Airway-invasion-associated pulmonary computed tomography presentations characteristic of invasive pulmonary Aspergillosis in non-immunocompromised adults: a National Multicenter Retrospective Survey in China.

BACKGROUND: The European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria are widely used in the diagnosis of invasive pulmonary aspergillosis (IPA), but they only apply to immunocompromised patients. We here aimed to identify clinical characteristics helpful to the diagnosis of IPA in non-immunocompromised patients. METHODS: This is a multicenter retrospective study. Data were collected from adult patients with IPA admitted to 15 tertiary hospitals in China from 2010 to 2016. RESULTS: We included 254 patients in the study, of whom 66 (26.0%) were immunocompromised, and 188 (74.0%) were not. Airway-invasion-associated computed tomography (CT) signs including patchy exudation along the airway (67.6% vs. 45.5%, P = 0.001) and thickened airway wall (42.0% vs. 16.7%, P < 0.001) were more common in non-immunocompromised patients than in immunocompromised ones, and angio-invasive CT signs were more common in immunocompromised patients (55.3% vs.72.7%, P = 0.013). Typical angio-invasive CT signs were delayed in non-immunocompromised IPA patients, whereas airway-invasive signs appear earlier. Host immunocompromised condition was associated with ICU admission and/or intubation (OR 1.095; 95% CI 1.461-6.122; P = 0.003). Poor prognosis (35.5% vs. 21.1%, P = 0.005) was more common in immunocompromised patients. CONCLUSION: Airway-invasion-associated CT presentations at early stages of the disease are characteristic of IPA in non-immunocompromised hosts.

PPARγ agonists regulate tobacco smoke-induced Toll like receptor 4 expression in alveolar macrophages.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor that exerts multiple biological effects. Growing evidence suggests that PPARγ plays an important role in inflammation; however, the effects of this transcription factor on the inflammation caused by smoking are unclear. METHODS: We measured the expression of inflammatory cytokines (leukotriene B4, LTB4 and interleukin 8, IL-8), PPARγ and toll-like receptors (TLR2 and TLR4) in alveolar macrophages (AMs) harvested from rats exposed to cigarette smoke (CS) for 3 months in vivo. Some of the rats were pre-treated with rosiglitazone (PPARγ agonist, 3 mg/kg/day, ip), rosiglitazone (3 mg/kg/day, ip) + BADGE (bisphenol A diglycidyl ether, a PPARγ antagonist, 30 mg/kg/day, ig), or BADGE alone (30 mg/kg/day, ig). We also measured the expression of PPARγ, TLR2, TLR4 and nuclear factor-kappaB (NF-κB) in AMs gained from normal rats, which exposed to 5% CSE (cigarette smoke extract) for 12 hrs, respectively pretreated with PBS, rosiglitazone (30 uM), rosiglitazone (30 uM) + BADGE (100 uM), 15 d-PGJ2 (PPARγ agonist, 5 uM), 15 d-PGJ2 (5 uM) + BADGE (100 uM), or BADGE (100 uM) alone for 30 min in vitro. RESULTS: In vivo, rosiglitazone counteracted CS-induced LTB4 and IL-8 release and PPARγ downregulation, markedly lowering the expression of TLR4 and TLR2. In vitro, both rosiglitazone and 15 d-PGJ2 inhibited CS-induced inflammation through the TLR4 signaling pathway. CONCLUSIONS: These results suggest that PPARγ agonists regulate inflammation in alveolar macrophages and may play a role in inflammatory diseases such as COPD.

Regulation of cigarette smoke-induced toll-like receptor 4 expression by peroxisome proliferator-activated receptor-gamma agonists in bronchial epithelial cells.

BACKGROUND AND OBJECTIVE: This study was designed to determine the effects of peroxisome proliferator-activated receptor-gamma (PPARγ) on airway inflammatory response to cigarette smoke (CS) exposure. METHODS: For the in vivo experiments, 50 male Wistar rats were randomly assigned to one of four groups and were exposed to CS and pretreatment with a PPARγ agonist, rosiglitazone or a vehicle (saline). PPARγ antagonist bisphenol A diglycidyl ether (BADGE) or saline was administered before rosiglitazone treatment. Leukotriene B4 (LTB4) and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay. PPARγ and toll-like receptor 4 (TLR4) expression levels were assessed by immunohistochemistry and real-time polymerase chain reaction. For the in vitro experiments, human bronchial epithelial cells were stimulated with CS or phosphate buffer saline, pretreated with PPARγ agonist rosiglitazone or 15-deoxy-(Δ12,14)-PG J2 before CS exposure. BADGE was administered prior to the agonist treatment. PPARγ, TLR4 and inhibitor of κB (IκBα) expression levels were assessed by Western bot. RESULTS: CS exposure decreased PPARγ expression, as well as increased IL-8, LTB4 and TLR4 expression levels in bronchial epithelial cells in vivo and in vitro. Moreover, PPARγ ligands counteracted CS-induced airway inflammation by reducing IL-8 and LTB4 expression levels that are associated with TLR4 and nuclear factor-kappa B (NF-κB). CONCLUSION: CS exposure increased the pro-inflammatory activity of bronchial epithelial cells by affecting PPARγ expression. Moreover, PPARγ may play a significant role as a modulator of the TLR4-dependent inflammatory pathway through NF-κB in bronchial epithelial cells.

[Adult hospital acquired pneumonia: a multicenter study on microbiology and clinical characteristics of patients from 9 Chinese cities].

OBJECTIVE: To investigate the etiology and clinical characteristics of hospital-acquired pneumonia (HAP) in China and to provide evidence for appropriate therapy. METHODS: We performed a prospective multicenter study in 13 Chinese urban tertiary hospitals. All HAP cases diagnosed at respiratory general ward and respiratory intensive care unit (RICU) from August 2008 to December 2010 were studied. Epidemiological data, etiology and clinical characteristics of enrolled patients were collected. Sputum or tracheal aspirate and blood cultures, Legionella antibodies and Streptococcus pneumoniae urinary antigen tests were performed. Bacteria to antimicrobial susceptibility test was performed. RESULTS: A total of 610 cases of HAP were diagnosed during the study, with an overall incidence of 1.4% among 42 877 hospitalized patients, while the incidence was 0.9% (362/41 261) in respiratory general ward and 15.4% (248/1616) in RICU. 93.9% (573 cases) of patients had at least one underlying disease, and 91.0% (555 cases) had exposure to at least one antimicrobial agent within 90 days prior to HAP diagnosis. Pathogens were identified in 487 patients, with Acinetobacter baumannii [30.0% (183/610)], Pseudomonas aeruginosa [22.0% (134/610)], Staphylococcus aureus [13.4% (82/610)] and Klebsiella pneumonia [9.7% (59/610)] being the most common pathogens. Eighteen patients (3.0%) had infection with fastidious bacteria. A. baumannii and S. aureus were the more frequent pathogens in the ventilator-associated pneumonia (VAP) cases [50.5% (97/192) and 21.4% (41/192)] as compared to non-VAP cases [20.6% (86/418) and 9.8% (41/418), P < 0.01]. A. baumannii and S. aureus were also frequent pathogens in cases with a score of more than 20 by the acute physiology and chronic health evaluation II (APACHEII) scoring [45.7% (69/151) and 20.5% (31/151)], as compared to cases with a score of less than 20 of APACHE II [24.8% (114/459) and 11.1% (51/459), P < 0.01]. A. baumannii showed high resistance rates to carbapenems [more than 70% (109/142)], and the susceptibility to cefoperazone/sulbactam, polymyxin B and tigecycline were 40.8% (58/142), 99.3% (141/142) and 95.8% (136/142) respectively. Resistance rates of P. aeruginosa to meropenem and imipenem were 48.8% (40/82) and 70.7% (58/82) respectively. Methicillin-resistant S. aureus (MRSA) accounted for 87.8% (43/49) in all strains of S. aureus. Mortality rate of VAP cases was 34.5% (61/177), significantly more than that of HAP patients [22.3% (135/605), P < 0.05]. The average hospital stay of patients with HAP was (23.8 ± 20.5) days, significantly more than that of the average for inpatients [(13.2 ± 13.6) days, P < 0.01] during the study period. Mean costs of HAP were (108 950 ± 116 608) yuan, significantly higher than the average hospital costs of respiratory inpatients (17 999 ± 33 364) yuan. CONCLUSIONS: Among Chinese patients hospitalized in urban tertiary medical centers, HAP incidence and mortality rate were high, which increased the patients' hospital stay and the medical costs. Common pathogens were A. baumannii, P. aeruginosa, S. aureus and K. pneumonia. The common bacteria of HAP in China showed high resistance rates to antibiotics.

The Efficacy and Safety of Xinjia Xuanbai Chengqi Granules in Acute Exacerbation of COPD: A Multicentre, Randomised, Double-Blind, Controlled Trial.

Purpose: The study aimed to explore the efficacy and safety of Xinjia Xuanbai Chengqi granules (XJXBCQ) combined with conventional medicine in the treatment of acute exacerbation of chronic pulmonary disease (AECOPD). Patients and Methods. This multicentre, double-blind, parallel, placebo-controlled, randomised clinical trial conducted in China from January 2019 to February 2021 recruited 330 participants who were allocated into three groups. All participants underwent conventional basic treatment with oxygen therapy, antibiotics, and a bronchodilator. Besides, group A received XJXBCQ granules and budesonide suspension for inhalation; group B received XJXBCQ granules and half dosage of budesonide suspension; and group C received budesonide suspension and a placebo. All therapies lasted for 5 days, and participants were followed up for 30 days after discharge. The primary outcomes were efficacy, traditional Chinese medicine (TCM) syndrome score, and clinical symptom score. Secondary outcomes included the blood gas analysis, serum inflammatory markers, adverse events, mortality, theoretical discharge time, actual hospitalisation time, proportion of patients requiring invasive mechanical ventilation, proportion of patients transferred to an intensive care unit (ICU), and readmission rate within 30 days after discharge. Results: XJXBCQ adjunct with conventional treatment could significantly improve the total efficacy (P < 0.05). Meanwhile, group A showed significantly better results than group C in the TCM syndrome score, phlegm score, and Wexner constipation score (P < 0.05). For modified British medical research council (mMRC), on day 3 (-0.17, 95% confidence interval [CI]: -0.33--0.01) and day 4 (-0.20, 95% CI: -0.39--0.02), group A performed statistically better than group C. No significant differences in other secondary outcomes were detected. Conclusion: XJXBCQ is beneficial and safe for AECOPD treatment and could be considered an adjunctive therapy for promoting the relief of clinical symptoms. This trial is registered with ChiCTR1800016915.

[A multicentre retrospective study of pulmonary mycosis clinically proven from 1998 to 2007].

OBJECTIVE: To investigate the pathogens, clinical manifestations, prognosis of and the risk factors for pulmonary mycosis in China. METHODS: All cases of pulmonary mycosis from 16 centers in 10 cities from Jan. 1998 to Dec. 2007 that met the diagnostic criteria were included for clinical, microbiological and radiological analysis. RESULTS: Totally 474 cases of pulmonary mycosis were retrieved. The top 5 pulmonary mycosis was pulmonary aspergillosis (180 cases, 37.9%), pulmonary candidiasis (162 cases, 34.2%), pulmonary cryptococcosis (74 cases, 15.6%), pneumocystis carinii pneumonia (23 cases, 4.8%) and pulmonary mucormycosis (10 cases, 2.1%). The constituent ratio in the last 3 years was similar to that in the former 7 years. The main pathogens of pulmonary candidiasis were Candida albicans (308/474, 65.0%) and Candida tropicalis (57/474, 12.0%), which were sensitive to common azoles. Compared with bacterial pneumonia, pulmonary mycosis showed more symptoms of hemoptysis (147/474, 31.0%) and pleural effusion (95/474, 20.0%), and less radiological specificity. Classical halo sign (4/474, 0.8%) and crescentic sign (17/474, 3.6%) were only shown in several cases of pulmonary mycosis. The most common underlying diseases were tumor (including solid tumor and malignant hematological diseases) (94/474, 19.8%), chronic obstructive pulmonary disease (52/474, 11.0%), pulmonary tuberculosis (50/474, 10.5%) and diabetes (48/474, 10.1%). Compared with the other common pulmonary mycosis, pulmonary cryptococcosis affected younger patients, and more cases were community-acquired, but fewer cases with underlining diseases or compromised immune function, and had a better prognosis. CONCLUSION: The ahead five species of pulmonary mycosis in China were orderly pulmonary aspergillosis, pulmonary candidosis, pulmonary cryptococcosis, pneumocystis carinii pneumonia and pulmonary mucormycosis. The main pathogens of pulmonary candidosis were Candida albicans and Candida tropicalis, which were sensitive to common azoles. Compared with the other common pulmonary mycosis, pulmonary cryptococcosis catch younger patients, had more community-acquired cases, and had better prognosis.

Correction: Cycling hypoxia affects cell invasion and proliferation through direct regulation of claudin1 / claudin7 expression, and indirect regulation of p18 through claudin7.

[This corrects the article DOI: 10.18632/oncotarget.14397.].

Effectiveness of Xin Jia Xuan Bai Cheng Qi Decoction in treating acute exacerbation of chronic obstructive pulmonary disease: study protocol for a multicentre, randomised, controlled trial.

INTRODUCTION: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) brings a serious impact on patients' quality of life, and has extremely high morbidity and mortality worldwide. Although there are many therapies being developed to alleviate symptoms and reduce mortality, a few studies have supported which treatment method is the best. Traditional Chinese medicine (TCM) has shown good potential in the prevention and treatment of AECOPD, especially in terms of supplementation and reduction of dosage and adverse effect of Western medicine. The purpose of this study is to compare the effectiveness of combination of TCM and Western medicine with conventional therapy alone for AECOPD, and to ensure whether the combined therapy may reduce the use of systemic glucocorticoid in AECOPD without influencing efficacy. METHODS AND ANALYSIS: A multicentre, randomised, double-blind, placebo-controlled study was conducted to enrol a total of 360 eligible patients who will be randomised into integrated Chinese and Western medicine group A, B and Western standard Medicine group C. After 5 days of intervention and 1 month of follow-up, the efficacy and safety of Xin Jia Xuan Bai Cheng Qi Decoction in patients with AECOPD will be observed. The results of evaluation indicators include: clinical symptoms, biochemical indicators such as blood gas analysis, inflammatory markers, hospitalisation time, TCM syndrome evaluation, biological indicators such as airway, intestinal flora sequencing. ETHICS AND DISSEMINATION: This trail has been approved by the Ethics Committee of China-Japan Friendship Hospital. The results will be disseminated in international peer-reviewed journals and be presented in academic conferences. The results will also be disseminated to patients by telephone, inquiring on patient's poststudy health status during the follow-up. TRIAL REGISTRATION NUMBER: ChiCTR1800016915.

Altered pulmonary capillary permeability in immunosuppressed guinea pigs infected with Legionella pneumophila serogroup 1.

In immunosuppressed hosts, Legionella pneumophila (Lp) infection usually develops into severe pneumonia, which is pathologically characterized by increased vascular permeability and pulmonary edema. At present, mechanisms associated with changes in pulmonary capillary permeability (PCP) and the pathogenesis of pulmonary edema in immunosuppressed hosts with Lp infection are unclear. Therefore, in the present study an animal model of normal and immunosuppressed guinea pigs infected with Lp was established. An isolated perfused lung system was used to investigate the extent of changes in PCP. Pathological and immunofluorescence examinations were performed to explore the mechanism underlying these changes. The results indicated that PCP increased with the highest magnitude in immunosuppressed guinea pigs infected with Lp, with repeated ANOVA indicating synergism between infection and immunosuppression (P=0.0444). Hematoxylin and eosin staining and electron microscopy revealed more severe morphological damages in the lung tissues and pulmonary capillaries of the immunosuppressed animals infected with Lp compared with normal animals infected with Lp. Immunofluorescence analysis showed that immunosuppression reduced the expression of the vascular endothelial cell junction protein VE-cadherin (P=0.027). Following Lp infection, VE-cadherin expression was significantly lower in the immunosuppressed guinea pigs compared with their immunocompetent counterparts (P=0.001). These results suggest that immunosuppression combined with Lp infection induces more significant damage to pulmonary capillaries compared with Lp infection alone, resulting in a significantly increased PCP.

Accumulation of aquaporin-1 during hemolysin-induced necrotic cell death.

Altered tissue water homeostasis may contribute to edema formation during various stresses including bacterial infection. We observed induction of aquaporin-1 (AQP1) during Staphylococcus aureus infection of cultured cells indicating a potential mechanism underlying altered water homeostasis during infection. To investigate mechanisms of AQP1 induction, we examined the effects of the S. aureus alpha-hemolysin on AQP1 abundance in Balb/c fibroblasts. Fibroblasts incubated with 30 microg/ml hemolysin exhibited a 5-10 fold increase in AQP1 protein within 4-6 hours of exposure. The use of multiple signaling cascade inhibitors failed to affect hemolysin-mediated accumulation of AQP1. However, immunoprecipitation revealed an initial accumulation of ubiquitinated AQP1 followed by a decrease to baseline levels after 4 hours. Immunofluorescence indicated that following hemolysin exposure, AQP1 was no longer on the plasma membrane, but was found in a population of submembrane vacuoles. AQP1 redistribution was further indicated by surface biotinylation experiments suggesting diminished AQP1 abundance on the plasma membrane as well as redistribution out of lipid raft fractions. Live cell confocal microscopy revealed that the pattern of cell volume change observed following hemolysin exposure was altered in cells in which AQP1 was silenced. We conclude that alpha-toxin alters proteasomal processing and leads to intracellular accumulation of AQP1, which may likely contribute to disrupted cell volume homeostasis in infection.

Curcumin attenuates chronic intermittent hypoxia-induced brain injuries by inhibiting AQP4 and p38 MAPK pathway.

Chronic intermittent hypoxia (CIH) is one of the main features of obstructive sleep apnea (OSA), which is also commonly associated with neurocognitive impairments. The present study aimed to elucidate the beneficial effect of curcumin on CIH-induced brain injuries. Male balb/c mice (6 ∼ 8 weeks) were exposed to normoxia or a pattern of CIH (8 h/day, cycles of 180 s each, hypoxia: 5% O2 for 50 s, reoxygenation: 21% O2 for 50 s) for 10 weeks, along with daily curcumin treatment (50, 100, or 200 mg/kg, intragastrically) or its vehicle. The results showed that CIH induced significant brain edema, as well as neuronal apoptosis and astrogliosis in the cerebral cortex, brainstem, and cerebellum regions of brain. In addition, increased astrocytic AQP4 expression and activation of p38 MAPK pathway were observed after CIH exposure. Curcumin dose-dependently mitigated the brain edema and relevant cell alterations, showing a neuroprotective effect in CIH-induced brain injury. Together, these results suggest curcumin ameliorates the CIH-induced brain injuries, including brain edema, neuronal death and astrogliosis. The beneficial role of curcumin is mediated partially by regulating AQP4 and p38 MAPK pathway.

Cycling hypoxia affects cell invasion and proliferation through direct regulation of claudin1 / claudin7 expression, and indirect regulation of P18 through claudin7.

Claudins (CLDNs), the major integral membrane proteins at tight junction, play critical roles in apical cell-to-cell adhesion, maintenance of epithelial polarity, and formation of impermeable barriers between epithelial cells.We investigated in this study the expression of CLDNs- Claudin1 (CLDN1) and Claudin7 (CLDN7), and their relation to tumor progression in nasopharyngeal cancer (NPC). CLDN7, rather than CLDN1, showed higher expression in both undifferentiated tumor tissue and the poorly differentiated CNE2 cells, compared with differentiated tissue and the highly differentiated CNE1 cells. Furthermore, knockdown of CLDN7 dramatically inhibited the metastasis and invasion of CNE2 cells suggesting that CLDN7 could act as a biomarker for NPC metastasis.Cycling hypoxia could induce significant changes in CLDN1 and CLDN7 expression in NPC cells. Genetics analysis demonstrated that CLDN1/CLDN7 were not only regulated directly by HIF1a but also affected each other through a feedback mechanism. CLDN7 acted as a bridge to promote HIF1a-induced P18 expression and cell differentiation. Taken together, our results provide evidence that adjusting the oxygenation time and cycles in NPC might be an effective method to prevent / delay the metastasis of poorly differentiated NPC cells.

[Avian influenza (H5N1) cured successfully in human: a case report].

OBJECTIVE: To improve understanding of avian influenza in humans by presenting a case of avian influenza (H(5)N(1)). METHODS: Clinical and laboratory data of this case of avian influenza (H(5)N(1)) in humans were described, and related literature was reviewed. RESULTS: The female patient was 31 years old. She lived in epidemic district of avian influenza and had a history of close contact with sick poultry. The patient initially presented fever and chills accompanied by myalgia, and then followed by cough, blood-tinged sputum, dyspnea and frequent diarrhea. Laboratory findings indicated leukopenia, dysfunction of cellular immunity, abnormal enzymes of liver, and hypoxia. Patchy infiltration involved two lungs progressed rapidly on chest radiograph. ECG showed that T waves of V(1 - 5) were reverted. The patient was diagnosed with avian influenza (H(5)N(1)) by hemagglutination inhibition and microneutralization assay combined with epidemiological and clinical data. Supportive therapy, corticosteroids, antibacterial, and antiviral agents were administered. Complications were treated accordingly during the course. She got better overtime and recovered. The laboratory abnormalities and chest radiograph returned to normal before discharge. The patient's relatives and doctors involved in the medical care were free from infection. CONCLUSIONS: Supportive treatment is important for patients with avian influenza. Complications should be prevented and treated in time.

Decreased expression of AQP1 and AQP5 in acute injured lungs in rats.

OBJECTIVE: To determine if aquaporin1 (AQP1) and aquaporin5 (AQP5) are expressed in the alveolar capillary membrane in rats. Moreover, to investigate the alteration of AQP1 and AQP5 in acute injured lungs. METHODS: The distribution of AQP1 and AQP5 in alveolar capillary membrane were investigated by immunohistochemistry and immunoelectron microscopy with affinity-purified antibodies to human AQP1 and AQP5. To study the possibility that alveolar capillary membrane AQP1 and AQP5 undergo altered regulation, we established a rat model using alveolar instillation of lipopolysaccharide (LPS). RESULTS: Immunolabelling showed AQP1 was stained primarily in the microvascular endotheli a of normal lungs, while AQP5 was expressed in type I pneumocytes. Immunohisto chemical analysis showed a significant decrease in the expression of AQP1 and AQP5 in injured lungs at 4h-48h after LPS instillation. AQP1 protein was resumed partly at 24h after LPS instillation and steroid administration, whereas AQP5 was unchanged. CONCLUSION: The decreased expressions of AQP1 and AQP5 in injured lungs suggest that both of them may play a role in abnormal fluid transportation.

[Iodoacetamide-induced aquaporin 1 expression in fibroblasts is energy-dependent].

OBJECTIVE: To investigate the impact of energy metabolism at the cellular level on the expression of the water channel protein aquaporin 1 (AQP1). METHODS: Balb/c mouse fibroblasts were incubated with iodoacetamide (IA) in vitro, and the changes in AQP1 expression were detected by immunoblotting and immunohistochemistry at 0, 4, and 6 h. RESULTS: IA induced the expression of AQP1 at 4 and 6 h accompanied with cell death. Reverse transcription PCR showed an increased expression of AQP1 mRNA in the cells. AQP1 expression was also upregulated by the inhibitor of microtubule and cytochrome C oxidase. CONCLUSION: A pretranslational regulation occurs in IA-induced AQP1 expression in mouse fibroblasts, and the up-regulated AQP1 accumulation is characterized by mitochondria-related energy dependence.