Lung cancer remains a leading healthcare challenge due to its high mortality and incidence. To develop a new therapeutic approach, dihydroartemisinin (DHA) was combined with chrysin (CRS) to test their effects on both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cells. The results demonstrated that the DHA + CRS combination not only significantly reduced the effective concentrations of both drugs but also robustly induced apoptosis in both cancer types. Utilizing next-generation sequencing, topoisomerase II alpha (TOP2A) was identified as a critical molecular target mediating the apoptosis-enhancing effects of this combination therapy. Validation experiments, including TOP2A overexpression and siRNA-mediated silencing, confirmed TOP2A's pivotal role in the apoptotic pathway activated by DHA + CRS. Mechanistically, the combination therapy reduced TOP2A expression, leading to DNA damage accumulation (evidenced by increased γH2A.X) and p53 upregulation. This study established a novel therapeutic strategy for treating the two major lung cancer subtypes by DHA and CRS combination at lower concentrations. The discovery of TOP2A as a therapeutic target opens new avenues for drug discovery, potentially expanding the development of TOP2A-targeted therapies.
Lung ischemia-reperfusion (I/R) injury is a major driver of acute lung dysfunction after procedures such as lung transplantation, yet effective pharmacological strategies remain limited. We evaluated whether evodiamine (EVO) mitigates lung I/R injury and explored potential mechanisms. Male C57BL/6 mice underwent left pulmonary hilar occlusion (60 min) followed by reperfusion (120 min) and received EVO, the SYK inhibitor BAY61-3606, or the combination. Compared with I/R alone, treatment reduced histopathological damage, inflammatory cytokine expression, apoptosis, and ferroptosis-associated marker changes (iron overload, PTGS2 induction, and loss of GPX4/SLC7A11). EVO was associated with decreased activation of the SYK/TLR4/NLRP3 inflammasome axis, and BAY61-3606 recapitulated several protective effects. Because the mechanistic inference is based on pharmacological inhibition, these findings support—rather than definitively prove—SYK-linked TLR4/NLRP3 signaling as an important node in EVO-mediated protection. Together, the data suggest that evodiamine alleviates acute lung I/R injury in part by restraining inflammatory signaling and modulating ferroptosis-related markers.
BACKGROUND:The positive effects of modulator therapies (MT) on various symptoms have been proven. There is no clear recommendation for stopping or reducing the dose of other therapies after using modulators. However, patients may feel better and stop their other therapies. The aim of this study was to compare Medication Regimen Complexity Index (MRCI) and Treatment Complexity Score (TCS) scores of adult CF patients before and after 1 year of their MT use and also to compare them with non-MT patients. METHODS:The medications and forced expiratory volume in 1 s (FEV1) of patients using MT were recorded on the first day and after 1 year, and those non-MT were recorded at 1-year intervals. MRCI and TCS were recorded simultaneously. RESULTS:In total, 105 patients were included (48.6% MT). Dornase alfa use decreased significantly in the MT group (p < 0.001), while azithromycin use increased significantly in the non-MT group (p = 0.016). No significant change was observed in the use of other therapies. In the MT, mean (SD) MRCI and TCS decreased significantly [28.37 (10.39) vs 23.77 (10.90); p < 0.001 and 8.86 (3.37) vs 7.51 (3.29); p < 0.001]. In the non-MT, mean (SD) MRCI and TCS increased significantly [23.65 (12.86) vs 26.13 (14.68); p < 0.001, and 7.29 (4.21) vs 7.79 (4.61) p = 0.021]. A negative significant correlation was observed between MRCI (p < 0.001), TCS (p < 0.001) and FEV1% at baseline and after 1-year. CONCLUSION:A decrease in the use of inhaled therapy was observed in MT group after 1 year. Our study demonstrates that patients receiving MT exhibit a reduction in medication use, whereas those not receiving MT show an increase, suggesting that MT may contribute to decreased treatment burden without worsening clinical outcomes in CF management.
Sepsis is a severe systemic inflammatory response in which the lungs are often the first organ affected. Given the known inhibitory effects of nicotinamide N-oxide (NAMO) on inflammatory cell activation, this study sought to assess its protective function in a mouse model of acute lung damage generated by sepsis. The caecal ligation and puncture (CLP) technique was employed to induce sepsis, and 40, 80, and 160 mg/kg NAMO were given intraperitoneally. In a dose-dependent manner, NAMO dramatically reduced inflammatory cell infiltration, interstitial lung oedema, neutrophil aggregation, and macrophage activation. In lung tissues and cells, NAMO therapy decreased lipid peroxidation (MDA), increased the activities of antioxidant enzymes (CAT, GSH-Px, and T-AOC), and decreased the mRNA expression levels of proinflammatory cytokines. Western blot analysis revealed that NAMO modulates the protein levels of GPX4 and SLC7A11, thereby reducing cell death, Fe2+ accumulation, and ROS levels. Mechanistically, silencing SIRT1 attenuated NAMO-induced activation of the AKT signalling pathway, indicating that SIRT1 is required for NAMO-mediated AKT activation. Moreover, NAMO effectively mitigated sepsis-induced ferroptosis by modulating iron metabolism-related markers through the SIRT1/AKT signalling pathway. In conclusion, NAMO inhibits ferroptosis and alleviates sepsis-induced acute lung injury by activating the SIRT1-mediated AKT signalling pathway.
The clinical use of the anti-cancer drug arsenic trioxide (ATO) has been limited due to its side effects and the development of cancer cell resistance, highlighting the need for combination therapy. In this study, we optimized and characterized the combination of antifungal drug posaconazole (PCZ) and ATO in A549 lung cancer cells using single-drug monotherapy and sequential/pretreatment combination assays. In the pretreatment approach, the cells were incubated with PCZ for 6 h, followed by incubation with ATO for 48 h. MTT assay indicated that the sequential (pretreatment) combination of ATO and PCZ produced an IC50 value of 25 μmol/L, whereas PCZ and ATO alone exhibited IC50 values of 100 μmol/L and 75 μmol/L, respectively. qRT-PCR analysis showed that treatment at the IC50 concentration of ATO upregulated HMGA2 and Bcl-2 gene expression, while the combination of ATO with PCZ significantly countered these effects. Additionally, overexpression of HMGA2, VEGF, and MMP-9 indicated a high potential for invasion and metastasis, particularly at 75 μmol/L ATO, as demonstrated by wound healing and transwell invasion assays. In contrast, the pretreatment combination showed high efficacy in inducing cytotoxicity in lung cancer cells with minimal risk of invasion and metastasis. The results indicated that this enhanced cytotoxicity occurs through apoptosis induction and modulation of the Hedgehog signaling pathway via targeting SMO and Gli1. Furthermore, flow cytometry and colony formation assays revealed that PCZ attenuates and reduces the apoptotic/necrotic effects of ATO. In conclusion, PCZ synergistically and effectively reduces the adverse cytotoxic effects of ATO in lung cancer cells, providing a promising new therapeutic strategy for lung cancer treatment.
Chronic airway diseases (CAD), including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis, are increasingly recognized as heterogeneous and overlapping syndromes that share treatable biological and clinical characteristics. The Treatable Traits (TT) approach is a precision medicine framework that transcends diagnostic labels. It identifies and targets modifiable pulmonary, extrapulmonary, and behavioral characteristics in each patient. Biomarkers are central to this paradigm, translating latent endotypes into measurable traits that inform diagnosis, treatment selection, and longitudinal monitoring.This review synthesizes contemporary evidence on the role of biomarkers in implementing the TT model across CAD. Peripheral and airway biomarkers, including blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and sputum cell profiles, enable the identification of type 2 inflammatory traits and the prediction of corticosteroid or biologic responsiveness. Imaging and quantitative computed tomography metrics extend trait definition to structural and functional domains. Meanwhile, multi-omic and microbiome signatures reveal the molecular endotypes that underpin disease heterogeneity. Canonical examples include BEC predicting the benefit of inhaled corticosteroids in COPD and FeNO indicating steroid responsiveness in asthma. Additionally, emerging data suggest that rapid trait identification during acute exacerbations may facilitate targeted biologic therapy, extending precision care into acute management contexts.Integrating biomarker-guided assessment with individualized therapy redefines the management of CAD by offering a pathway toward biologically precise, dynamically adaptive care. Continued research should focus on standardizing biomarker thresholds, validating composite panels, and translating omic and imaging discoveries into routine clinical tools to optimize outcomes across the chronic airway disease spectrum.
Idiopathic pulmonary fibrosis is a progressive interstitial lung disease associated with poor prognosis and high mortality rate. It is a chronic irreversible lung disorder, mainly characterized by matrix stiffening. This study aims to investigate the therapeutic potential of targeting ELK-1 transcription factor and mechanosensitive MDM4 receptor using Ivabradine (IVA), an HCN channel blocker, in bleomycin (BLM)-induced pulmonary fibrosis (PF) rat model. Total, differential cell counts and LDH activity were assessed in bronchoalveolar lavage fluid. Pulmonary levels of MDA, GSH, IL-1β, α-SMA, COL1A1, ELK-1, MDM4, p-53, caspase-3, cleaved caspase-3, and CX3CL-1 were measured. Our study demonstrated that IVA induced a marked decrease in MDA and increase in GSH levels. Also, rats treated with IVA revealed a significant reduction in inflammation scores, LDH, IL-1β, α-SMA and COL1A1 levels. IVA-treated group showed a marked downregulation of MDM4 and ELK-1 along with significant upregulation of p-53, caspase-3, cleaved caspase-3, and CX3CL-1 levels when compared to BLM-induced PF group. In conclusion, these findings highlight the therapeutic potential of IVA in the treatment of pulmonary fibrosis. The antifibrotic effects of IVA in the bleomycin-induced rat model may be attributed to restoring redox balance, alleviation of aberrant inflammatory response, sensitizing lung myofibroblasts to apoptosis and promoting their clearance by macrophages.
BACKGROUND:Oral selexipag, a prostacyclin receptor agonist, has been shown to delay pulmonary arterial hypertension (PAH) progression and reduce the risk of hospitalization for PAH. To ensure optimal patient outcomes with selexipag, careful treatment titration and expected side effect (SE) management are required. This study aimed to obtain expert consensus on the appropriate management of patients with PAH treated with selexipag. METHODS:United States (US) healthcare professionals (N = 17, 11 physicians; 5 nurse practitioners; 1 registered nurse) participated in this modified-Delphi panel comprising two online surveys and a consensus meeting. Consensus was defined as ≥80% panelists agreeing using a 9-point Likert scale. RESULTS:Panelists prescribed selexipag according to FDA label recommendations to patients with PAH. Panelists acknowledged considerations prompting adjustment in titration speed, agreeing that individual maximum dose is based on SE tolerability. It was agreed that the duration of SEs is variable and patient-specific, however, SEs often become manageable over time. Panelists identified methods for managing SEs, agreeing this should be proactive. Panelists highlighted the importance of communicating with patients to set expectations, to enhance engagement and adherence. Panelists agreed that treatment initiation, titration, and SE management should be individualized to suit each patient, with decision-making primarily based on patient characteristics and treatment preference. DISCUSSION:This panel provided expert opinions on the clinical use of and best practices for treatment titration and management of expected SEs for oral selexipag. Insights are valuable for developing standardized clinical guidelines and best practices, as well as ensuring personalized treatment to improve patient care.
Background The coexistence of asthma and chronic obstructive pulmonary disease (COPD), known as asthma-COPD overlap (ACO), presents unique diagnostic and therapeutic challenges. Although biological therapies such as Mepolizumab and Dupilumab have transformed the management of severe eosinophilic asthma, their role in ACO remains poorly defined due to the exclusion of this phenotype from most clinical trials. Methods This retrospective observational study aimed to evaluate the real-world effectiveness of Mepolizumab and Dupilumab in patients with ACO compared to those with severe uncontrolled asthma (SUA). We included 212 patients treated in a specialized asthma unit between 2017 and 2024, all with at least 12 months of follow-up. Treatment response was assessed using clinical tools (EXACTO scale and SEPAR-REMAS criteria). Results Among Mepolizumab-treated patients (ACO n = 10; SUA n = 132), those with ACO had significantly lower baseline FEV1 and lower rates of good/complete response (14.2% vs. 60%, p < 0.03) and clinical remission (0% vs. 20.9%). In the Dupilumab group (ACO n = 10; SUA n = 60), ACO patients showed lower baseline ACT scores and FEV1, with reduced response rates (25% vs. 55%) and no clinical remission, although differences were not statistically significant. Despite limited power due to small ACO sample sizes, the magnitude of these differences suggests a clinically relevant reduction in biologic effectiveness in ACO. Conclusion These findings emphasize the urgent need for dedicated studies in ACO, a population with a high disease burden and limited treatment guidance. Individualized therapeutic approaches should be prioritized until robust clinical trial data becomes available.
Staccato alprazolam (STAP) is a hand-held device that can provide rapid systemic delivery of alprazolam via pulmonary inhalation. UP0099/NCT04802746, a phase 1, randomized, double-blind, placebo-controlled trial, evaluated pulmonary safety of two consecutive doses of STAP administered 72 h apart (days 1, 4). Part A evaluated STAP 1 mg and 2 mg vs. placebo in a three-way crossover design in healthy adults. Part B evaluated STAP 2 mg vs. placebo in a two-arm parallel-group design in adults with mild asthma. In Part A (n = 30 randomized) on day 1, mean change from baseline in forced expiratory volume in 1 s (FEV1) showed a statistically significant decrease vs. placebo at 5 min postdose for STAP 1 mg and 5/20 min for STAP 2 mg. On day 4, there were no statistically significant negative changes from baseline in FEV1. Respiratory treatment-emergent adverse events (TEAEs) were reported by 8/29 and 12/29 participants on STAP 1 mg/2 mg, respectively (day 1), and 8/29 and 9/28 (day 4) (placebo: 0). In Part B (n = 25 placebo, n = 23 STAP) on days 1 and 4, mean change from baseline in FEV1 showed a statistically significant decrease for STAP 2 mg vs. placebo at 5/20 min and 6 h postdose. Respiratory TEAEs were reported by 16/23 participants on STAP 2 mg on day 1, 15/22 on day 4 (placebo: 0). Most respiratory TEAEs were mild in intensity. No evidence of clinically relevant airway obstruction or respiratory TEAEs indicative of bronchospasm with STAP were observed. Two doses of STAP (1 mg/2 mg) administered 72 h apart were well tolerated in healthy participants and those with mild asthma.
IPF is a chronic, progressive interstitial lung disease characterized by irreversible lung scarring, leading to exertional dyspnea and a gradual decline in pulmonary function. Its pathogenesis involves multiple mechanisms, including chronic inflammation, aberrant cytokine signaling, and alveolar epithelial injury. Currently, IPF remains incurable, and treatment primarily aims to slow disease progression and improve survival. This paper systematically reviews recent clinical trials of novel IPF drug therapies that have demonstrated promising efficacy, aiming to inform future drug development.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by aberrant tissue remodeling and excessive deposition of extracellular matrix components. Emerging evidence underscores the critical role of the immunometabolism in the pathogenesis of IPF, highlighting how dysregulated metabolic pathways modulate immune responses and contribute to fibrotic progression. Key molecular regulators such as PPARG (peroxisome proliferator activated receptor gamma) and SPP1 (secreted phosphoprotein 1), along with signaling pathways including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor 1-alpha (HIF-1α), orchestrate immune cell polarization, fibroblast activation, and extracellular matrix production. These insights reveal promising therapeutic targets at the intersection of metabolism and immunity. This review synthesizes current findings on immunometabolism interactions in IPF, emphasizing the potential of metabolic reprogramming and immune modulation as novel treatment strategies. Despite substantial advances, significant challenges persist in elucidating the precise mechanisms underlying these interactions and translating preclinical insights into effective clinical interventions. Future research should prioritize the identification of actionable metabolic biomarkers, refinement of molecular targets, and development of personalized therapeutic approaches. Addressing these gaps may pave the way for innovative therapies capable of halting or even reversing fibrosis, ultimately improving outcomes for patients with IPF.
Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, with clinical manifestations, disease progression, and response to therapy varying among individuals. This effect is mainly caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. In recent decades, other genes and their allelic variants, beyond CFTR mutations, have been proposed as genetic modifiers of CF phenotype. For instance, different polymorphic β2-adrenergic receptor (β2AR) polymorphic variants have been reported in CF individuals and appear to influence correct receptor function. β2AR belongs to the βAR family, which includes three subtypes: β1AR, β2AR, and β3AR. These receptors are crucial G protein-coupled receptors (GPCRs) expressed in various cell types and serve as key modulators of cAMP production, making their function particularly relevant in CF pathophysiology. β2AR is abundantly expressed in airway epithelial and smooth muscle cells, and studies revealed that it plays a crucial role in modulating CFTR activity and smooth muscle contractility through cAMP signaling. For these reasons, β2-agonists are widely used in clinical healthcare to treat patients with obstructive airway disorders, including CF. Emerging evidence has also supported a role for β3AR, which is expressed in the canine and human bronchial epithelium and have been reported to enhance ciliary motility and regulate CFTR function, making it a potential therapeutic target in CF.
Icaritin, a bioactive phytomolecule derived from Epimedium flavonoids (EFs), has been shown to have anti-inflammatory, anti-proliferative, and pro-apoptotic properties. However, its potential mechanisms in asthma airway inflammation have not been elucidated. In this study, Ovalbumin (OVA)-induced asthma mouse model and human bronchial epithelial cells (BEAS-2B) were used to illustrate the effects and mechanisms of Icaritin on airway inflammation. Specific airway resistance (sRAW) was used to detect the airway hyperresponsiveness (AHR). Hematoxylin-eosin (H&E) and periodic acid schiff (PAS) were used to detect the pathological changes. Bronchoalveolar lavage fluid (BALF) was used to detect the airway inflammatory cells. Serum and supernatants were used to detect the cytokines. Immunohistochemistry (IHC) and western blotting were used to detect the expression of TLR4, p-65, p-p65, IκBα, and p-IκBα. Cell Counting Kit-8 (CCK-8) was used to detect the cell viability. Icaritin suppressed AHR, attenuated eosinophilic infiltration and mucus hypersecretion, and significantly reduced the levels of OVA-specific cytokines in asthmatic mice. Moreover, Icaritin inhibited TLR4 expression, decreased phosphorylation of IκBα, and reduced NF-κB p65 activation in lung tissue of asthmatic mice. Further mechanistic studies showed that Icaritin reduces TLR4-induced inflammatory factor expression and blocks TLR4-activated NF-κB pathway in BEAS-2B cells. These findings demonstrate for the first time that Icaritin suppresses airway inflammation in asthma by inhibiting the TLR4/NF-κB pathway, suggesting its potential as a therapeutic agent for asthma.
BACKGROUND:To investigate whether FTO-mediated N6-methyladenosine (m6A) demethylation affects the proliferative/apoptotic phenotype of mouse pulmonary artery smooth muscle cells (PASMCs). METHODS:The hypoxia model of PASMCs was established to examine changes in FTO protein expression and m6A modification levels. Cell transfection, m6A expression profiling, mRNA stability testing, and protein-RNA binding assays were used to explore the effects of FTO and its downstream target, CACNA1d, on PASMC proliferation and apoptosis. RESULTS:Hypoxia downregulated FTO expression and upregulated m6A modification, leading to enhanced proliferation and reduced apoptosis in PASMCs. Overexpression of FTO reversed these effects, while FTO knockdown under normoxia mimicked the hypoxia-induced "pro-proliferative and anti-apoptotic" changes. Genome-wide m6A profiling identified CACNA1d as a potential downstream target of FTO, with YTHDC1 acting as the m6A reader. FTO binds CACNA1d mRNA and reduces its stability via m6A demethylation. CACNA1d knockdown partially mitigated the hypoxia-induced changes in PASMC proliferation and apoptosis. In addition, when the hypoxic culture was returned to normoxic culture, the level of apoptosis in PASMCs was restored to the pre-hypoxic level, and this was still observed after the overexpression of FTO or knockdown of CACNA1d expression. CONCLUSION:FTO downregulation in hypoxic PASMCs increases m6A modification, promoting proliferation and inhibiting apoptosis by enhancing CACNA1d expression.
OBJECTIVE:Antibiotics are commonly administered during acute exacerbations of chronic obstructive pulmonary disease (AECOPD) to manage infections and alleviate their symptoms. However, their use may result in adverse drug events (ADEs), potentially compromising patient safety and treatment effectiveness. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) provides valuable data for identifying such risks. This study aimed to analyze FAERS data to detect ADE signals associated with antibiotic use in patients with AECOPD, thereby supporting safer clinical practices. METHODS:Five antibiotics frequently used in AECOPD management, azithromycin, moxifloxacin, meropenem, gentamicin, and minocycline, were selected for analysis. FAERS data from January 1, 2004, to July 30, 2024, were extracted using OpenVigil 2.1 platform. Duplicate and incomplete reports were excluded. ADEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA). Data mining techniques, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to identify statistically significant ADE signals. RESULTS:111,179 ADE reports involving 100,602 patients were identified, including azithromycin (41,241 reports), moxifloxacin (46,770), meropenem (5,904), gentamicin (4,142), and minocycline (13,122). Serious events comprised 30.6 %-47.1 % of the reported ADEs, with the lowest proportion observed for meropenem, and the highest proportion observed for gentamicin. Females accounted for 57.0 % of the cases with known gender. Data mining identified 1946 ADE signals, including novel associations such as infectious chondromatosis (azithromycin), hemorrhagic obstructive retinal vasculitis (moxifloxacin), elevated procalcitonin (meropenem), Bartter syndrome (gentamicin), and nodular polyarteritis (minocycline). CONCLUSION:This study identified novel ADE signals associated with antibiotics used in AECOPD treatment, highlighting the importance of continuous pharmacovigilance. Clinicians should be informed of the emerging safety concerns to enhance patient care.
In this study, we investigated the functional interplay between bradykinin receptors and the transient receptor potential vanilloid-1 (TRPV1) channel in a mouse model of acute lung injury (ALI) induced by lipopolysaccharide (LPS). Lung and bronchoalveolar lavages were collected at 6 and 24 h after the induction of ALI and evaluated for changes in body weight, inflammatory marker levels, lung injury, and TRPV1 expression. Pretreatments with a TRPV1 antagonist (capsazepine) or B1 and B2 receptor antagonists, i.e., DALBK and HOE 140, respectively, were evaluated in this ALI mouse model. The histological score revealed higher levels of lung injury in mice treated with LPS (5 and 10 mg/kg), assessed at both 6 and 24 h, compared to the vehicle-treated group. A loss of body weight was observed within 24 h of ALI induction. Furthermore, collagen deposition, pulmonary oedema, leukocyte influx, and increased cytokine levels were also observed following LPS administration. Pretreatment with capsazepine, DALBK, or HOE 140 not only reversed all inflammatory parameters but also prevented the increased expression of TRPV1 observed in the lungs of mice subjected LPS-induced ALI. Our data suggest that, following LPS-induced ALI, bradykinin activates both B1 and B2 receptors associated with the subsequent activation of TRPV1. These findings suggest that bradykinin can activate both B1 and B2 receptors, which may contribute functionally to TRPV1 upregulation and activation during LPS-induced ALI. This novel pathway appears to sustain inflammation, offering a new therapeutic target for ALI and ARDS.
Clinical remission (CR) has emerged as a potential therapeutic goal in patients with severe asthma eligible for biologic agents. However, its impact on long-term outcomes in asthma patients managed with maintenance inhaler therapy remains unclear. In this retrospective cohort study, we evaluated adult asthma patients on maintenance inhalers to investigate the long-term outcomes associated with achieving CR. CR was defined as at least one year without exacerbations, well-controlled symptoms, no use of systemic corticosteroids, and stable lung function, assessed two years after asthma diagnosis. We compared the trajectory of forced expiratory volume in 1 s (FEV1) and the annual rate of exacerbations between CR and non-CR groups in a 1:1 propensity score-matched population. Among 549 patients followed for a median of 7 years, 88 (16 %) met the criteria for CR. After matching, 76 patients were included in each group. Compared to the non-CR group, the CR group showed a significantly lower proportion of patients with annual FEV1 decline exceeding 60 mL (8.6 % vs. 25 %, P = 0.010). A linear mixed-effects model showed that the CR group had a significantly slower rate of FEV1 decline, with an annual difference of 32.7 mL (95 % CI 6.7 to 58.7; P = 0.014) compared with the non-CR group. The CR group also had a lower annual rate of moderate-to-severe exacerbations (0.17 events/year [IQR 0, 0.37] vs. 0.42 events/year [IQR 0, 1], P = 0.007). In conclusion, achieving CR in asthma patients receiving maintenance inhaler therapy was associated with a slower decline in lung function and fewer exacerbations. These findings support the potential role of CR as a long-term therapeutic goal.
Though cigarette smoke (CS) is primary risk factor for Chronic obstructive pulmonary disease (COPD), rising air pollution and higher concentrations of particulate matter (PM2.5) in ambient air contribute substantially to COPD cases, particularly in smokers. However, the pathogenesis of COPD upon dual exposure to CS and PM2.5 is not entirely known. Therefore, the impact of combined exposure to CS (9 cigarettes/day for 4 days) and PM2.5 (single dose of 50 μg) on COPD pathogenesis was examined using mouse model in order to understand the key players behind the process. The data suggest that single exposure to PM2.5 in CS pre-exposed mice triggered a strong inflammatory response, marked by switch from macrophage to neutrophilic inflammation, leading to severe deterioration in lung function compared to single hits. Furthermore, combined exposure led to robust increase in the levels of pro-inflammatory cytokines (G-CSF/KC/MCP-1/TNF-α/IL-1β/IL-6) in BALF as compared to the respective individual exposure. Interestingly, Oleanolic acid (OA) treatment protects against CS + PM2.5-induced COPD-like pulmonary inflammation potentially by exerting antioxidant properties as reflected by data on BALF inflammatory cells, particularly neutrophils and various oxidative stress markers such as ROS/LPO/GSH/SOD/Catalase in lung tissue. Suppressed inflammation was associated with downregulation of gene expression of pro-inflammatory factors namely IL-1β, TNF-α, MIP-2 and normalization of proteinase-antiproteinase balance by downregulating gene expression of MMP-9 with simultaneous upregulation of its inhibitor TIMP-1. Reduced inflammatory response upon OA treatment correlates well with improved lung function. Overall, PM2.5 exposure flares up the CS-induced lung inflammation linked to COPD, which is effectively ameliorated by OA.
BACKGROUND:Biologics for asthma and related conditions target distinct immunologic pathways but may have differential effects on glucose metabolism. Emerging real-world evidence suggests a need to evaluate potential associations with diabetes mellitus (DM) and related metabolic adverse events (AEs). OBJECTIVE:To assess the disproportionality of DM and other metabolic AEs associated with six biologics approved for asthma and related conditions using data from the FDA Adverse Event Reporting System (FAERS). METHODS:Reported odds ratios (RORs) were calculated for metabolic events and DM for omalizumab, mepolizumab, benralizumab, reslizumab, dupilumab, and tezepelumab, comparing drug-specific AE profiles against the FAERS background. RESULTS:Omalizumab (ROR: 6.10) and benralizumab (ROR: 4.88) exhibited significant disproportionality regarding diabetes AEs, with mepolizumab also demonstrating an elevated ROR (2.80). For metabolic AEs, mepolizumab (ROR: 3.57) and omalizumab (ROR: 2.94) had the highest signals. Dupilumab showed the lowest RORs for both diabetes (0.10) and metabolic AEs (0.21). CONCLUSION:This FAERS-based analysis identified a potential pharmacovigilance signal for DM associated with several biologics used to treat asthma and related conditions, most notably omalizumab and benralizumab. Similar patterns were observed for metabolic AEs, which reinforces the need for post-marketing studies and clinical awareness in patients with or at risk for metabolic disorders.
