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.

Left ventricular remodeling in patients with acute type B aortic dissection after thoracic endovascular aortic repair: Short- and mid-term outcomes.

BACKGROUND: Left ventricular (LV) remodeling remains unknown in patients with acute Type B aortic dissection (aTBAD) after thoracic endovascular aortic repair (TEVAR) during follow-up. METHODS: Between May 2004 and January 2016, 163 consecutive patients (136 males, mean preoperative age: 51.06 ±â€¯10.79 years) with aTBAD underwent TEVAR. A linear mixed model was used to evaluate risk factor influencing on LV remodeling and investigate longitudinal changes in LV thickness, diameter, volume, function and mass at preoperation, postoperation, short- and mid-term follow-up. RESULTS: Median follow-up time was 48.0 months (quartiles 1-3, 31-84 months, maximum 147 months). LV thickness and mass followed a continuous downward trend over time. Interventricular septal thickness at end-diastole significantly decreased at mid-term follow-up (time, p < 0.001: preoperative 11.59 ±â€¯0.14 mm vs mid-term 10.82 ±â€¯0.15 mm, p < 0.001; postoperative 11.40 ±â€¯0.14 mm vs mid-term 10.82 ±â€¯0.15 mm, p = 0.006). LV posterior wall thickness at end-diastole was markedly reduced at mid-term follow-up (time, p < 0.001: preoperative 10.89 ±â€¯0.11 mm vs mid-term 10.02 ±â€¯0.11 mm, p < 0.001; postoperative 10.78 ±â€¯0.13 mm vs mid-term 10.02 ±â€¯0.11 mm, p < 0.001; short-term 10.56 ±â€¯0.15 mm vs mid-term 10.02 ±â€¯0.11 mm, p = 0.021). LV mass index markedly decreased during follow-up (time, p = 0.001: preoperative 129.60 ±â€¯3.55 g/m2 vs short-term 119.26 ±â€¯3.19 g/m2, p = 0.009; preoperative 129.60 ±â€¯3.55 g/m2 vs mid-term 115.79 ±â€¯3.62 g/m2, p = 0.003). LV function was improved, but not significantly so, during follow-up. Strict blood pressure control had no influence on LV remodeling. True lumen followed a continuous enlargement trend in terms of proximal thoracic aorta and celiac trunk level during follow-up. CONCLUSIONS: TEVAR can reverse LV remodeling and LV hypertrophy in patients with aTBAD during follow-up.

Azithromycin treats diffuse panbronchiolitis by targeting T cells via inhibition of mTOR pathway.

Azithromycin (AZM), that is a macrolide antibiotic, has been found to treat diffuse panbronchiolitis (DPB) effectively. However, the mechanism of action underlying the therapeutic effects remains unclear. We selected 64 patients with DPB from 305 patients who were diagnosed with DPB at the outpatient clinic in Shanghai Pulmonary Hospital from Jan 2010 to Oct 2014. The primary PBLs, CD4 + T cells, and Jurkat T cells were treated with AZM or erythromycin (EM), and the effects of AZM and EM on IL-17A and CXCL-2 production, proliferation, apoptosis and autophagy were evaluated. AZM and EM significantly inhibited IL-17A and CXCL-2 production in patients' PBLs (all P < 0.05). AZM significantly inhibited proliferation and promoted apoptosis of T cells from DPB patients. AZM can enhance autophagosome formation of T cells by suppressing S6RP phosphorylation, which is a downstream target of mTOR pathway (all P < 0.05). AZM and EM significantly decreased secreted IL-17A levels (P < 0.05) in the primary CD4 + T cells of patients with DPB. AZM may treat DPB patients by targeting cytokine production, proliferation, apoptosis and autophagy of T cell. The mechanism of therapeutic effects of AZM on DPB may be associated with a specific inhibition of mTOR pathway in the T lymphocytes.

Single Stage Hybrid Repair for DeBakey Type I Aortic Dissection in High Risk Patients.

OBJECTIVES: To evaluate the efficacy of the less invasive hybrid zone 0 (Z0) total aortic arch repair (HAR, ascending repair + complete debranching + thoracic endovascular aortic repair [TEVAR]) without deep hypothermic circulatory arrest in management of DeBakey type I aortic dissection (IAD). The adverse outcome was defined as a single composite endpoint comprising peri-operative mortality, permanent neurological deficit, and renal failure necessitating haemodialysis at discharge. METHODS: A retrospective review of prospectively collected data was conducted of 120 consecutive patients (mean EuroSCORE = 11.6%) with IAD undergoing HAR (urgent/emergency, n = 97, 80.8%) involving reconstruction of the ascending aorta (zone 0) and total arch exclusion with TEVAR during a 7.5 year period. Multivariable analysis of 27 potential pre-operative and intra-operative risk factors was performed to examine the early composite endpoint and short and long-term overall mortality. RESULTS: The total early (30 day or in hospital) mortality was 9.2% (n = 11). The incidence of the composite endpoint was 11.7% (n = 14). On multivariable analysis, malperfusion syndromes were predictors of the composite endpoint (odds ratio [OR], 4.789; 95% CI 1.362-16.896; p = .015), and previous cerebrovascular accident (OR, 13.74; 95% CI 2.330-81.039; p = .004) and myocardial ischaemia time (OR, 1.038; 95% CI 1.015-1.061; p = .001) predicted short and long-term overall mortality. The overall survival was 84.7% during a median follow up of 3.4 years. Freedom from late aortic adverse events was 93.1% at 5 years, including secondary aortic intervention and endoleak. The maximum diameters of the true lumen increased significantly in stented thoracic (14.4 ± 6.5 mm to 29.7 ± 5.3 mm, p < .001), lower thoracic (14.2 ± 6 mm to 21.6 ± 7.2 mm, p < .001) and abdominal (11.7 ± 4.8 mm to 17.4 ± 4.1 mm, p < .001) aorta. Complete thrombosis of the peri-stent false lumen was achieved in 88.2% of CT scans (82/93) performed a mean of 12 ± 17 months (median 5 months; 25-75% quartile, 2-12 months) post-operatively. CONCLUSIONS: IAD was treated safely and durably by Z0 HAR, and peri-operative mortality and morbidity were not substantially higher despite the older age and high risk of patients.

Erratum: Identification of a nanobody specific to a human pulmonary surfactant protein A.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Identification of a nanobody specific to human pulmonary surfactant protein A.

Nanobody (Nb) is a promising vector for targeted drug delivery. This study aims to identify an Nb that can specifically target the lung by binding human pulmonary surfactant protein A (SP-A). Human lung frozen tissue sections were used for 3 rounds of biospanning of our previously constructed Nb library for rat SP-A to establish a sub-library of Nb, which specifically bound human lung tissues. Phage-ELISA was performed to screen the sub-library to identify Nb4, which specifically bound human SP-A. The binding affinity Kd of Nb4 to recombinant human SP-A was 7.48 × 10-7 M. Nb4 (19 kDa) was stable at 30 °C-37 °C and pH 7.0-7.6 and specifically bound the SP-A in human lung tissue homogenates, human lung A549 cells, and human lung tissues, whereas didn't react with human liver L-02 cells, kidney 293T cells, and human tissues from organs other than the lung. Nb4 accumulated in the lung of nude mice 5 minutes after a tail vein injection of Nb4 and was excreted 3 hours. Short-term exposure (one month) to Nb4 didn't cause apparent liver and kidney toxicity in rats, whereas 3-month exposure resulted in mild liver and kidney injuries. Nb4 may be a promising vector to specifically deliver drugs to the lung.

Serum Krebs von den Lungen-6 level as a diagnostic biomarker for interstitial lung disease in Chinese patients.

OBJECTIVES: The purpose of this study was to determine the diagnostic and prognostic values of serum KL-6 levels in Chinese patients with interstitial lung disease (ILDs). METHODS: A total of 1084 subjects including 373 cases of ILDs, 584 cases of non-ILD pulmonary diseases, and 127 healthy individuals were recruited from three clinical centers in China between January 2011 and December 2013. A total of 106 patients undergoing treatments for ILDs in Shanghai Pulmonary Hospital between January 2011 and December 2013 were enrolled. Baseline and posttreatment serum KL-6 levels were determined. RESULTS: Serum KL-6 levels in patients with ILDs were significantly higher than those in patients with non-ILD pulmonary diseases or in healthy individuals (1492.09 ± 2230.08 U/mL vs 258.67 ± 268.73 U/mL or 178.73 ± 71.17 U/mL, all P < 0.05). At the cut-off value of 500 U/mL, the sensitivity and specificity of serum KL-6 as a diagnostic marker for ILDs was 77.75% and 94.51%, respectively. The Kappa value was 0.743 (P < 0.001). The area below the receiver operating characteristic curve was 0.922 with a 95% Confidence interval of 0.904-0.941 (P < 0.001). The posttreatment serum KL-6 levels significantly reduced in patients with improved ILDs, whereas markedly increased in patients with exacerbated ILDs (All P < 0.05). CONCLUSIONS: Serum KL-6 levels might be a promising diagnostic biomarker for ILDs in Chinese patients. The prognostic value of serum KL-6 levels for ILDs remains to be verified by large-scaled studies.

Establishment of the mouse model of acute exacerbation of idiopathic pulmonary fibrosis.

PURPOSE: To explore and establish an animal model of AE-IPF. METHODS: An animal model of idiopathic pulmonary fibrosis (IPF) was established using bleomycin (BLM). Then, BLM was administered a second time on day 21 to induce AE-IPF (which mimics human AE-IPF). Evaluation of the success of animal model was based on the survival of mice, as well as assessment of pathological changes in lung tissue. Preliminary investigation into the immunological mechanism of AE-IPF was also explored via the detection and identification of the inflammatory cells in mouse bronchoalveolar lavage fluid (BALF) and the concentrations of six cytokines (IL-4, IL-6, IL-10, IL-17A, MIG, and TGF-ß1) in BALF supernatants, which were closely associated with IPF and AE-IPF. The intervention role of IL-17A antibody to AE was explored. RESULTS: By week 4 after the second BLM administration, the mortality in the AE-IPF group was significantly greater (45%, 9/20) than that in stable-IPF group (0/18) (P = .0017). The average body weight in AE-IPF group was significantly lower than that in stable group (P < .0001). In AE-IPF group, inflammation and fibrosis were severer by histopathology analysis. In BALF, IL-17A, MIG (CXCL-9), IL-6, and TGF-ß1 levels in AE group were significantly higher. The percentages of neutrophils and Th17 cells in BALF were significantly higher in AE group (P < .01; P = .0281). IL-17A antibody could attenuated the lung inflammation induced by twice BLM challenges. CONCLUSION: A mouse model of AE-IPF can be established using two administrations of BLM; Th17 cells may play a key role during the pathological process of AE-IPF.

Effectiveness of Secundum Atrial Septal Defect Occlusion with the Septal Occluder through Right-chest Small Incision: Clinical Analysis of 140 Cases.

Objective To evaluate the feasibility and effectiveness of secundum atrial septal defect(ASD)occlusion with the septal occluder through right-chest small incision. Methods The clinical data of 140 secundum ASD patients (47 males and 93 females) aged 3-63 years who were treated in our center from August 2004 to July 2014 were retrospectively analyzed. The diameter of ASD was 6 to 36 mm. Under general anesthesia, all patients underwent intraoperative transtsophageal echocardiography (TEE), during which no associated cardiac deformity was found. All patients received ASD occlusion via a small incision (3-4 cm) at the right anterior chest. The occluders were released with the help of TEE. Results The atrial septal defect closure was successfully completed in 134 cases. Six cases received surgical closure of ASD after the failure of occlusion. The reasons of conversion included postoperative dislodgement of occlusion device (n=2, both were central type with large size) and technically unsuitable for occlusion (n=4, in whom residual shunt was found in 2 case, sieve pore type in 1 case, and intraoperative dislodgement in 1 case). All of these 6 patients were treated surgically under cardiopulmonary bypass. No dislocation of the device or atrial shunt was found within 3 to 48 months after the operation. Conclusion Occlusion via small chest incision of ASD under TEE guidance without cardiopulmonary bypass is a safe, minimally invasive, effective, and convenient treatment and worth clinical application.

Clinical Characteristics of Connective Tissue Disease-Associated Interstitial Lung Disease in 1,044 Chinese Patients.

BACKGROUND: Because the prevalence of connective tissue disease (CTD)-associated interstitial lung disease (ILD; CTD-ILD) in China is unknown, we wanted to analyze the clinical characteristics of this disease in Chinese patients. METHODS: The medical records of patients who received a diagnosis of ILD and treated in Shanghai Pulmonary Hospital from January 1999 to January 2013 were reviewed. Based on the records, patients who also received a diagnosis of CTD were identified, and their records of follow-up examinations for a minimum of 12 months until the end of December 2013 were reviewed. RESULTS: Of the 2,678 patients who received a diagnosis of ILD, 1,798 (67%) were identified as having CTD-ILD; 299 (11.2%) had idiopathic pulmonary fibrosis (IPF). Complete clinical data were available for 1,044 patients with CTD-ILD and 178 with IPF. We found that 332 of the 1,044 patients with CTD-ILD (32%) did not receive an accurate diagnosis at the initial hospital admission, 195 (18.7%) of the 1,044 patients showed persistent negative test results for autoantibodies, and 262 (25.1%) of the 1,044 patients had negative autoantibodies at the initial hospital admission and then became positive at follow-up examinations. Of the 288 patients who had confirmed CTD-ILD, 41 (14%) showed pulmonary symptoms as the initial clinical manifestation (PSIM) and 247 (86%) showed extrapulmonary symptoms as the initial clinical manifestation (EPSIM). For the 756 patients who had undifferentiated CTD-ILD, the proportion of PSIM and EPSIM was 44% and 56%, respectively. For patients who presented with PSIM, 23 who had confirmed CTD-ILD (56%) and 216 who had unconfirmed CTD-ILD (65%) did not receive an accurate diagnosis at the initial visit but were ultimately diagnosed at subsequent follow-up examinations. CONCLUSIONS: Patients with CTD-ILD do not receive an accurate diagnosis at the initial hospital admission possibly because of negative serologic test results for autoantibodies and the absence of obvious extrapulmonary symptoms. Thus, patients with ILD should be examined for extrapulmonary symptoms and tested for autoantibodies at follow-up examinations.

N-acetylcysteine attenuates cigaret smoke-induced pulmonary exacerbation in a mouse model of emphysema.

OBJECTIVE: The purpose of this study was to investigate the effects of cigaret smoke (CS) on a mouse model of emphysema and examine the protective role of N-acetylcysteine (NAC) in the CS-induced exacerbation of pulmonary damage in the mice. METHOD: Particulate matter (PM) in sidestream cigaret smoke aerosol was analyzed by a scanning mobility particle sizer spectrometer. A mouse model of emphysema was established by an injection of porcine pancreatic elastase (PPE) into the trachea. Mice with emphysema were then exposed to filtered air, or sidestream CS with intragastric administration of NAC or normal saline. Mouse body weight, survival, pulmonary tissue histology, total antioxidant capacity (T-AOC) and malonaldehyde (MDA) contents in lung tissue, and inflammatory responses were examined. RESULTS: Particles with a size of ≤346 nm constituted 99.06% of CS PM. Mice exhibited ruptured alveolar septal, alveolar fusion, significantly increased mean lining interval, and reduced mean alveolar number (all p < 0.05), 21 d after PPE injection. Exposure of mice with emphysema to CS exacerbated the pulmonary tissue damage, caused weight loss, significantly increased mortality, decreased T-AOC, elevated MDA contents in lung tissue, and increased interleukin (IL)-1ß levels in bronchoalveolar lavage (BAL) fluids (all p < 0.05). Administration of NAC attenuated those CS-induced adverse effects in the mice and increased anti-inflammatory factor IL-10 levels in BAL fluids significantly (all p < 0.05). CONCLUSIONS: Exposure of mice with emphysema to CS exacerbated the pulmonary damage, and NAC reduced the CS-mediated pulmonary damage by preventing oxidative damage and reducing inflammatory responses.

Screening for Differentially Expressed Proteins Relevant to the Differential Diagnosis of Sarcoidosis and Tuberculosis.

BACKGROUND: In this study, we sought to identify differentially expressed proteins in the serum of patients with sarcoidosis or tuberculosis and to evaluate these proteins as markers for the differential diagnosis of sarcoidosis and sputum-negative tuberculosis. METHODS: Using protein microarrays, we identified 3 proteins exhibiting differential expression between patients with sarcoidosis and tuberculosis. Elevated expression of these proteins was verified using the enzyme-linked immunosorbent assay (ELISA) and was further confirmed by immunohistochemistry. Receiver operating characteristic (ROC) curve, logistic regression analysis, parallel, and serial tests were used to evaluate the diagnostic efficacy of the proteins. RESULTS: Intercellular Adhesion Molecule 1(ICAM-1) and leptin were screened for differentially expressed proteins relevant to sarcoidosis and tuberculosis. Using ROC curves, we found that ICAM-1 (cutoff value: 57740 pg/mL) had an area under the curve (AUC), sensitivity, and specificity of 0.718, 62.3%, and 79.5% respectively, while leptin (cutoff value: 1193.186 pg/mL) had an AUC, sensitivity, and specificity of 0.763, 88.3%, and 65.8%, respectively. Logistic regression analysis revealed that the AUC, sensitivity, and specificity of combined leptin and ICAM-1 were 0.787, 89.6%, and 65.8%, respectively, while those of combined leptin, ICAM-1, and body mass index (BMI) were 0.837, 90.9%, and 64.4%, respectively, which had the greatest diagnostic value. Parallel and serial tests indicated that the BMI-leptin parallel with the ICAM-1 serial was the best diagnostic method, achieving a sensitivity and specificity of 86.5% and 73.1%, respectively. Thus, our results identified elevated expression of ICAM-1 and leptin in serum and granulomas of sarcoidosis patients. CONCLUSIONS: ICAM-1 and leptin were found to be potential markers for the diagnosis of sarcoidosis and differential diagnosis of sarcoidosis and sputum-negative tuberculosis.

A novel nanobody specific for respiratory surfactant protein A has potential for lung targeting.

Lung-targeting drugs are thought to be potential therapies of refractory lung diseases by maximizing local drug concentrations in the lung to avoid systemic circulation. However, a major limitation in developing lung-targeted drugs is the acquirement of lung-specific ligands. Pulmonary surfactant protein A (SPA) is predominantly synthesized by type II alveolar epithelial cells, and may serve as a potential lung-targeting ligand. Here, we generated recombinant rat pulmonary SPA (rSPA) as an antigen and immunized an alpaca to produce two nanobodies (the smallest naturally occurring antibodies) specific for rSPA, designated Nb6 and Nb17. To assess these nanobodies' potential for lung targeting, we evaluated their specificity to lung tissue and toxicity in mice. Using immunohistochemistry, we demonstrated that these anti-rSPA nanobodies selectively bound to rat lungs with high affinity. Furthermore, we intravenously injected fluorescein isothiocyanate-Nb17 in nude mice and observed its preferential accumulation in the lung to other tissues, suggesting high affinity of the nanobody for the lung. Studying acute and chronic toxicity of Nb17 revealed its safety in rats without causing apparent histological alterations. Collectively, we have generated and characterized lung-specific nanobodies, which may be applicable for lung drug delivery.