 203 strains were confirmed as carbapenemases -producing strains. The most predominant carbapenemase gene was bla_IMP-4 (81.3%, 165/203), followed by bla_KPC-2 (25.1%, 51/203) and bla_NDM-1 (23.2%, 47/205). Of the 203 strains, 28 (13.8%) had both bla_KPC-2 and bla_IMP-4 genes, 23 (11.3%) had both bla_IMP-4 and bla_NDM-1 genes, 20 (9.9%) had bla_KPC-2, bla_IMP-4 and bla_NDM-1 three genes. MLST analysis showed that there were 48 ST typologies (including 7 new STs), of which ST-11 was the most prevalent (59.6%, 121/203). Phylogenetic analysis showed that 203 CRKP isolates came from 7 clusters and exhibited a strong correlation with the isolation source. eBURST analyses indicated that CRKP isolates have undergone different evolutionary processes. Patients with ST-11 CRKP underwent more mechanical ventilation (50% vs 32.9%, P=0.020) and gastric catheterization (15.7% vs 6.1%, P=0.042) within 3 months before sample collection, and also had higher drug-resistance rate than non-ST-11 CRKP. Comparing with CSKP (carbapenem-sensitive Klebsiella pneumoniae), gastrointestinal disease (odds ratio [OR]=6.168, P=0.003), nosocomial infection (OR=5.573, P=0.012), antibiotic exposure (OR=4.131, P=0.004), urinary catheterization (OR=3.960, P=0.031) and venous/arterial catheterization (OR=2.738, P=0.026) within the preceding 3 months were independent risk factors for CRKP infection. Conclusion: The IMP-4 was the most predominant carbapenemase and bla_IMP-4 bearing Klebsiella pneumoniae ST-11 was spreading in the hospital. Nosocomial infections, antibiotic exposure, and urinary and venous/arterial catheterization within 3 months were the risk factors for developing CRKP infection.

Background: Sputum nitrate/nitrite, which is the main component of reactive nitrogen species, is a potential biomarker of disease severity and progression in bronchiectasis. This study aimed to determine the association between nitrate/nitrite and exacerbations and airway microbiota in bronchiectasis.Methods: We measured total nitrate/nitrite concentration in sputum samples collected from 85 patients with stable bronchiectasis, performed 16S ribosomal RNA sequencing of sputum samples and predicted the denitrification ability of airway microbiota using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Relationships between sputum total nitrate/nitrite and disease severity, exacerbations and airway microbiota were examined.Results: Higher total sputum nitrate/nitrite was associated with more severe bronchiectasis defined by E-FACED (exacerbation, forced expiratory volume in 1 s, age, chronic colonisation byPseudomonas aeruginosa, radiological extension and dyspnoea) (p=0.003) or Bronchiectasis Severity Index (p=0.006) and more exacerbations in the prior 12 months (p=0.005). Moreover, total sputum nitrate/nitrite was significantly higher in patients with worse cough score (p=0.03), worse sputum purulence score (p=0.01) and worse Medical Research Council dyspnoea score (p=0.02). In addition, the total sputum nitrate/nitrite of theP. aeruginosacolonised (PA) group was higher than that of the non-P. aeruginosacolonised (NPA) group (p=0.04), and the relative abundance ofP. aeruginosawas positively correlated with total nitrate/nitrite (r=0.337, p=0.002). Denitrification module (M00529) was also significantly enriched in the PA group compared to the NPA group through PICRUSt analyses. Using receiver-operating characteristic analysis, total nitrate/nitrite was associated with exacerbations during 1-year follow-up (area under the curve 0.741, p=0.014).Conclusions: Sputum nitrate/nitrite is a biomarker of disease severity and associated withP. aeruginosacolonisation in bronchiectasis.

Background: This study aimed to identify a novel inflammatory index and construct a nomogram for predicting in‐hospital mortality due to severe fever with thrombocytopenia syndrome (SFTS).Methods: This cohort included 610 patients with SFTS hospitalized in Wuhan Union Hospital between March 2017 and November 2022. The ratio of C‐reactive protein (CRP) to the prognostic nutritional index (PNI) was calculated and used to reflect patients' inflammatory status. Propensity score matching (PSM) was utilized to balance confounding factors between the low‐ and high‐CRP/PNI groups. SFTS individuals from Jinyinhu Hospital were used as the validation cohort.Results: Patients with SFTS and high CRP/PNI were significantly correlated with a higher percentage of severe and critical SFTS types and higher in‐hospital mortality rates than those with low CRP/PNI. CRP/PNI was the potent risk indicator for in‐hospital mortality in individuals with SFTS. The CRP/PNI nomogram showed a good predictive value for in‐hospital mortality in patients with SFTS. After PSM, the predictive performance of CRP/PNI for 28‐day mortality was excellent. Finally, the CRP/PNI could still assess patients with SFTS at different risks based on SFTS data from another medical center.Conclusion: The CPR/PNI ratio exhibited a strong positive correlation with the SFTS disease type and could predict in‐hospital mortality in the early stages of SFTS. The CPR/PNI ratio could substantially help clinicians facilitate the early identification of patients with high‐risk SFTS and the timely initiation of intensive therapy.

Th1/Th2 balances may play a vital role in the processes of inflammation and fibrosis. OM-85 BV encouraged preferential development of the Th1-type immunity characterized by amplified IFN-γ and decreased IL-4 production. The objective of this study was to evaluate the inhibitory effect of OM85 on bleomycin (BLM)-induced pulmonary fibrosis in C57 and its possible mechanisms. In vitro experiments, OM85 inhibited protein expression of Notch1 and Hes1 induced by TGF-β1 and influence proliferation of fibroblast cell. OM85 also reduced the α-SMA expression induced by TGF-β1 in fibroblast. In vivo experiments, pulmonary fibrosis model was established by three-dose intratracheal instillation of BLM (1mg/kg). While control C57 received saline, C57 of the treated group simultaneously were then exposed to an aerosol containing 10.5 mg of OM85 dissolved in 10 mL of sterile PBS solution at day42,44,46,49,51,53. BLM induced pulmonary fibrosis, increased lung hydroxyproline levels, total cell counts, macrophages, neutrophils and Lymphocytes counts and expression of Notch1 and Hes1 in lung tissue. In addition, Th1 response is suppressed as shown by diminished IFN-γ in bronchoalveolar lavage fluid (BALF), and enhancement of Th2 response is marked by increased IL-4 in BALF. OM85 administration significantly attenuated these effects. The findings reveal the therapeutic potential of OM85 for BLM-induced pulmonary fibrosis in female C57, which were at least partly due to inhibition notch1 and Hes1 expression and regulation of Th1/Th2 balance.

Objective: Continuous positive airway pressure (CPAP) is the primary modality for treating sleep apnea after acute ischemic stroke (AIS). However, not all patients are well adherent to CPAP. Finding an alternative modality of ventilation to CPAP is essential.Methods: This prospective randomized clinical trial was conducted from 1 May 2022 to 8 January 2023 at the Department of Neurology, Wuhan Union Hospital. Participants diagnosed with sleep apnea after AIS were grouped according to block randomization principles into the usual care group (nasal cannula and facemask), nasal continuous positive airway pressure (nCPAP) group, and high‐flow nasal cannula (HFNC) group. Rates of pulmonary infection and endotracheal intubation within 1 week of hospitalization and 28‐day mortality (poststroke) were the primary outcomes (early prognosis).Results: In the trial, 178 patients (119 males [66.85%]; mean [SD] age, 61.04 [11.78] years) were eventually enrolled in the usual care group (n = 63), the nCPAP group (n = 55), and the HFNC group (n = 60). After ventilation, the nCPAP and HFNC groups were more effective than the usual care group in reducing the rate of pulmonary infection, endotracheal intubation, and improving neurological function and sleep apnea severity. However, there was no difference in 28‐day mortality. Additionally, the improvement in prognosis was consistent between nCPAP and HFNC. In the comparison of comfort, the HFNC group was superior to nCPAP.Interpretation: nCPAP and HFNC reduced early pulmonary infection rates and endotracheal intubation rates. For patients with poor compliance with nCPAP, HFNC may be the best alternative.