Targeted Modulation of Redox and Immune Homeostasis in Acute Lung Injury Using a Thioether-Functionalized Dendrimer.

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It is characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions and immune homeostasis in the lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG is developed, to scavenge both proinflammatory cytokines and reactive oxygen species (ROS) and restore homeostasis during ALI treatment. The dendrimers are synthesized using an efficient and orthogonal thiol-ene "click" chemistry approach that involves incorporating thioether moieties within the dendritic architectures to neutralize the ROS. The ROS scavenging of Sr-G4-PEG manifests in its capacity to sequester proinflammatory cytokines. The synergistic effects of scavenging ROS and sequestering inflammatory cytokines by Sr-G4-PEG contribute to redox remodeling and immune homeostasis, along with the modulation of the NLRP3-pyroptosis pathway. Treatment with Sr-G4-PEG enhances the therapeutic efficacy of ALIs by alleviating alveolar bleeding, reducing inflammatory cell infiltration, and suppressing the release of inflammatory cytokines. These results suggest that Sr-G4-PEG is a potent nanotechnological candidate for remodeling redox and immune homeostasis in the treatment of ALIs, demonstrating the great potential of dendrimer-based nanomedicine for the treatment of respiratory pathologies.

Clinical characteristics and risk factors for late-onset pneumocystis jirovecii pneumonia in kidney transplantation recipients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a common and troublesome complication of kidney transplantation. In the era of prophylaxis, the peak incidence of PJP after kidney transplantation and specific characteristics of late-onset PJP have always been debated. METHODS: We performed a retrospective study by analysing the data of post-transplantation pneumonia in adult kidney transplantation recipients between March 2014 and December 2021 in The Affiliated First Hospital of University of Science and Technology of China (USTC). A total of 361 patients were included and divided into early-onset PJP, late-onset PJP and non-PJP groups. The characteristics of each group and related risk factors for the late-onset patients were investigated. RESULTS: Some patients developed PJP 9 months later with a second higher occurrence between month 10 and 15 after transplantation. Compared with non-PJP, ABO-incompatible and cytomegalovirus (CMV) viremia were significantly associated with late onset of PJP in multivariate analysis. The use of tacrolimus, CMV viremia, elevated CD8(+) T cell percent and hypoalbuminemia were risk factors for late PJP. Receiver operating characteristic curve analysis demonstrated that a combination of those factors could increase the sensitivity of prediction remarkably, with an area under the curve of 0.82, a sensitivity of 80% and a specificity of 83%. CONCLUSIONS: PJP could occur months after kidney transplantation. ABO-incompatible transplant recipients are at high risk of PJP. In the later stages of transplantation, CMV viremia, T lymphocyte subsets percentage and serum albumin levels should be monitored in patients using tacrolimus.

Coagulation dysfunction in patients with AECOPD and its relation to infection and hypercapnia.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have coagulation abnormalities. However, the factors that lead to coagulation dysfunction in acute exacerbation of COPD (AECOPD) remain insufficiently explored. This study aimed to investigate the factors affecting coagulation status in patients with COPD and their influence on thrombosis. METHODS: Data of COPD patients, including 135 cases in acute exacerbation stage and 44 cases in stable stage from Nov 2016 to Nov 2019 in our hospital, were collected. Healthy people (n = 135) were enrolled as the controls. The coagulation parameters, blood gas indexes and blood routine examination results were collected and analyzed. RESULTS: White blood count (WBC), neutrophil count, neutrophil percentage (N%), platelet (PLT), prothrombin time (PT), international normalized ratio (INR), fibrinogen (FIB), and activated partial thromboplastin time (APTT) increased, plasma thrombin time (TT) decreased in AECOPD group compared with the control group. In AECOPD group, PT, APTT, and FIB were positively correlated with neutrophils and C-reaction protein levels. PT was positively correlated with PCO2 and negatively with pH. Thrombosis was observed in five acute exacerbation and three stable stage COPD patients. CONCLUSIONS: Patients with AECOPD presented abnormal coagulation status, which was correlated to infection and hypercapnia and might be potentially the risk factor of thrombosis.

Heparin locks with low and high concentration in haemodialysis patients: A systematic review and meta-analysis.

AIM: There is no evidence-based consensus on the optimal concentration for heparin locks; several randomized controlled trials (RCTs) have evaluated the concentration of heparin locks, yet the results remain inconsistent. We aimed to assess heparin locks with low and high concentration in haemodialysis patients. METHODS: We performed a systematic review and meta-analysis of RCTs focusing on the concentration in heparin locks. Studies were identified by searching PUBMED, EMBASE, Science Direct, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI) and Wanfang databases (from inception to 15 March 2020). Summary risk ratios or mean differences with 95% confidence interval were calculated. RESULTS: A total of 370 patients with four RCTs were included. Heparin locks with 1000 U/ml could significantly reduce the activated partial thromboplastin time (APTT) compared with 5000 U/ml. No significant differences were seen in the occurrence of catheter-related thrombosis, the length of catheter stay, the rates of bleeding and catheter occlusions between the two groups. CONCLUSIONS: Lower concentrations in heparin lock are optimal for shortening APTT in haemodialysis patients; further studies are needed to elucidate the role of heparin concentration in the lock practice.

[Mechanism of signal molecule high mobility group box protein 1 mediated by Toll-like receptor 2 in murine asthma].

OBJECTIVE: To explore the role and mechanism of signal molecule high mobility group box protein 1 (HMGB1) mediated by Toll-like receptor 2 (TLR2) in a murine asthma model. METHODS: Fourteen specific pathogen free (SPF) female C57 and TLR2(-/-) mice each were randomly divided into 4 groups of C57 control, C57 asthma, TLR2(-/-) control and TLR2(-/-) asthma (n = 7 each). The animals were sensitized and challenged with ovalbumin (OVA) for asthmatic modeling. The same amount of normal saline was used in the control group. The supernatant of bronchoalveolar lavage fluid (BALF) was collected for detecting the level of HMGB1 by enzyme-linked immunosorbent assay (ELISA). And the expression of HMGB1 in lung tissue was detected by Western blot and immunohistochemistry. RESULTS: Asthmatic murine model was successfully established. The level of HMGB1 in the BALF of C57 asthma group was significantly higher than that in C57 control, TLR2(-/-) asthma and TLR2(-/-) control groups ((59.0 ± 13.9) vs (42.3 ± 1.6), (47.5 ± 2.3), (42.4 ± 1.4) ng/L; P = 0.001, 0.001, 0.037) . The results of immunohistochemistry showed that the marker of HMGB1 in lung tissue was less than those in the C57 control and TLR2(-/-) control groups. However, the C57 asthma and TLR2(-/-) asthma groups were obviously more and they were located in airway epithelium. Western blot showed that the expression of HMGB1 was significantly higher in C57 asthma group than that in the C57 control, TLR2(-/-) asthma and TLR2(-/-) control groups (0.92 ± 0.29 vs 0.18 ± 0.09, 0.31 ± 0.16, 0.21 ± 0.14; P = 0.007, 0.022, 0.009). CONCLUSIONS: HMGB1 promotes the airway inflammation mediated by TLR2. And it may participate in the pathogenesis of asthma.

Melatonin regulates circadian clock proteins expression in allergic airway inflammation.

Asthma demonstrates a strong circadian rhythm with disrupted molecular clock. Melatonin which can directly regulate circadian rhythm has been reported to alleviate asthma, but whether this effect is related to its regulation on circadian clock has not yet been known. Here, female C57BL/6 mice were challenged with ovalbumin (OVA) to establish allergic airway inflammation, and were treated with melatonin or Luzindole to investigate whether the expressions of circadian clock proteins were changed in response to OVA and were affected by exogenous/endogenous melatonin. Airway inflammation, mucus secretion, protein expressions of circadian proteins (Bmal1, Per1, Clock, Timeless, Cry1 and Cry2), melatonin biosynthetase (ASMT, AANAT) and melatonin receptor (Mel-1A/B-R) were analyzed accordingly. The results showed that in the successfully established allergic airway inflammation model, inflammatory cells infiltration, expressions of circadian clock proteins in the lung tissues of OVA-challenged mice were all notably up-regulated as compared to that of the vehicle mice. Meanwhile, the protein expression of ASMT and the level of melatonin in the lung tissues were reduced in allergic mice, while the expression of melatonin receptor Mel-1A/B-R was markedly increased. After addition of exogenous melatonin, the OVA-induced airway inflammation was pronouncedly ameliorated, while simultaneously the OVA-induced expressions of Per1 and Clock were further increased. However, a melatonin receptor antagonist Luzindole further augmented the OVA-induced airway inflammation, accompanied with remarkably decreased expressions of Per1, Bmal1, Cry1 and Cry2 but notably increased expression of Timeless. Collectively, our results demonstrated that the expression of circadian clock proteins was increased in the lungs during allergic airway inflammation, and Per1 was a clock protein that can be regulated by both exogenous and endogenous melatonin, suggesting Per1 may be an important potential circadian clock target for melatonin as a negative regulatory factor against Th2-type airway inflammation.

Itaconate Suppresses the Activation of Mitochondrial NLRP3 Inflammasome and Oxidative Stress in Allergic Airway Inflammation.

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1-/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in allergic airway inflammation.

As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2-/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2-/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2-/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2-/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2-/- mice abolished while transfer of TLR2-/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.

Case report: Indolent drug-related pneumonitis with alectinib therapy in the treatment of non-small cell lung cancer.

Molecular targeting therapy is becoming the standard of care for some patients with anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma. Drug-related pneumonitis (DRP) has been identified as an infrequent but potentially severe adverse effect. Herein, we report a 50-year-old woman with ALK-rearranged advanced lung adenocarcinoma who developed interstitial lung disease associated with alectinib therapy. At 102-day of treatment, chest CT revealed scattered ground glass opacities (GGOs) involving both lungs. Since she was asymptomatic and alectinib provided a beneficial tumor treatment response, alectinib therapy was continued. However, 2 months later, she presented with progressive dyspnea and diffuse GGOs on chest computed tomography. There was no evidence for infection or other etiologies for her lung complication. Alectinib was discontinued and steroid therapy was initiated which was followed by improvement in respiratory symptoms and chest CT findings; DRP was diagnosed. Although rare, alectinib therapy can cause DRP of indolent onset.

Evaluation of a community intervention program on knowledge, attitudes, and practices regarding severe fever with thrombocytopenia syndrome in Anhui Province, China.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is a novel infectious disease with no specific therapeutics and vaccines. We hypothesize that health education in vulnerable people would ameliorate their knowledge, attitudes and practices (KAP) regarding SFTS and reduce its prevalence. Methods: A four-stage cluster cross-section study in sixteen community units was performed. Sixteen groups were allocated to the intervention or control groups. A 6 months education program was administrated. The primary outcome was KAP scores 6 months after intervention. Predictors of KAP score changes were also analyzed. Results: Eight hundred and fifteen valid questionnaires pre-intervention and 767 ones post-intervention were retreated. No significant differences were found in demographic characteristics and KAP scores before intervention. A significant improvement in KAP score (16.8 ± 4.7 vs. 22.0 ± 4.2, p < 0.001) in the intervention group was observed compare with the controls. Educational level and intervention program were the common predictors of KAP score changes. Conclusions: Education improved KAP scores in SFTS vulnerable people which may contribute to the control of the disease.

Epidemiological and clinical features of SARS-CoV-2 cluster infection in Anhui Province, Eastern China.

BACKGROUND: COVID-19 has spread worldwide and become a pandemic. We report the epidemiological and clinical characteristics of cluster infections. METHODS: Data of clustered cases were retrieved from the public health emergency monitoring information system of China. We analyzed the incubation period, generation gap, secondary attack rate, and viral load in various grouped cases. RESULTS: A total of 60 COVID-19 infection clusters including 226 patients and 19 asymptomatic cases involving four generations were analyzed. With the increase of transmission generations, secondary attack rate decreased (P＜0.001) and severity alleviated (P = 0.008). The median incubation period and intergenerational interval were 9 and 6 days, respectively. The secondary attack rate was 7.1% in the index cases, 5.0% in the first generation, 1.0% in the second generation, and 4.7% overall. Severe cases were seen more in the index (13, 65%) and first generation (7, 35%) ones, who had a significantly higher viral load than the mild and moderate ones. CONCLUSIONS: With the increase of transmission generation, secondary infection rate and severity decreased. Severe patients had a higher virus load. Patients in the incubation period and asymptomatic carriers were potential infection sources who might play an important role in transmission.

D-dimer level is related to the prognosis of patients with small cell lung cancer.

BACKGROUND: Although the significance of D-dimer in cancer patients has been extensively studied and plasma D-dimer levels have been reported to be abnormally high in certain types of lung cancer patients, its prognostic value for small cell lung cancer (SCLC) remains largely unknown. METHODS: One hundred and seven newly diagnosed SCLC patients were enrolled in this study. Variables including the clinical features, pre-treatment levels of D-dimer, serum neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were extracted. The correlations between D-dimer levels and prognosis of the patient were analysed with Kaplan-Meier survival analysis. RESULTS: Plasma D-dimer levels were elevated in 57.01% of patients. Patients with extensive stage disease had higher D-dimer levels compared with those at limited stage. D-dimer levels were positively correlated with NSE and CEA levels. The elevated D-dimer levels were significantly associated with the SCLC-related mortality. Patients with elevated D-dimer levels had a shorter median survival time than those with normal levels, and a significant difference existed between the two groups. CONCLUSIONS: Increased D-dimer levels suggested a shorter survival time in SCLC patients. Pre-treatment D-dimer level is useful in estimating the prognosis of patients with SCLC.

TLR2 Regulates Allergic Airway Inflammation and Autophagy Through PI3K/Akt Signaling Pathway.

Toll-like receptors (TLRs) are innate pattern recognition receptors that play a critical role in allergic inflammation, yet their contribution to autophagy in asthma remains poorly defined. Here, we investigate the role of Toll-like receptor 2 (TLR2) in phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway-mediated autophagy in ovalbumin-induced airway inflammation in mice. Wild-type (WT) and TLR2-knockout (TLR2-/-) C57BL/6 mice were ovalbumin-sensitized and ovalbumin-challenged. In ovalbumin-challenged WT mice, enhanced expression of TLR2 in lung tissue, remarkable inflammatory cell infiltrates, goblet cell hyperplasia, and increased mucus production were observed. The number of inflammatory cells and interleukin-13 (IL-13) levels increased, while interferon-gamma (IFN-γ) levels decreased in bronchoalveolar lavage fluid. Expression of PI3K, phospho-Akt, Beclin-1 and LC3-II was enhanced significantly. These changes were mitigated dose-dependently in 3-methyl adenine-treated mice. In contrast, similar but weaker changes were found in ovalbumin-challenged TLR2-/- mice, and the changes were not significantly attenuated by 3-methyl adenine treatment. These results indicate that TLR2 confers a pivotal role in allergic airway inflammation via regulating the PI3K/Akt signaling pathway-related autophagy in mice.

Air pollution and chronic airway diseases: what should people know and do?

The health effects of air pollution remain a public health concern worldwide. Exposure to air pollution has many substantial adverse effects on human health. Globally, seven million deaths were attributable to the joint effects of household and ambient air pollution. Subjects with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma are especially vulnerable to the detrimental effects of air pollutants. Air pollution can induce the acute exacerbation of COPD and onset of asthma, increase the respiratory morbidity and mortality. The health effects of air pollution depend on the components and sources of pollutants, which varied with countries, seasons, and times. Combustion of solid fuels is a major source of air pollutants in developing countries. To reduce the detrimental effects of air pollution, people especially those with COPD or asthma should be aware of the air quality and take extra measures such as reducing the time outdoor and wearing masks when necessary. For reducing the air pollutants indoor, people should use clean fuels and improve the stoves so as to burn fuel more efficiently and vent emissions to the outside. Air cleaners that can improve the air quality efficiently are recommended.

Prophylaxis and Treatment of Pneumocystis jiroveci Pneumonia in Lymphoma Patients Subjected to Rituximab-Contained Therapy: A Systemic Review and Meta-Analysis.

Pneumocystis jiroveci pneumonia (PCP) is frequently reported in lymphoma patients treated with rituximab-contained regimens. There is a trend toward a difference in PCP risk between bi- and tri-weekly regimens. The aims of this systemic review and meta-analysis were to estimate the risk for PCP in these patients, compare the impact of different regimens on the risk, and evaluate the efficacy of prophylaxis. The cohort studies with incept up to January 2014 were retrieved from the Cochrane Library, Medline, Embase, and Web of Science databases. Studies that compared the incidence of PCP in patients with and without rituximab treatment were conducted. Studies that reported the results of prophylaxis were concentrated to evaluate the efficacy of prophylaxis. Fixed effect Mantel-Haenszel model was chosen as the main analysis method. Funnel plots were examined to estimate the potential selection bias. Egger's test and Begg's test were used for the determination of possible small study bias. Eleven cohort studies that met the inclusion criteria were finally included. Results indicated that rituximab was associated with a significantly increased risk for PCP (28/942 vs 5/977; risk ratio: 3.65; 95% confidence interval 1.65 to 8.07; P=0.001), and no heterogeneity existed between different studies (I2=0%). Little significant difference in PCP risk was found between bi-weekly and tri-weekly regimens (risk ratio: 3.11; 95% confidence interval 0.92 to 10.52, P=0.068). PCP risk was inversely associated with prophylaxis in patients treated with rituximab (0/222 vs 26/986; risk ratio: 0.28; 95% confidence interval 0.09 to 0.94; P=0.039). In conclusion, PCP risk was increased significantly in lymphoma patients subjected to rituximab-contained chemotherapies. Difference in PCP risk between bi-weekly and tri-weekly regimens was not significant. Additionally, prophylaxis was dramatically effective in preventing PCP in rituximab-received lymphoma patients, suggesting that rituximab should be recommended for these patients.

Pneumocystis jiroveci pneumonia in patients with non-Hodgkin's lymphoma after Rituximab-containing regimen: two cases of report and literature review.

Rituximab, a monoclonal antibody against CD20+ antigen specific B cell, has been increasingly used in the treatment of non-Hodgkin's lymphoma and some other autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. It is noted that Rituximab could enhanced the efficacy of CHOP-based chemotherapy. Meanwhile it could increase the opportunity of lung infection. Pneumocystis jiroveci pneumonia (PCP), a rare opportunistic infection that was not reported in the large-scale clinical trials of Rituximab, was found recently in patients with non-Hodgkin's lymphoma treated with remedy containing Rituximab. We herein report two cases of PCP in lymphoma patients after Rituximab-containing chemotherapy. Both patients were successfully treated, with trimethoprim-sulfamethoxazole (TMP-SMX) in one case and Caspofungin alone in the other. We also reviewed the literature and concluded that PCP is an infrequent but potentially life-threatening infection in patients with non-Hodgkin's lymphoma subjected to Rituximab-containing regimen. Therefore, adequate prophylaxis, timely diagnosis and treatment are necessary.