Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia.

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 mikroM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor - Nomega-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-alpha and IL-1beta in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia, Hyperoxia, Airway hyperreactivity, Resveratrol, Pro-inflammatory cytokines.

Simvastatin attenuates silica-induced pulmonary inflammation and fibrosis in rats via the AMPK-NOX pathway.

BACKGROUND: Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms. METHODS: The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway. RESULTS: Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and transforming growth factor-ß1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions. CONCLUSIONS: Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.

Inconsequential role for chemerin-like receptor 1 in the manifestation of ozone-induced lung pathophysiology in male mice.

We executed this study to determine if chemerin-like receptor 1 (CMKLR1), a Gi/o protein-coupled receptor expressed by leukocytes and non-leukocytes, contributes to the development of phenotypic features of non-atopic asthma, including airway hyperresponsiveness (AHR) to acetyl-ß-methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non-atopic asthma in wild-type mice and mice incapable of expressing CMKLR1 (CMKLR1-deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3), a criteria pollutant and non-atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi-functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1-deficient as compared to wild-type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype-related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype-related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis.

Anticancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

Baicalein exerts beneficial effects in lipopolysaccharide-induced pulmonary inflammation by modulating macrophage polarization and inhibiting pyroptosis.

The disruption of the immune system by viral attack is a major influencing factor in the lethality of COVID-19. Baicalein is one of the key effective compounds against COVID-19. The molecular mechanisms regarding the anti-inflammatory properties of Baicalein are still unclear. In this study, we established LPS-induced mice to elucidate the role of Baicalein in the treatment of acute lung injury (ALI) and its potential molecular mechanisms. In vivo experiments showed that Baicalein could significantly ameliorate LPS-induced acute lung injury and reduce proteinous edema in lung tissue. In addition, Baicalein inhibited M1 macrophage polarization, promote M2 macrophage polarization, and regulate inflammatory responses. Furthermore, Baicalein could inhibit the expression of protein molecules associated with pyroptosis and mitigate the lung tissue injury. In summary, we revealed the therapeutic effects of Baicalein in acute lung injury, providing the theoretical basis for its clinical application.

The impact of formaldehyde exposure on lung inflammatory disorders: Insights into asthma, bronchitis, and pulmonary fibrosis.

Lung inflammatory disorders are a major global health burden, impacting millions of people and raising rates of morbidity and death across many demographic groups. An industrial chemical and common environmental contaminant, formaldehyde (FA) presents serious health concerns to the respiratory system, including the onset and aggravation of lung inflammatory disorders. Epidemiological studies have shown significant associations between FA exposure levels and the incidence and severity of several respiratory diseases. FA causes inflammation in the respiratory tract via immunological activation, oxidative stress, and airway remodelling, aggravating pre-existing pulmonary inflammation and compromising lung function. Additionally, FA functions as a respiratory sensitizer, causing allergic responses and hypersensitivity pneumonitis in sensitive people. Understanding the complicated processes behind formaldehyde-induced lung inflammation is critical for directing targeted strategies aimed at minimizing environmental exposures and alleviating the burden of formaldehyde-related lung illnesses on global respiratory health. This abstract explores the intricate relationship between FA exposure and lung inflammatory diseases, including asthma, bronchitis, allergic inflammation, lung injury and pulmonary fibrosis.

The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials.

OBJECTIVE: Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. METHODS: PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. RESULTS: Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). CONCLUSIONS: In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.

Nano-microflora Interaction Inducing Pulmonary Inflammation by Pyroptosis.

Antimicrobial nanomaterials frequently induce inflammatory reactions within lung tissues and prompt apoptosis in lung cells, yielding a paradox due to the inherent anti-inflammatory character of apoptosis. This paradox accentuates the elusive nature of the signaling cascade underlying nanoparticle (NP)-induced pulmonary inflammation. In this study, we unveil the pivotal role of nano-microflora interactions, serving as the crucial instigator in the signaling axis of NP-induced lung inflammation. Employing pulmonary microflora-deficient mice, we provide compelling evidence that a representative antimicrobial nanomaterial, silver (Ag) NPs, triggers substantial motility impairment, disrupts quorum sensing, and incites DNA leakage from pulmonary microflora. Subsequently, the liberated DNA molecules recruit caspase-1, precipitating the release of proinflammatory cytokines and activating N-terminal gasdermin D (GSDMD) to initiate pyroptosis in macrophages. This pyroptotic cascade culminates in the emergence of severe pulmonary inflammation. Our exploration establishes a comprehensive mechanistic axis that interlinks the antimicrobial activity of Ag NPs, perturbations in pulmonary microflora, bacterial DNA release, macrophage pyroptosis, and consequent lung inflammation, which helps to gain an in-depth understanding of the toxic effects triggered by environmental NPs.

Daphnetin alleviates silica-induced pulmonary inflammation and fibrosis by regulating the PI3K/AKT1 signaling pathway in mice.

Silicosis is a hazardous occupational disease caused by inhalation of silica, characterized by persistent lung inflammation that leads to fibrosis and subsequent lung dysfunction. Moreover, the complex pathophysiology of silicosis, the challenges associated with early detection, and the unfavorable prognosis contribute to the limited availability of treatment options. Daphnetin (DAP), a natural lactone, has demonstrated various pharmacological properties, including anti-inflammatory, anti-fibrotic, and pulmonary protective effects. However, the effects of DAP on silicosis and its molecular mechanisms remain uncover. This study aimed to evaluate the therapeutic effects of DAP against pulmonary inflammation and fibrosis using a silica-induced silicosis mouse model, and investigate the potential mechanisms and targets through network pharmacology, proteomics, molecular docking, and cellular thermal shift assay (CETSA). Here, we found that DAP significantly alleviated silica-induced lung injury in mice with silicosis. The results of H&E staining, Masson staining, and Sirius red staining indicated that DAP effectively reduced the inflammatory response and collagen deposition over a 28-day period following lung exposure to silica. Furthermore, DAP reduced the number of TUNEL-positive cells, increased the expression levels of Bcl-2, and decreased the expression of Bax and cleaved caspase-3 in the mice with silicosis. More importantly, DAP suppressed the expression levels of NLRP3 signaling pathway-related proteins, including NLRP3, ASC, and cleaved caspase-1, thereby inhibiting silica-induced lung inflammation. Further studies demonstrated that DAP possesses the ability to inhibit the epithelial mesenchymal transition (EMT) induced by silica through the inhibition of the TGF-ß1/Smad2/3 signaling pathway. The experimental results of proteomic analysis found that the PI3K/AKT1 signaling pathway was the key targets of DAP to alleviate lung injury induced by silica. DAP significantly inhibited the activation of the PI3K/AKT1 signaling pathway induced by silica in lung tissues. The conclusion was also verified by the results of molecular and CETSA. To further verify this conclusion, the activity of PI3K/AKT1 signaling pathway was inhibited in A549 cells using LY294002. When the A549 cells were pretreated with LY294002, the protective effect of DAP on silica-induced injury was lost. In conclusion, the results of this study suggest that DAP alleviates pulmonary inflammation and fibrosis induced by silica by modulating the PI3K/AKT1 signaling pathway, and holds promise as a potentially effective treatment for silicosis.

NLRP3/GSDMD mediated pyroptosis induces lung inflammation susceptibility in diesel exhaust exposed mouse strains.

BACKGROUND: Genetic diversity among species influences the disease severity outcomes linked to air pollution. However, the mechanism responsible for this variability remain elusive and needs further investigation. OBJECTIVE: To investigate the genetic factors and pathways linked with differential susceptibility in mouse strains associated with diesel exhaust exposure. METHODS: C57BL/6 and Balb/c mice were exposed to diesel exhaust (DE) for 5 days/week for 30 min/day for 8 weeks. Body weight of mice was recorded every week and airway hyperresponsiveness towards DE exposure was recorded after 24 h of last exposure. Mice were euthanised to collect BALF, blood, lung tissues for immunobiochemical assays, structural integrity and genetic studies. RESULTS: C57BL/6 mice showed significantly decreased body weight in comparison to Balb/c mice (p < 0.05). Both mouse strains showed lung resistance and damage to elastance upon DE exposure compared to respective controls (p < 0.05) with more pronounced effects in C57BL/6 mice. Lung histology showed increase in bronchiolar infiltration and damage to the wall in C57BL/6 mice (p < 0.05). DE exposure upregulated pro-inflammatory and Th2 cytokine levels in C57BL/6 in comparison to Balb/c mice. C57BL/6 mice showed increase in Caspase-1 and ASC expression confirming activation of downstream pathway. This showed significant activation of inflammasome pathway in C57BL/6 mice with ∼2-fold increase in NLRP3 and elevated IL-1ß expression. Gasdermin-D levels were increased in C57BL/6 mice demonstrating induction of pyroptosis that corroborated with IL-1ß secretion (p < 0.05). Genetic variability among both species was confirmed with sanger's sequencing suggesting presence of SNPs in 3'UTRs of IL-1ß gene influencing expression between mouse strains. CONCLUSIONS: C57BL/6 mice exhibited increased susceptibility to diesel exhaust in contrast to Balb/c mice via activation of NLRP3-related pyroptosis. Differential susceptibility between strains may be attributed via SNPs in the 3'UTRs of the IL-1ß gene.

A retrospective study of combination therapy with glucocorticoids and pirfenidone for PD-1 inhibitor-related immune pneumonitis.

Immune checkpoint inhibitor pneumonitis (ICIP) is thought to be a self-limiting disease; however, an effective treatment option does not currently exist. This study aimed to determine the clinical efficacy of combination therapy with glucocorticoids and pirfenidone for ICIP related to programmed cell death protein-1 (PD-1) inhibitors. We conducted a retrospective analysis of 45 patients with advanced non-small cell lung cancer who developed ICIP following PD-1 inhibitor and albumin-bound paclitaxel or carboplatin treatment at our hospital. The PD-1 inhibitor was discontinued, and glucocorticoids were used alone or in combination with pirfenidone to treat ICIP. The relevant clinical data of these patients were collected and analyzed. Compared with the glucocorticoid alone group, the glucocorticoid-pirfenidone group showed significant improvement in forced vital capacity (FVC), carbon monoxide diffusing capacity [%], peripheral capillary oxygen saturation, and 6-minute walk distance (P < .05). There were benefits with respect to the St. George's Respiratory Questionnaire score and the recurrence rate of ICIP, but there was no significant difference between the 2 groups (P > .05). Adding pirfenidone to glucocorticoid treatment was shown to be safe and may be more beneficial than glucocorticoids alone for improving pulmonary interstitial lesions, reversing ICIP, and preventing its recurrence.

Clinical Characteristics, Management and Prognostic Factors of Immune Checkpoint Inhibitor-Associated Pneumonia in Chinese Cancer Patients.

OBJECTIVE: To investigate the clinical characteristics, treatment methods, outcomes, and variables influencing the outcomes of checkpoint inhibitor-related pneumonitis (CIP) among Chinese cancer patients. STUDY DESIGN: Descriptive Study. Place and Duration of the Study: Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China, from January 2019 to December 2022. METHODOLOGY: Patients with CIP were inducted. Clinical data including patient characteristics, ICI protocols; and the clinical features, treatments, and outcomes of CIP were collected and analysed. RESULTS: One hundred and forty-six patients were included. Median time to onset in the CIP was 17.0 weeks (range: 0.4 - 74.7). Mild CIP and severe CIP accounted for 84.93% and 15.07% of cases, respectively. All patients with CIP received methylprednisolone treatment, with an average starting dose of 1.64 mg/kg (0.59-6.00 mg/kg), and 79 (54.11%) of them received anti-infective therapy. One hundred and thirteen (77.04%) patients had improved symptoms of pneumonia, with only 33 (22.60%) patients displaying no improvement. Multivariate analysis revealed that the severity of CIP [OR = 0.167 (95% CI 0.061-0.461), p <0.001] and the starting dose of methylprednisolone [OR = 0.314 (95% CI 0.129-0.764), p <0.001] were independent predictors of outcomes of CIP, while the use of antibiotic was not. CONCLUSION: The severity of CIP and the initial dosage of methylprednisolone administered are significant factors that impact the outcomes of CIP in Chinese cancer patients after ICI treatment. Appropriate use of glucocorticoids and antibiotics is a necessary management strategy to control CIP effectively. KEY WORDS: Immune checkpoint inhibitors, Immune-related adverse events, Checkpoint inhibitor-related pneumonitis, Glucocorticosteroids, Antibiotics, Prognostic factors.

Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real-World Patient Data.

PURPOSE: Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. METHODS: Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. RESULTS: The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. CONCLUSION: To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.

Macrophage-derived exosomal HMGB3 regulates silica-induced pulmonary inflammation by promoting M1 macrophage polarization and recruitment.

BACKGROUND: Chronic inflammation and fibrosis are characteristics of silicosis, and the inflammatory mediators involved in silicosis have not been fully elucidated. Recently, macrophage-derived exosomes have been reported to be inflammatory modulators, but their role in silicosis has not been explored. The purpose of the present study was to investigate the role of macrophage-derived exosomal high mobility group box 3 (HMGB3) in silica-induced pulmonary inflammation. METHODS: The induction of the inflammatory response and the recruitment of monocytes/macrophages were evaluated by immunofluorescence, flow cytometry and transwell assays. The expression of inflammatory cytokines was examined by RT-PCR and ELISA, and the signalling pathways involved were examined by western blot analysis. RESULTS: HMGB3 expression was increased in exosomes derived from silica-exposed macrophages. Exosomal HMGB3 significantly upregulated the expression of inflammatory cytokines, activated the STAT3/MAPK (ERK1/2 and p38)/NF-κB pathways in monocytes/macrophages, and promoted the migration of these cells by CCR2. CONCLUSIONS: Exosomal HMGB3 is a proinflammatory modulator of silica-induced inflammation that promotes the inflammatory response and recruitment of monocytes/macrophages by regulating the activation of the STAT3/MAPK/NF-κB/CCR2 pathways.

Physicochemical properties of 26 carbon nanotubes as predictors for pulmonary inflammation and acute phase response in mice following intratracheal lung exposure.

Carbon nanotubes (CNTs) vary in physicochemical properties which makes risk assessment challenging. Mice were pulmonary exposed to 26 well-characterized CNTs using the same experimental design and followed for one day, 28 days or 3 months. This resulted in a unique dataset, which was used to identify physicochemical predictors of pulmonary inflammation and systemic acute phase response. MWCNT diameter and SWCNT specific surface area were predictive of lower and higher neutrophil influx, respectively. Manganese and iron were shown to be predictive of higher neutrophil influx at day 1 post-exposure, whereas nickel content interestingly was predictive of lower neutrophil influx at all three time points and of lowered acute phase response at day 1 and 3 months post-exposure. It was not possible to separate effects of properties such as specific surface area and length in the multiple regression analyses due to co-variation.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

Corticosteroid in non-COVID-19 induced community-acquired pneumonia, a meta-analysis.

BACKGROUND: Corticosteroid treatment in non-COVID-19 induced Community-acquired pneumonia (CAP) remains inconclusive. OBJECTIVES: We aimed to assess the role of corticosteroid treatment in CAP. METHODS: We conducted a comprehensive search of online databases, including PubMed, Embase, and Cochrane, to identify articles published from January 1, 2000, to May 5, 2023. Double-blind RCTs were selected. Two authors screened studies and extracted data. The evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: We analyzed data from 12 RCTs, involving 2446 patients. Corticosteroids therapy may reduce short-term mortality in patients with severe CAP (sCAP) and shorten the hospital length of stay in patients with CAP. Furthermore, corticosteroids treatment can decrease the risk of requiring mechanical ventilation, developing septic shock and multiple organ dysfunction syndrome (MODS). There were no significant differences between the corticosteroid and control groups concerning gastrointestinal bleeding and nosocomial infection. The use of corticosteroids could increase the risk of hyperglycemia. CONCLUSION: Corticosteroid treatment for sCAP has the potential to provide benefits in reducing short-term mortality, but this conclusion necessitates more evidence. Besides, we found no evidence that strongly prevents us from using corticosteroids in patients with sCAP or those at risk of progressing to sCAP.

Crystalline silica-induced pulmonary inflammation and autoimmunity in mature adult NZBW/f1 mice: age-related sensitivity and impact of omega-3 fatty acid intervention.

OBJECTIVE: Occupational exposure to respirable crystalline silica (cSiO2) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO2 exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO2 and DHA effects in mature lupus-prone adult mice, more representative of cSiO2-exposed worker age. METHODS: Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO2 weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset. RESULTS: VEH/CON mice showed no pathology. cSiO2/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO2/CON lungs exhibited elevated cellularity, chemokines, CD3+ T-cells, CD45R + B-cells, IgG + plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects. DISCUSSION: The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO2-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO2-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice. CONCLUSION: These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.

Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management.

The advent of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of malignant solid tumors in the last decade, producing lasting benefits in a subset of patients. However, unattended excessive immune responses may lead to immune-related adverse events (irAEs). IrAEs can manifest in different organs within the body, with pulmonary toxicity commonly referred to as immune checkpoint inhibitor-related pneumonitis (CIP). The CIP incidence remains high and is anticipated to rise further as the therapeutic indications for ICIs expand to encompass a wider range of malignancies. The diagnosis and treatment of CIP is difficult due to the large individual differences in its pathogenesis and severity, and severe CIP often leads to a poor prognosis for patients. This review summarizes the current state of clinical research on the incidence, risk factors, predictive biomarkers, diagnosis, and treatment for CIP, and we address future directions for the prevention and accurate prediction of CIP.