'Pterocephalodes hookeri-Onosma hookeri' decoction protects against LPS-induced pulmonary inflammation via inhibiting TLR4/ NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: As the second-largest traditional medical system in China, Tibetan medicine has a long history and abundant resources. To promote the development of the Tibetan medicine industry, it is essential to study the pharmacological activities of Tibetan medicine based on its traditional usage methods. AIM OF THE STUDY: Pneumonia has been a worldwide health problem with high morbidity and mortality rates, especially in the context of the COVID-19 epidemic. Given the unique advantages of traditional Tibetan medicine in treating pulmonary diseases, further research is warranted to develop potential anti-pneumonia drugs. MATERIALS AND METHODS: In our study, the potential combined decoction from traditional Tibetan medicine was determined by the data mining method. The antioxidant activity in vitro, anti-inflammatory effects on the macrophage cell model, as well as the anti-pulmonary inflammation effects on the LPS-induced mice model, have been explored to investigate the potential anti-pneumonia role of the decoction. Additionally, we conducted network pharmacology analysis to identify the potential targets against pneumonia, which were further confirmed by western blot assays. RESULTS: Following the combination therapy of Pterocephalodes hookeri (C.B.Clarke) V.Mayer & Ehrend. and Onosma hookeri var. longiflora (Duthie) A.V.Duthie ex Stapf ('P-O'), the clearance of DPPH radical and the total reducing power were all improved, as well as alleviated the toxicity. On the in vitro level, 'P-O' pre-treatment reduced the secretion of NO, TNF-α, IL-6, and IL-1ß in LPS-stimulated RAW264.7 cells, while promoting the concentration of IL-10. Meanwhile, on the in vivo level, the 'P-O' pre-treating also could alleviate LPS-induced pulmonary inflammation by reducing the pulmonary edema and leakage of the lung microvascular, improving the pathological change of lung tissue and regulating the cytokines content in bronchoalveolar lavage fluid (BALF). Furthermore, network pharmacology analysis revealed that the mechanism of 'P-O' in treating pneumonia in a multi-component, multi-target, and multi-pathway network, with the TLR4/NF-κB signaling pathway playing a crucial role, as demonstrated by the western blot assay results. CONCLUSION: In summary, the combination therapy of 'P-O' exhibited good antioxidant activity and anti-inflammatory activity in vitro, as well as a therapeutic effect against pulmonary inflammation in vivo. These findings provide evidence for the clinical application of 'P-O' and offer new approaches for treating pneumonia.

Protective effect of ß-glucan on Poly(I:C)-induced acute lung injury/inflammation: Therapeutic implications of viral infections in the respiratory system.

AIMS: Acute lung inflammation, particularly acute respiratory distress syndrome (ARDS), is caused by a variety of pathogens including bacteria and viruses. ß-Glucans have been reported to possess both anti-inflammatory and immunomodulatory properties. The current study evaluated the therapeutic effect of ß-glucans on polyinosinic:polycytidylic acid (Poly(I:C)) induced lung inflammation in both hamster and mice models. MAIN METHODS: Poly(I:C)-induced ALI/inflammation models were developed in hamsters (2.5 mg/kg) and mice (2 mg/kg) by delivering the Poly(I:C) intratracheally, and followed with and without ß-glucan administration. After treatment, lung mechanics were assessed and lung tissues were isolated and analyzed for mRNA/protein expression, and histopathological examinations. KEY FINDINGS: Poly(I:C) administration, caused a significant elevation of inflammatory marker's expression in lung tissues and showed abnormal lung mechanics in mice and hamsters. Interestingly, treatment with ß-glucan significantly (p < 0.001) reversed the Poly(I:C)-induced inflammatory events and inflammatory markers expression in both mRNA (IL-6, IL-1ß, TNF-α, CCL2 and CCL7) and protein levels (TNF-α, CD68, myeloperoxidase, neutrophil elastase, MUC-5Ac and iNOS). Lung functional assays revealed that ß-glucan treatment significantly improved lung mechanics. Histopathological analysis showed that ß-glucan treatment significantly attenuated the Poly(I:C) induced inflammatory cell infiltration, injury and goblet cell population in lung tissues. Consistent with these findings, ß-glucan treatment markedly reduced the number of neutrophils and macrophages in lung tissues. Our findings further demonstrated that ß-glucan could reduce inflammation by suppressing the MAPK pathway. SIGNIFICANCE: These results suggested that ß-glucan may attenuate the pathogenic effects of Poly(I:C)-induced ALI/ARDS via modulating the MAPK pathway, indicating ß-glucan as a possible therapeutic agent for the treatment of viral-pulmonary inflammation/injury.

Subway station dust-induced pulmonary inflammation may be due to the dysfunction of alveolar macrophages: Possible contribution of bound elements.

With its increasing value as a means of public transportation, the health effects of the air in subway stations have attracted public concern. In the current study, we investigated the pulmonary toxicity of dust collected from an air purifier installed on the platform of the busiest subway station in Seoul. We found that the dust contained various elements which are attributable to the facilities and equipment used to operate the subway system. Particularly, iron (Fe), chromium (Cr), zirconium (Zr), barium (Ba), and molybdenum (Mo) levels were more notable in comparison with those in dust collected from the ventilation chamber of a subway station. To explore the health effects of inhaled dust, we first instilled via the trachea in ICR mice for 13 weeks. The total number of pulmonary macrophages increased significantly with the dose, accompanying hematological changes. Dust-laden alveolar macrophages and inflammatory cells accumulated in the perivascular regions in the lungs of the treated mice, and pulmonary levels of CXCL-1, TNF-α, and TGF-ß increased clearly compared with the control. The CCR5 and CD54 level expressed on BAL cell membranes was also enhanced following exposure to dust, whereas the CXCR2 level tended to decrease in the same samples. In addition, we treated the dust to alveolar macrophages (known as dust cells), lysosomal and mitochondrial function decreased, accompanied by cell death, and NO production was rapidly elevated with concentration. Moreover, the expression of autophagy- (p62) and anti-oxidant (SOD-2)-related proteins increased, and the expression of inflammation-related genes was dramatically up-regulated in the dust-treated cells. Therefore, we suggest that dysfunction of alveolar macrophages may importantly contribute to dust-induced inflammatory responses and that the exposure concentrations of Cr, Fe, Mo, Zr, and Ba should be considered carefully when assessing the health risks associated with subway dust. We also hypothesize that the bound elements may contribute to dust-induced macrophage dysfunction by inhibiting viability.

The effect of bradykinin 1 receptor antagonist BI 1026706 on pulmonary inflammation after segmental lipopolysaccharide challenge in healthy smokers.

BACKGROUND: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx. METHODS: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema. RESULTS: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups. CONCLUSIONS: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model. TRIAL REGISTRATION: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

Identification and prediction of immune checkpoint inhibitors-related pneumonitis by machine learning.

Background: Immune checkpoint inhibitor (ICI)-related pneumonitis (IRP) is a common and potentially fatal clinical adverse event. The identification and prediction of the risk of ICI-related IRP is a major clinical issue. The objective of this study was to apply a machine learning method to explore risk factors and establish a prediction model. Methods: We retrospectively analyzed 48 patients with IRP (IRP group) and 142 patients without IRP (control group) who were treated with ICIs. An Elastic Net model was constructed using a repeated k-fold cross-validation framework (repeat = 10; k = 3). The prediction models were validated internally and the final prediction model was built on the entire training set using hyperparameters with the best interval validation performance. The generalizability of the final prediction model was assessed by applying it to an independent test set. The overall performance, discrimination, and calibration of the prediction model were evaluated. Results: Eleven predictors were included in the final predictive model: sindillizumab, number of ≥2 underlying diseases, history of lung diseases, tirelizumab, non-small cell lung cancer (NSCLC), percentage of CD4+ lymphocytes, body temperature, KPS score ≤70, hemoglobin, cancer stage IV, and history of antitumor therapy. The external validation of the risk prediction model on an independent test set of 37 patients and showed good discrimination and acceptable calibration ability: with AUC of 0.81 (95% CI 0.58-0.90), AP of 0.76, scaled Brier score of 0.31, and Spiegelhalter-z of -0.29 (P-value:0.77). We also designed an online IRP risk calculator for use in clinical practice. Conclusion: The prediction model of ICI-related IRP provides a tool for accurately predicting the occurrence of IRP in patients with cancer who received ICIs.

Platycodonis Radix Alleviates LPS-Induced Lung Inflammation through Modulation of TRPA1 Channels.

Platycodonis Radix (PR), a widely consumed herbal food, and its bioactive constituents, platycodins, have therapeutic potential for lung inflammation. Transient Receptor Potential Ankyrin 1 (TRPA1), which is essential for the control of inflammation, may be involved in the development of inflammation in the lungs. The aim of this study was to determine the TRPA1-targeted effects of PR against pulmonary inflammation and to investigate the affinity of PR constituents for TRPA1 and their potential mechanisms of action. Using a C57BL/6J mouse lipopolysaccharides (LPS) intratracheal instillation pneumonia model and advanced analytical techniques (UPLC-Q-TOF-MS/MS, molecular docking, immuno-fluorescence), five platycodins were isolated from PR, and the interaction between these platycodins and hTRPA1 was verified. Additionally, we analyzed the impact of platycodins on LPS-induced TRPA1 expression and calcium influx in BEAS-2B cells. The results indicated that PR treatment significantly reduced the severity of LPS-triggered inflammation in the mouse model. Interestingly, there was a mild increase in the expression of TRPA1 caused by PR in healthy mice. Among five isolated platycodins identified in the PR extract, Platycodin D3 (PD3) showed the highest affinity for hTRPA1. The interaction between platycodins and TRPA1 was verified through molecular docking methods, highlighting the significance of the S5-S6 pore-forming loop in TRPA1 and the unique structural attributes of platycodins. Furthermore, PD3 significantly reduced LPS-induced TRPA1 expression and calcium ion influx in BEAS-2B cells, substantiating its own role as an effective TRPA1 modulator. In conclusion, PR and platycodins, especially PD3, show promise as potential lung inflammation therapeutics. Further research should explore the precise mechanisms by which platycodins modulate TRPA1 and their broader therapeutic potential.

Immune-related adverse events associated with nab-paclitaxel/paclitaxel combined with immune checkpoint inhibitors: a systematic review and network meta-analysis.

Objective: The combination of nanoparticle albumin-bound paclitaxel (nab-PTX)/paclitaxel (PTX) with immune checkpoint inhibitors (ICIs) has demonstrated significant efficacy in cancer patients. However, the safety of these combination regimens remains conflicting in former researches. Therefore, in order to address this issue, we performed a systematic review and network meta-analysis (NMA) to evaluate and compare the safety profile. Methods: We performed a systematic review by searching randomized controlled trials (RCTs) from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and Web of Science up to August 15, 2022. The primary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) immune-related adverse events (irAEs). Secondary outcomes were all-grade (grade 1-5) and high-grade (grade 3-5) irAEs of subgroups of ICIs. Results: There were 22 RCTs included in the NMA, involving a total of 15 963 patients diagnosed with any type of cancer. ICIs+nab-PTX was associated with a noticeably decreased risk of grade 3-5 pneumonitis (odds ratio [OR]=0.28, 95% credible interval [CrI]: 0.09,0.90) compared to ICI monotherapy; ICIs+PTX showed a lower risk of grade 1-5 hyperthyroidism (OR=0.46, 95% CrI: 0.22-0.96) and grade 1-5 hypothyroidism (OR=0.49, 95% CrI: 0.26-0.93) than ICIs. Compared with PD-1, PD-1+PTX was associated with a statistically significantly lower risk of grade 1-5 pneumonitis (OR=0.32, 95% CrI: 0.11-0.92). PD-L1 resulted in a noticeably lower risk of grade 1-5 hypothyroidism (OR=0.34, 95% CrI: 0.12-1.00) than PD-L1+PTX. Nearly all treatment regimens containing ICIs demonstrated significantly higher risks of irAEs compared to the standard chemotherapy groups. Conclusion: Nab-PTX/PTX+ICIs demonstrated an approach leading to decreased risk of irAEs compared with ICI monotherapy. This finding supports that ICIs+nab-PTX/PTX may be a safer treatment strategy. Moreover, we also found that the combination regimens containing ICIs had a higher risk of irAEs than standard chemotherapy. Additionally, ICIs+nab-PTX demonstrated a decreased risk of irAEs compared to ICIs+PTX. PD-1 inhibitors were associated with a higher risk of irAEs than PD-L1 inhibitors.

A nomogram model for predicting the risk of checkpoint inhibitor-related pneumonitis for patients with advanced non-small-cell lung cancer.

OBJECTIVE: Immunotherapy extensively treats advanced non-small-cell lung cancer (NSCLC). Although immunotherapy is generally better tolerated than chemotherapy, it can cause multiple immune-related adverse events (irAEs) involving multiple organs. Checkpoint inhibitor-related pneumonitis (CIP) is a relatively uncommon irAE that, in severe cases, can be fatal. Potential risk factors for the occurrence of CIP are currently poorly understood. This study sought to develop a novel scoring system for predicting the risk of CIP based on a nomogram model. METHODS: We retrospectively collected advanced NSCLC patients who received immunotherapy at our institution between January 1, 2018, and December 30, 2021. All patients who met the criteria were randomly divided into the training set and testing set (in a ratio of 7:3), and cases fulfilling the CIP diagnostic criteria were screened. The patients' baseline clinical characteristics, laboratory tests, imaging, and treatment information were extracted from the electronic medical records. The risk factors associated with the occurrence of CIP were identified based on the results of logistic regression analysis on the training set, and a nomogram prediction model was developed. The discrimination and prediction accuracy of the model was evaluated using the receiver operating characteristic (ROC) curve, the concordance index (C-index), and the calibration curve. Decision curve analysis (DCA) was used to evaluate the clinical applicability of the model. RESULTS: The training set comprised 526 (CIP: 42 cases), and the testing set comprised 226 (CIP: 18 cases) patients, respectively. In the training set, the final multivariate regression analysis revealed that age (p = 0.014; odds ratio [OR] = 1.056; 95% Confidence Interval [CI] =1.011-1.102), Eastern Cooperative Oncology Group performance status (p = 0.002; OR = 6.170; 95% CI = 1.943-19.590), history of prior radiotherapy (p < 0.001; OR = 4.005; 95% CI = 1.920-8.355), baseline white blood cell count (WBC) (p < 0.001; OR = 1.604; 95% CI = 1.250-2.059), and baseline absolute lymphocyte count (ALC) (p = 0.034; OR = 0.288; 95% CI = 0.091-0.909) were identified as independent risk factors for the occurrence of CIP. A prediction nomogram model was developed based on these five parameters. The area under the ROC curve and C-index of the prediction model in the training set and testing set were 0.787 (95% CI: 0.716-0.857) and 0.874 (95% CI: 0.792-0.957), respectively. The calibration curves are in good agreement. The DCA curves indicate that the model has good clinical utility. CONCLUSION: We developed a nomogram model that proved to be a good assistant tool for predicting the risk of CIP in advanced NSCLC. This model has the potential power to help clinicians in making treatment decisions.

Assessing the Effects of Nicotinamide Mononucleotide Supplementation on Pulmonary Inflammation in Male Mice Subchronically Exposed to Ambient Particulate Matter.

BACKGROUND: Chronic lung injury and dysregulated cellular homeostasis in response to particulate matter (PM) exposure are closely associated with adverse health effects. However, an effective intervention for preventing the adverse health effects has not been developed. OBJECTIVES: This study aimed to evaluate the protective effects of nicotinamide mononucleotide (NMN) supplementation on lung injury and elucidate the mechanism by which NMN improved immune function following subchronic PM exposure. METHODS: Six-week-old male C57BL/6J mice were placed in a real-ambient PM exposure system or filtered air-equipped chambers (control) for 16 wk with or without NMN supplementation in drinking water (regarded as Con-H2O, Exp-H2O, Con-NMN and Exp-NMN groups, respectively) in Shijiazhuang City, China (n=20/group). The effects of NMN supplementation (500mg/kg) on PM-induced chronic pulmonary inflammation were assessed, and its mechanism was characterized using single-cell transcriptomic sequencing (scRNA-seq) analysis of whole lung cells. RESULTS: The NMN-treated mice exhibited higher NAD+ levels in multiple tissues. Following 16-wk PM exposure, slightly less pulmonary inflammation and less collagen deposition were noted in mice with NMN supplementation in response to real-ambient PM exposure (Exp-NMN group) compared with the Exp-H2O group (all p<0.05). Mouse lung tissue isolated from the Exp-NMN group was characterized by fewer neutrophils, monocyte-derived cells, fibroblasts, and myeloid-derived suppressor cells induced by subchronic PM exposure as detected by scRNA-seq transcriptomic analysis. The improved immune functions were further characterized by interleukin-17 signaling pathway inhibition and lower secretion of profibrotic cytokines in the Exp-NMN group compared with the Exp-H2O group. In addition, reduced proportions of differentiated myofibroblasts and profibrotic interstitial macrophages were identified in the NMN-supplemented mice in response to PM exposure. Furthermore, less immune function suppression and altered differentiation of pathological cell phenotypes NMN was related to intracellular lipid metabolism activation. DISCUSSION: Our novel findings suggest that NMN supplementation mitigated PM-induced lung injury by regulating immune functions and improving lipid metabolism in male mice, providing a putative intervention method for prevention of human health effects associated with PM exposure. https://doi.org/10.1289/EHP12259.

Pneumonitis with combined immune checkpoint inhibitors and chemoradiotherapy in locally advanced non-small-cell lung cancer: a systematic review and meta-analysis.

Aims: This study systematically evaluated cases of pneumonitis following combined immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer (LA-NSCLC). Methods: Studies from Embase, PubMed and the Cochrane Library on patients with LA-NSCLC who received CRT and ICIs were reviewed. The primary outcomes were rates of all-grade, grade 3-5 and grade 5 pneumonitis. Results: Overall, 35 studies involving 5000 patients were enrolled. The pooled rates of all-grade, grade 3-5 and grade 5 pneumonitis were 33.0% (95% CI: 23.5-42.6), 6.1% (95% CI: 4.7-7.4) and 0.8% (95% CI: 0.3-1.2), respectively, with 7.6% of patients discontinuing ICIs because of pneumonitis. Conclusion: The incidence rates of pneumonitis following combined CRT and ICIs for LA-NSCLC were acceptable. However, the pulmonary toxicity of concurrent CRT and nivolumab plus ipilimumab should be noted.

Combined immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) may cause severe pneumonitis due to overlapped pulmonary toxicity. However, the safety data on pneumonitis are limited to a small number of prospective clinical trials and retrospective studies with limited evidence. Thus we conducted a systematic review of pneumonitis in relation to the combination treatment. A total of 35 studies, involving 5000 patients, were included for the final analysis. The pooled rates of all-grade, grade 3­5 and grade 5 pneumonitis were 33.0, 6.1 and 0.8%, respectively, and 7.6% of patients stopped taking ICIs because of pneumonitis. The pneumonitis rates following combined CRT and ICIs for LA-NSCLC were acceptable, but the pulmonary toxicity of concurrent CRT and nivolumab plus ipilimumab should be noted.

Proton pump inhibitor use and risk of pneumonia: a self-controlled case series study.

BACKGROUND: Recent research indicates that use of proton pump inhibitors (PPIs) is associated with pneumonia, but existing evidence is inconclusive because of methodological issues. This study aimed to answer whether PPI-use increases risk of pneumonia while taking the methodological concerns of previous research into account. METHODS: This population-based and nationwide Swedish study conducted in 2005-2019 used a self-controlled case series design. Data came from national registries for medications, diagnoses, and mortality. Conditional fixed-effect Poisson regression provided incidence rate ratios (IRR) with 95% confidence intervals (CI) for pneumonia comparing PPI-exposed periods with unexposed periods in the same individuals, thus controlling for confounding. Analyses were stratified by PPI-treatment duration, sex, age, and smoking-related diseases. Use of histamine type-2 receptor antagonists (used for the same indications as PPIs) and risk of pneumonia was analysed for assessing the validity and specificity of the results for PPI-therapy and pneumonia. RESULTS: Among 519,152 patients with at least one pneumonia episode during the study period, 307,709 periods of PPI-treatment occurred. PPI-use was followed by an overall 73% increased risk of pneumonia (IRR 1.73, 95% CI 1.71-1.75). The IRRs were increased across strata of PPI-treatment duration, sex, age, and smoking-related disease status. No such strong association was found between histamine type-2 receptor antagonist use and risk of pneumonia (IRR 1.08, 95% CI 1.02-1.14). CONCLUSIONS: PPI-use seems to be associated with an increased risk of pneumonia. This finding highlights a need for caution in using PPIs in individuals with a history of pneumonia.

Effects of intrauterine and post-natal exposure to air pollution on children's pneumonia: Key roles in different particulate matters exposure during critical time windows.

BACKGROUND: Despite mounting evidence linked pneumonia with air pollution, it is unclear what main pollutant(s) exposure in which critical window(s) play a key role in pneumonia. OBJECTIVE: To examine effects of intrauterine and post-natal exposure to air pollution on children's doctor-diagnosed pneumonia (DDP). METHODS: A combination of cross-sectional and retrospective cohort study was conducted at Changsha, China during 2019-2020. Personal exposure to outdoor air pollutants at each child's home address was estimated using inverse distance weighted (IDW) method based on data from 10 air quality monitoring stations. Associations between personal air pollution exposure and DDP were evaluated. RESULTS: Children's DDP was associated with intrauterine and post-natal exposure to PM2.5, PM2.5-10, and PM10, adjusted ORs (95% CI) of 1.17 (1.04-1.30), 1.09 (1.01-1.17), and 1.07 (1.00-1.14) for IQR increase in intrauterine exposure and 1.12 (1.02-1.22), 1.13 (1.06-1.21), and 1.28 (1.16-1.41) for post-natal exposure. Intrauterine PM2.5 exposure and post-natal PM10 exposure were associated with a higher risk of pneumonia. We identified the 2nd trimester, 3rd trimester, and first year as critical windows respectively for PM2.5, PM2.5-10, and PM10 exposure. Daytime exposure to traffic-related air pollution especially during early life increased DDP. CONCLUSION: Intrauterine and post-natal exposure to particulate matters played a dominant role in children's DDP.

Nebulised mesenchymal stem cell derived extracellular vesicles ameliorate E. coli induced pneumonia in a rodent model.

BACKGROUND: Mesenchymal stem cell (MSC) derived extracellular vesicles (EVs) have been proposed as an alternative to cell therapy, creating new possible delivery modalities such as nebulisation. We wished to investigate the therapeutic potential of directly nebulised MSC-EVs in the mitigation of Escherichia coli-induced pneumonia. METHODS: EV size, surface markers and miRNA content were assessed pre- and post-nebulisation. BEAS2B and A459 lung cells were exposed to lipopolysaccharide (LPS) and treated with nebulised bone marrow (BM) or umbilical cord (UC) MSC-EVs. Viability assays (MTT) and inflammatory cytokine assays were performed. THP-1 monocytes were stimulated with LPS and nebulised BM- or UC-EVs and phagocytosis activity was measured. For in vivo experiments, mice received LPS intratracheally (IT) followed by BM- or UC-EVs intravenously (IV) and injury markers assessed at 24 h. Rats were instilled with E. coli bacteria IT and BM- or UC-EVs delivered IV or by direct nebulisation. At 48 h, lung damage was assessed by physiological parameters, histology and inflammatory marker presence. RESULTS: MSC-EVs retained their immunomodulatory and wound healing capacity after nebulisation in vitro. EV integrity and content were also preserved. Therapy with IV or nebulised MSC-EVs reduced the severity of LPS-induced lung injury and E. coli-induced pneumonia by reducing bacterial load and oedema, increasing blood oxygenation and improving lung histological scores. MSC-EV treated animals also showed lower levels of inflammatory cytokines and inflammatory-related markers. CONCLUSIONS: MSC-EVs given IV attenuated LPS-induced lung injury, and nebulisation of MSC-EVs did not affect their capacity to attenuate lung injury caused by E. coli pneumonia, as evidenced by reduction in bacterial load and improved lung physiology.

Study protocol: pneumonia and inhaled corticosteroid treatment patterns in chronic obstructive pulmonary disease - a cohort study using sequence analysis (PICCS).

INTRODUCTION: Treatment with inhaled corticosteroids (ICS) is a widely used treatment in chronic obstructive pulmonary disease. The main effects include a reduction in the number of exacerbations and, for some patients, an increase in expected mortality. Unfortunately, the treatment is also linked to an increased risk of pneumonia, and very little is known about which patients experience this increased risk. There is a need for identification of patient characteristics associated with increased risk of pneumonia and treatment with ICS. METHODS AND ANALYSIS: This is a register-based cohort study that uses the nationwide Danish registers. Data from several registers in the years 2008-2018 will be merged on an individual level using the personal identification numbers that are unique to every citizen in Denmark. Clusters based on pneumonia incidence and ICS treatment patterns will be explored with a sequence analysis in a 3-year follow-up period. ETHICS AND DISSEMINATION: This is a register-based study and research ethics approval is not required according to Danish Law and National Ethics Committee Guidelines. The results will be submitted to peer-reviewed journals and reported at appropriate national and international meetings.

Pulmonary microbiota intervention alleviates fine particulate matter-induced lung inflammation in broilers.

Fine particulate matter (PM2.5) released during the livestock industry endangers the respiratory health of animals. Our previous findings suggested that broilers exposed to PM2.5 exhibited lung inflammation and changes in the pulmonary microbiome. Therefore, this study was to investigate whether the pulmonary microbiota plays a causal role in the pathogenesis of PM2.5-induced lung inflammation. We first used antibiotics to establish a pulmonary microbiota intervention broiler model, which showed a significantly reduced total bacterial load in the lungs without affecting the microbiota composition or structure. Based on it, 45 AA broilers of similar body weight were randomly assigned to three groups: control (CON), PM2.5 (PM), and pulmonary microbiota intervention (ABX-PM). From 21 d of age, broilers in the ABX-PM group were intratracheally instilled with antibiotics once a day for 3 d. Meanwhile, broilers in the other two groups were simultaneously instilled with sterile saline. On 24 and 26 d of age, broilers in the PM and ABX-PM groups were intratracheally instilled with PM2.5 suspension to induce lung inflammation, and broilers in the CON group were simultaneously instilled with sterile saline. The lung histomorphology, inflammatory cytokines' expression levels, lung microbiome, and microbial growth conditions were analyzed to determine the effect of the pulmonary microbiota on PM2.5-induced lung inflammation. Broilers in the PM group showed lung histological injury, while broilers in the ABX-PM group had normal lung histomorphology. Furthermore, microbiota intervention significantly reduced mRNA expression levels of interleukin-1ß, tumor necrosis factor-α, interleukin-6, interleukin-8, toll-like receptor 4 and nuclear factor kappa-B. PM2.5 induced significant changes in the ß diversity and structure of the pulmonary microbiota in the PM group. However, no significant changes in microbiota structure were observed in the ABX-PM group. Moreover, the relative abundance of Enterococcus cecorum in the PM group was significantly higher than that in the CON and ABX-PM groups. And sterile bronchoalveolar lavage fluid from the PM group significantly promoted the growth of E. cecorum, indicating that PM2.5 altered the microbiota's growth condition. In conclusion, pulmonary microbiota can affect PM2.5-induced lung inflammation in broilers. PM2.5 can alter the bacterial growth environment and promote dysbiosis, potentially exacerbating inflammation.

Fine particulate matter (PM2.5) in broiler houses has a negative impact on broiler respiratory tracts, and PM2.5 exposure can induce lung inflammation and cause microbiota dysbiosis. The pulmonary microbiota is involved in maintaining immune homeostasis in the lungs, and a variety of lung diseases exhibit microbiota disturbances. However, the correlation between the pulmonary microbiota and PM2.5-induced lung inflammation is poorly understood. This study aimed to investigate whether the pulmonary microbiota influenced PM2.5-induced lung inflammation. We use antibiotics to reduce the quantity of bacteria in the lungs without destroying their composition. PM2.5 was then used to induce lung inflammation in both untreated and intervened pulmonary microbiota broilers. Compared to untreated microbiota broilers, intervened microbiota broilers had less morphological lung tissue injury and lower inflammatory factor expression levels after PM2.5 exposure. Furthermore, the intervened microbiota broilers' microbiota structure remained normal, while the untreated microbiota broilers showed dysbiosis. This dysbiosis is closely linked to changes in the microbial growth environment due to the inflammatory response. This suggested that the pulmonary microbiota affects PM2.5-induced lung inflammation in broilers. Dysbiosis caused by inflammation that alters the conditions for bacterial growth may exacerbate inflammation.

Childhood pneumonia in Beijing: Associations and interactions among selected demographic and environmental factors.

Among infectious diseases, pneumonia is the greatest cause of mortality in children less than 5 years old. Approximately 27% of Beijing's 3-8 year-old children have had pneumonia at least once. The sole reservoir of pneumonia pathogens is the human nasopharynx. We investigated associations and interactions among two kinds of environmental risk factors: i) airborne pathogens, namely closed bedroom window and shared bedroom and ii) pollutants, namely traffic pollution and environmental tobacco smoke (ETS). We evaluated breastfeeding's (BF) protective value against childhood pneumonia. The database consists of responses to a questionnaire in a cross-sectional study. Crude and adjusted Odds Ratios were assessed independently for each risk factor. Combinations of the studied risk factors were analyzed using multivariate logistic regression. Risk factors were evaluated for interactions on the additive scale using the metrics Relative Excess Risk due to Interaction (RERI), Attributable Proportion (AP) and Synergy Index (S). All independent risk factors were significant for children's pneumonia. We also found evidence of possible synergistic interaction between pairs of risk factors that was stronger when one of the risk factors was a closed bedroom window. Remarkably, window opening was associated with reduced risk of pneumonia for children living near heavy traffic pollution. Longer duration BF was more protective than shorter, and exclusive BF was more protective than partial BF against childhood pneumonia. In conclusion, low ventilation (closed bedroom windows), shared bedroom, ETS, and traffic exposure were associated with increased risk of pneumonia. Exclusive BF for more than six months had the greatest protective value against pneumonia.

Healthcare Resource Utilization, Cost and Clinical Outcomes in Patients Diagnosed with COPD Initiating Tiotropium Bromide/Olodaterol versus Fluticasone Furoate/Umeclidinium/Vilanterol Based on Exacerbation History.

Background: ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history. Methods: COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated. Results: Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup. Conclusion: These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Clinicoradiological course of abemaciclib-induced pneumonitis with histology findings.

A woman in her late 40s presented with multiple abnormal shadows on high-resolution CT (HRCT), was treated with abemaciclib for recurrent right breast cancer post-surgery and chemoradiation therapy. During the 10-month chemotherapy, HRCT revealed a recurrent pattern of a partly appearing and disappearing organising pneumonia pattern without clinical symptoms. Bronchoalveolar lavage analysis revealed lymphocytosis, while transbronchial lung biopsy revealed alveolitis with epithelial cell injury. Based on the diagnosis of drug-induced pneumonitis due to abemaciclib, the discontinuation of abemaciclib and administration of prednisolone were effective. Abnormal shadow on HRCT disappeared gradually, while elevated Krebs von den Lungen (KL)-6 and surfactant protein (SP)-D levels were restored to normal range. This is the first case report of abemaciclib-induced pneumonitis with histology findings. Since the severity of abemaciclib-induced pneumonitis ranges from mild to fatal, regular monitoring of pneumonitis with radiography, HRCT, and measurement of KL-6 and SP-D levels should be considered.

Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer.

Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate with a topoisomerase I payload that targets the human epidermal growth factor receptor 2 (HER2). T-DXd is approved for patients with previously treated HER2-positive or HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) metastatic/unresectable breast cancer (BC). In a second-line HER2-positive metastatic BC (mBC) population (DESTINY-Breast03 [ClinicalTrials.gov identifier: NCT03529110]), T-DXd demonstrated significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (12-month rate: 75.8% v 34.1%; hazard ratio, 0.28; P < .001), and in patients with HER2-low mBC treated with one prior line of chemotherapy (DESTINY-Breast04 [ClinicalTrials.gov identifier: NCT03734029]), T-DXd demonstrated significantly longer PFS and overall survival than physician's choice chemotherapy (10.1 v 5.4 months; hazard ratio, 0.51; P < .001, and 23.4 v 16.8 months; hazard ratio, 0.64; P < .001, respectively).Interstitial lung disease (ILD) is an umbrella term used for a group of diseases characterized by lung injury including pneumonitis, which can lead to irreversible lung fibrosis. ILD is a well-described adverse event associated with certain anticancer therapies, including T-DXd. An important part of T-DXd therapy for mBC consists of monitoring for and managing ILD. Although information on ILD management strategies is included in the prescribing information, additional information on patient selection, monitoring, and treatment can be beneficial in routine clinical practice. The objective of this review is to describe real-world, multidisciplinary clinical practices and institutional protocols used for patient selection/screening, monitoring, and management related to T-DXd-associated ILD.

Association between anticholinergic medication uses and the risk of pneumonia in elderly adults: a meta-analysis and systematic review.

OBJECTIVE: To conduct a meta-analysis and systematic review on the association between anticholinergic medication uses and the risk of pneumonia in elderly adults. MATERIALS AND METHODS: Medical databases were searched included PubMed, Web of Science, EBSCO and Google Scholar (up to December 7, 2022). Studies evaluating association between anticholinergic medication uses and the risk of pneumonia in elderly adults were included. Studies without available data were excluded. We made meta-analysis by using adjusted odds ratio (aOR) with 95% confidence intervals (CIs) from random-effects model. The risk of bias was assessed using ROBINS-I tool and statistical heterogeneity using the I2 statistic. Registration: INPLASY202330070. RESULTS: A total of six studies with 107,012 participants were included. Meta-analysis results showed that anticholinergic medication uses was related with an increased risk of pneumonia (aOR = 1.59; 95%CI, 1.32-1.92) and stroke-associated pneumonia (aOR = 2.02; 95%CI, 1.76-2.33). Moreover, risk estimates of pneumonia for high-potency anticholinergics (aOR = 1.96; 95%CI, 1.22-3.14) were higher than those for low-potency anticholinergics (aOR = 1.58; 95%CI, 1.27-1.97). And increased risk of pneumonia was associated with the anticholinergic medication uses within 30 days (aOR = 2.13; 95%CI, 1.33-3.43), within 90 days (aOR = 2.03; 95%CI, 1.26-3.26) and chronic use (aOR = 1.65; 95%CI, 1.09-2.51). CONCLUSIONS: The risk of pneumonia is increased in elderly adults with anticholinergic medication, especially with higher-potency anticholinergic drugs and in the initiation phase of anticholinergic medication. Clinicians should monitor their use in older patients carefully, especially when the pneumonia-related signs and symptoms are identified.

Anticholinergic medication could increase the risk of pneumonia in elderly adults.The risk of pneumonia was higher in the initiation phase of anticholinergic medication and when the older patients was medicated with higher-potency anticholinergic drugs.Clinicians should monitor anticholinergic drugs use in older patients carefully, especially when the pneumonia-related signs and symptoms are identified.