Chronic Obstructive Pulmonary Disease (COPD) and lung cancer (LC), both predominantly linked to smoking, exhibit a poorly understood relationship. Current hypotheses suggest that oxidative stress and sustained inflammation induced by cigarette smoke create a favourable environment for the development of both diseases. Repeated cycles of injury and repair seen in COPD may also contribute to the onset of Tumorigenesis. This study aims to unravel the molecular mechanisms underlying the transition from COPD to LC through a combination of in silico analyses and animal experiments. In silico study included a total of 18 BioProjects for Non-small cell lung cancer (NSCLC) and 7 BioProjects for COPD derived from the National Center for Biotechnology Information-Sequence Read Archive (NCBI-SRA). The differential gene expression analysis, enriched pathway analysis and network analysis were performed using the patients’ transcriptomic Next-generation sequencing (NGS) data from both diseases. The study suggested that the Tumor Necrosis Factor (TNF), a pro-inflammatory cytokine, as a potential link between COPD and NSCLC. In vivo experiments were performed with vitamin C-deficient guinea pigs exposed to para-benzoquinone (p-BQ), a component of cigarette smoke and quinone pollution that causes emphysematous damage, while lower doses potentially promote cellular proliferation, making it a good animal model. Histological analyses and immune-detection-based protein analyses reveal a heterogeneous distribution of p-BQ-induced oxidative stress, thereby creating distinct inflammatory states simultaneously. Biphasic activation of TNF-α plays a dual role, showing two opposing phenomena in different phases: acute, with apoptosis and chronic, with proliferation, by activating Caspase 8 and NF-κB, respectively. Gradual remodeling of tissue remodeling sheds light on pre-malignant changes in the chronic phase. As COPD and lung cancer co-exist clinically, this observation potentially contributes to the development of targeted therapies for patients with both diseases.
Asthma and COPD are chronic respiratory conditions characterised by persistent airway inflammation, elevated inflammatory biomarkers (CRP, TNF-α, IL-6, IL-10), and frequent hypomagnesaemia, which worsens disease severity despite standard treatments. This study evaluates the efficacy and safety of Magnesium glycinate (440 mg/day) as add on therapy in the management of asthma and COPD. This randomised, double-blind, placebo-controlled trial enrolled 224 adults (112 Asthma and 112 COPD) with confirmed hypomagnesemia (Serum magnesium < 1.6 mg/dL) at Arogyavaram Medical Centre, India. Participants received oral magnesium glycinate 440 mg daily (n = 112) or placebo (n = 112) for 12 months alongside standard therapy. Primary outcomes were changes in CRP, TNF-α, IL-6, and IL-10. Secondary outcomes included FEV1/FVC ratio, serum magnesium, quality of life, medication adherence, and adverse drug reactions. Mixed-effects models and t-tests were used (P < 0.05). Magnesium glycinate supplementation significantly reduced systemic inflammation and improved pulmonary function in both asthma and COPD patients compared with placebo, as demonstrated by reductions in CRP (asthma: -0.97 mg/L, 95% CI -1.34 to -0.61, P < 0.001; COPD: -3.42 mg/L, 95% CI -4.23 to -2.61, P < 0.001) and improvements in FEV1 (asthma: +0.23 L, p = 0.002; COPD: +0.19 L, p = 0.004). Alongside an increase in the anti-inflammatory cytokine IL-10 (+2.8 pg/mL, 95% CI + 0.61 to +4.99, p = 0.013) and the intervention was well tolerated with no serious adverse events compared to placebo. Adjunctive magnesium glycinate safely reduces inflammatory biomarkers, particularly CRP, in hypomagnesemic asthma and COPD patients, with stronger cytokine modulation in COPD.
N6-methyladenosine (m6A) modification is a crucial post-transcriptional regulatory mechanism for gene expression. In our previous bioinformatic analysis, we found that many m6A genes are involved in asthma pathogenesis; however, the precise regulatory mechanism has not been experimentally validated. Using an in-vitro asthma model (platelet-derived growth factor [PDGF]-BB-stimulated rat airway smooth muscle cells [AMSCs]), we validated dysregulated m6A-related genes using qRT-PCR. Functional assays (CCK-8 and wound healing assays) revealed that Igf2bp2 knockdown suppressed AMSC proliferation and migration. Integrated analysis of mRNA-sequencing (Igf2bp2-silenced AMSCs) and RIP-seq identified three asthma-associated targets: Dact1, Dixdc1, and Pdk4. Intriguingly, Dixdc1 transcripts harbored multiple m6A motifs, consistent with the RIP-seq data. Actinomycin D assays demonstrated the IGF2BP2-mediated post-transcriptional stabilization of Dixdc1 mRNA, a mechanism corroborated by both PDGF-BB-treated AMSCs and ovalbumin-induced asthmatic rats. Clinically, IGF2BP2-DIXDC1 co-expression was evident in the GEO human airway datasets and asthmatic rat tissues. Pharmacologically, resveratrol attenuated asthmatic phenotypes by suppressing this axis. Our findings delineate an m6A-dependent pathway, wherein IGF2BP2 stabilized Dixdc1 to drive airway remodeling, positioning resveratrol as a potential therapeutic agent targeting epitranscriptomic dysregulation in asthma.
Cystic fibrosis (CF) has become increasingly treatable with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-targeted therapies. However, the availability and efficacy of these treatments depend on each patient's CFTR genotype, necessitating careful follow-up to detect effective benefits. This study builds on our previous findings by applying the Optical Beta-Adrenergic Sweat Test (OBAST) as a complement to the classical sweat Cl- testing (ST) to better evaluate the restoration of CFTR activity in vivo. We quantified the sweat droplet number (SDN) and the ratio between CFTR-dependent (beta-adrenergic Cocktail-induced, C-phase) and the CFTR-independent (Methacholine-induced, M-phase) sweat rates (C/M ratio) in 128 non-CF subjects and 143 people with CF (PwCF). Among the PwCF, 39 were treated with various combinations of the CFTR modulators, including Lumacaftor/Ivacaftor (LI), Tezacaftor/Ivacaftor (TI) and/or Elexacaftor/Tezacaftor/Ivacaftor (ETI). SDN detected an earlier response to CFTR modulators, yielding lower p-values than the C/M rate ratio, particularly during ETI therapy. Thus, SDN counting provides a simpler and faster method than C/M ratio for monitoring the effects of CFTR modulators on CFTR function, without compromising sensitivity or reliability. This enables more precise tracking of drug efficacy in individual subjects. In six PwCF, who underwent at least two different CFTR-targeted therapies, we also assessed lung function and nasal potential difference (NPD) in addition to ST, SDN, and the C/M ratio. We propose OBAST as a reliable complementary tool to standard tests, especially valuable when CFTR-targeted drugs are not approved for rare CFTR genotypes, when clinical response appears limited, and/or when sweat [Cl-] results are inconclusive.
BACKGROUND:Acute respiratory distress syndrome (ARDS) is characterized by increased alveolar-capillary permeability and neutrophil-driven inflammation. Anumigilimab, a novel, fully human, monoclonal antibody, competitively antagonizes the granulocyte colony-stimulating factor (G-CSF) receptor. This trial aimed to assess its potential in modulating pulmonary inflammation induced by segmental lipopolysaccharide (LPS) challenge. METHODS:In this randomized, double-blind, placebo-controlled Phase 1b trial (NCT05653713), healthy adults were randomized 1:1 to receive a single intravenous dose of anumigilimab 0.6 mg/kg or placebo (0.9% saline), followed by LPS challenge on Day 3. Biomarkers were measured in bronchoalveolar lavage (BAL) and blood before and after LPS challenge. The primary endpoint was the percentage reduction from baseline in mean absolute neutrophil cell count in BAL following LPS challenge. Secondary endpoints included additional BAL biomarkers of neutrophilic inflammation and tissue injury. Pharmacokinetics, pharmacodynamics, and safety were also assessed. RESULTS:Participants were randomly assigned to anumigilimab (n = 23) or placebo (n = 22). LPS challenge induced expected increases in BAL neutrophils and inflammatory biomarkers, with no significant difference between groups. Target engagement was confirmed by elevated plasma and BAL G-CSF concentrations and transient reductions in peripheral neutrophil counts following anumigilimab administration. Pharmacokinetic/pharmacodynamic parameters were consistent with prior clinical data. Anumigilimab was well tolerated; mild transient neutropenia occurred in four participants treated, with no serious adverse events. CONCLUSIONS:While anumigilimab had an acceptable safety profile in healthy volunteers, and favorable pharmacokinetic/pharmacodynamic characteristics, it did not attenuate LPS-induced neutrophilic inflammation. Further preclinical investigations are warranted before advancing its clinical development in ARDS.
