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Journal articleWang M, He Y, Hu H, et al., 2026, , Redox Rep, Vol: 31
BACKGROUND: Fatty acid oxidation (FAO) is implicated in lung diseases, but its role in bronchial asthma is not fully understood. We investigated its effect on airway epithelial barrier integrity. METHODS: Using a house dust mite (HDM)-induced murine asthma model and HDM, IL-4, IL-13, or TNF-α stimulated human primary bronchial epithelial cells (BECs) and bronchial epithelial (Beas-2b) cells, we modulated FAO with L-carnitine (agonist) and Etomoxir (inhibitor). BECs and Beas-2b cells were infected with lentivirus-mediated CPT1A shRNA prior to stimulation. Barrier function, mitochondrial oxidative stress, inflammation, and metabolism were assessed. RESULTS: FAO level in lungs negatively correlated with increased inflammation and tissue injury in HDM-induced asthmatic mice (all p < 0.05), while positively regulating tight junction protein expression. In BECs and Beas-2b cells, Etomoxir treatment and CPT1A knockdown exacerbated the impairment of FAO caused by various stimulants (all p < 0.05). Furthermore, FAO negatively regulated HDM/cytokine-induced epithelial barrier damage, hyperactive inflammatory response, and mitochondrial dysfunction in Beas-2b cells (all p < 0.05). In contrast, treatment with L-carnitine significantly alleviated these pathophysiological features in both in vivo and in vitro models. CONCLUSION: FAO plays a protective role in the occurrence and development of asthma by maintaining airway epithelial cell homeostasis and barrier function.
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Journal articleVassileva SM, Khamas SS, Dyhre-Petersen N, et al., 2026, , Respir Med, Vol: 262
Volatile organic compounds (VOCs) in exhaled breath reflect biological processes in the lungs. Exploring VOC profiles in severe asthma patients starting biologics may reveal treatment-related biological changes over time. This study aimed to assess the performance and feasibility of applying a sparse partial least squares-discriminant analysis (sPLS-DA) analytical approach in detecting longitudinal changes in exhaled VOCs of patients with severe asthma initiating biologic treatment. Exhaled breath was collected in the 3狼R-ABC study, a multicenter observational prospective cohort study, at baseline and 4 months after starting biologics (benralizumab or dupilumab). VOCs were trapped on thermal desorption tubes and analyzed by gas chromatography-mass spectrometry. Paired sPLS-DA was used to distinguish baseline from post-treatment VOC profiles, and Kendall rank correlation assessed associations with clinical parameters at baseline. Data from two sites (Amsterdam and Copenhagen) were available of 25 severe asthma patients. The sPLS-DA resulted in a model containing five VOCs (methyl isobutyl ketone, 2-ethyl-1-hexanol, 5-methyl octadecane, 2-methylundecane and 1,1'-oxybis(decane)) with an area under the receiver operating characteristic curve of 0.89 (95% confidence interval: 0.79-0.99) for distinguishing baseline and 4 months post treatment. At baseline, a positive correlation was observed between 2-ethyl-1-hexanol and asthma control (Asthma Control Questionnaire); τ=0.40, p<0.01. A negative correlation was found between 1,1'- oxybis(decane) and blood eosinophil counts (τ=-0.30, p=0.04). Based on our results, the proposed analytical approach appears feasible for analyzing longitudinal data in patients with severe asthma initiating biologics. Further validation in larger cohorts is warranted to confirm robustness and generalizability.
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Journal articleWu WW, Wang J, Ma WAQ, et al., 2026, , Respirology
BACKGROUND AND OBJECTIVE: Cardiovascular disease (CVD) is a prevalent comorbidity in asthma, yet its impact on clinical outcomes across disease states remains poorly characterised. METHODS: We analysed data from two independent prospective cohorts. Cohort I comprised 1058 stable asthma patients (CVD: n = 107; non-CVD: n = 951) followed for 12 months to assess asthma exacerbations. Cohort II comprised 825 patients hospitalised for an acute exacerbation (CVD: n = 233; non-CVD: n = 592). Missing data were handled by multiple imputation, and the CVD and non-CVD groups were balanced using propensity score overlap weighting. Associations were estimated using negative binomial, gamma, and logistic regression. Mediation and dominance analyses were performed as exploratory analyses. RESULTS: Patients with CVD exhibited greater airflow obstruction and a predominantly non-T2 inflammatory profile characterised by increased neutrophilic inflammation. White blood cells, neutrophils, and monocytes partially mediated the association between CVD and lower FEV1/FVC ratio, while monocytes additionally mediated the association between CVD and severe exacerbations. In Cohort I, CVD was independently associated with severe exacerbations (adjusted IRR = 1.96, 95% CI (1.12, 3.44)), hospitalisations, and emergency visits. In Cohort II, CVD was associated with longer hospital stay (adjusted IRR = 1.14, 95% CI (1.01, 1.30)) and higher direct costs, with stroke and coronary heart disease as leading contributors to prolonged stay. CONCLUSION: CVD is independently associated with worse clinical outcomes across the asthma disease spectrum. These findings support recognition of CVD as an important treatable trait in asthma and highlight the need for integrated cardiopulmonary management.
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Journal articleDunne OM, Fulton CR, Griffin CS, et al., 2026, , ERJ Open Research, Pages: 01356-2026
<jats:p>The pathophysiology of refractory chronic cough (RCC) and the aetiology of associated cough hypersensitivity syndrome remains unclear, partly due to the absence of a suitable disease-specific sensory neuronal model. This study was designed to investigate whether induced pluripotent stem cell (iPSC)-derived sensory neurons (iPSC-Ns) from patients with RCC exhibit distinct phenotypic characteristics when compared to those from healthy controls (HC).</jats:p> <jats:p>Peripheral blood samples obtained from patients with RCC and HC were reprogrammed to iPSCs and subsequently differentiated into sensory neurons using defined culture conditions over 40days. The neurogenic differentiation and functional characteristics of the iPSC-Ns were confirmed using molecular assays, live cell calcium mobilisation assays and patch clamp recordings. Transcriptomic differences between RCC and HC derived iPSC-Ns were assessed by RNA-sequencing.</jats:p> <jats:p>Successful differentiation of iPSC-Ns from iPSCs was observed as cells acquired a neuronal morphology, neuronal gene expression (peripherin), the neuronal marker β3-tubulin, and functional sodium channels. TRPV1 and P2X3 responses were heightened in RCC derived iPSC-Ns compared to HC with responses to capsaicin or αβmeATP blocked by the antagonists capsazepine or AF-353 respectively. Differential expression of 853 genes was noted between RCC- and HC-derived iPSC-Ns, with genes enriched in RCC-derived iPSC-Ns associated with sensory neuronal functions.</jats:p> <jats:p>Generation of an iPSC derived neuronal model from patients with RCC is feasible and offers insights into the pathophysiology of cough hypersensitivity syndrome. Heightened purinergic responses observed in iPSC-Ns from RCC compared to HC are consistent with the concept of cough hypersensitivity and support targeting P2X3 receptors as a therapeutic strat
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Journal articleJosa-Culler矇 A, Koch S, Demeyer H, et al., 2026, , ERJ Open Research, Pages: 00813-2026
<jats:sec> <jats:title>Background</jats:title> <jats:p>Regular walking activity can improve the prognosis in people with chronic obstructive pulmonary disease (COPD). However, its benefit may be reduced when living in highly polluted areas.</jats:p> </jats:sec> <jats:sec> <jats:title>Aim</jats:title> <jats:p>To assess the combined effects of walking activity and air pollution on the rate of moderate-to-severe exacerbation in COPD.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> This prospective cohort study included 262 people with COPD from five European countries (United Kingdom, Spain, Belgium, Switzerland, Greece). Regular walking activity amount (walking bout step count, walking duration) and intensity (90thpercentile (P90) and average walking speed) was measured at baseline for seven days <jats:italic>via</jats:italic> single wearable devices. Residential concentrations of particulate matter<2.5µm (PM <jats:sub>2.5</jats:sub> ), black carbon (BC), nitrogen dioxide (NO <jats:sub>2</jats:sub> ) and ozone (O <jats:sub>3</jats:sub> ) were estimated using land-use regression models for the previous two years. Moderate-to-severe exacerbations over a two-year follow-up were obtained from medical records and paper diaries. We estimated the interaction between walking activity and air pollution on long-term exacerbation rate with multivariable mixed-effects negative binomial models. </jats:p>
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Journal articleMorelli T, Purcell M, Panaguiton J, et al., 2026, , Thorax, Vol: 81, Pages: 988-998
BACKGROUND: Respiratory syncytial virus (RSV) causes substantial winter pressure on adult services. In the UK, RSV vaccination currently targets adults aged ≥75 years and care home residents; it remains uncertain whether this age criterion alone meaningfully discriminates risk of poor outcome among adults hospitalised with RSV. METHODS: We pooled three UK hospital cohorts (one prospective, two retrospective) of adults admitted with acute respiratory infection (ARI) and PCR-confirmed RSV. The primary outcome was intensive care unit/high dependency unit (ICU/HDU) admission or all-cause mortality within 60 days. Prespecified predictors (age, sex and comorbidities) entered a least absolute shrinkage and selection operator (LASSO) penalised logistic regression; selected variables were refitted using standard logistic regression. Discrimination, calibration and decision-analytic performance were assessed using 1000-bootstrap internal validation and decision-curve analysis. RESULTS: Among 334 adults, 37 (11.1%) experienced the primary outcome. An age-only rule mirroring current UK vaccine age-eligibility (≥75 years) demonstrated only modest discrimination (optimism-adjusted area under the receiver operating characteristic curve (AUC) 0.58, 95% CI 0.48 to 0.65) and a compressed distribution of predicted risks. A four-predictor model-including age, COPD, active/previous cancer and dementia-achieved higher discrimination AUC (0.77 (0.69 to 0.85)), a wider spread of predicted risks and the greatest net benefit across clinically plausible escalation thresholds (5-20%). CONCLUSIONS: In adults hospitalised with RSV-associated ARI, simple age-based heuristics-including the UK ≥75-year threshold-showed only modest ability to discriminate risk of ICU/HDU admission/60-day mortality once hospitalised. Comorbidity-inclusive approaches may provide more informative hospital-level risk stratification and warrant evaluation in future RSV vaccine-effectiveness and outcome st
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Journal articleRowbotham NJ, Jeanpierre M, Bush A, et al., 2026, , Thorax, Vol: 81, Pages: 1017-1019
Protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a tyrosine phosphatase involved in T cell receptor signal transduction and cytokine response. Loss of function variants have previously been linked with immune mediated diseases such as inflammatory bowel disorders, rheumatoid arthritis and type 1 diabetes. We present a case of childhood interstitial lung disease with a newly identified pathogenic (PTPN2) gene variant in a boy aged 4 years.
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Journal articleButton B, Edwards A, Chung KF, et al., 2026, , Sci Rep, Vol: 16
Heat wave burden is rapidly rising and exacerbating human respiratory illnesses. Yet, how to protect human airways, short of deep and sustained reductions in greenhouse gas emissions, remains unclear. Here, we find, by theoretical, in vitro experimental, and human clinical studies, that heatwave exposure elevates risks of cough hypersensitivity, which can be reversed by the inhalation of alkaline hypertonic divalent salts (HDS). We find that upper-airway mucosal collapse occurs on exposing human bronchial epithelial (HBE) cell cultures to an arid heatwave atmosphere (35 ºC, 30% RH), resulting in elevated (p < 0.05) expression of genes associated with cough hypersensitivity, including TRPV4, PIEZO1, P2X3R and ENaC subunit proteins α and β (SCNN1A, SCNN1B) post 8 h-while not post 3 h-relative to baseline. We find by continuum mechanic analysis, and confirm experimentally in HBE cell cultures, that airway mucosal collapse reverses for greater than 3 h post deposition of HDS (magnesium) aerosols with pH above the cysteine pKa (approximately 8.3), while not at pH 7 or 8, nor by hypertonic saline at any pH. In a randomized, double-blind, placebo controlled study (REACH) in Riyadh, Saudi Arabia, HDS pH 9 aerosols reduced daily cough bout rate relative to placebo by 59% (p = 0.03) after 2 weeks treatment (n = 6), while, in a preceding RCC study, HDS pH 8 aerosols reduced cough bout rate by only 4% (p > 0.05) (n = 7). Alkaline HDS aerosols may be protective of human respiratory health with global warming.
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Journal articleMassenet T, Abuhelal S, Rastegar L, et al., 2026,
Rapid screening of aldehydes by SICRIT-HRMS: understanding ionization behavior in breath analysis
, ACS Measurement Science Au, ISSN: 2694-250XExhaled breath aldehydes represent clinically relevant biomarkers of oxidative stress and lipid peroxidation, yet their reliable online detection remains analytically challenging due to their trace concentrations, chemical reactivity, and structural similarity. This study highlights Soft Ionization by Chemical Reaction in Transfer coupled to high-resolution cyclic ion mobility mass spectrometry (SICRIT-cIMS-HRMS) for the direct detection and characterization of 16 clinically relevant volatile aldehydes in exhaled breath.A controlled offline spiking methodology using Tedlar® sampling bags was developed, enabling systematic investigation of ionization behavior under realistic breath matrix conditions. Comparative analysis in ultra-pure nitrogen and exhaled breath matrices revealed that SICRIT preferentially generates protonated [M+H], dehydrated [M+H−HO], and oxidation-derived species, with exhaled breath shifting ionization patterns toward oxygen-containing adducts. Ionization competition from N,N-dimethylacetamide, a Tedlar® bag contaminant, was identified and mitigated through standardized bag usage protocols.Quantitative assessment demonstrated good linearity (R² ≥ 0.99 for 13 aldehydes), with LOD values ranging from 1.33 to 25.13 ppbv. Intra-day variability was low across all adducts (CV < 11%), while inter-day variability was significantly lower for [M+H] species (CV < 13%) compared to oxidation-derived adducts, establishing protonated ions as the preferred targets for long-term biomarker monitoring.Cyclic ion mobility separation was evaluated for isomer differentiation. Although tentative separation of 2-ethylhexanal and octanal was observed, sensitivity losses approaching three orders of magnitude were encountered, likely attributed to instrument geometry and travelling wave-based ion transmission. Nevertheless, the demonstrated ability of ion mobility to discriminate VOCs from chemical noise and isobaric interferences is encour
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Journal articleJim矇nez-Saiz R, Iborra S, Blanco C, et al., 2026, , Allergy
Type 2 (T2) immunity is classically associated with defense against helminths and environmental threats, from a physiological perspective, and with allergies and eosinophilic inflammatory diseases, in a pathological sense. However, growing evidence reveals that T2 pathways also support other essential homeostatic functions, including tissue protection and repair. There are major clues from the early evolution of T2 responses for protection against massive tissue damage and positive selection for survival against parasites starting over 500 million years ago. These responses likely co-evolved stepwise with immune-regulatory circuits, culminating in the emergence of the fully functional human-type IgG4 in the great apes (Hominidae) within the last ~10 million years. The involvement of body barriers along with the strong influence of local epithelial cells and their interaction with the microbiome and the immune system is a common characteristic of T2 inflammation. An expanding list of new T2 diseases is being reported, characterized by epithelial cell and immune system activation, epithelial barrier damage, and microbial dysbiosis, including opportunistic pathogen colonization and loss of commensals. This evolving understanding coincides with the clinical success of biologics targeting key T2 mediators such as IL-4, IL-5, IL-13, IL-31, TSLP, and IgE, which have transformed the management of severe allergic diseases and other T2-driven pathologies. However, the contribution of T2 immunity to homeostatic programs raises questions about the long-term consequences of sustained T2 suppression. In this review, we examine the dual role of T2 immunity in health and disease, revisit its evolutionary origins, highlight its protective functions beyond allergy, and discuss the potential implications of prolonged T2 pathway blockade.
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Journal articlePiccirilli E, Troia SG, Fontanella S, et al., 2026, , AJNR Am J Neuroradiol, Vol: 47, Pages: 2416-2423
BACKGROUND AND PURPOSE: The adult hippocampal head (HH) is characterized by sulci and digitations visible both histologically and on MRI. The aim of the study was to describe the emergence and progression of HH digitations in the fetal brain across different gestational ages (GAs) using MRI. MATERIALS AND METHODS: A retrospective assessment was performed on 383 fetal brain MRIs (19-39 weeks' GA) acquired on 1.5T (n = 351) and 3T (n = 32) scanners. Imaging included single-shot fast spin-echo T2, T1-weighted sequences, and axial DWI. The fetal HH was identified on coronal T2 images, and HH morphologic variants were classified using an established adult classification system: class 0 (no sulci, 1 digitation), class 1 (1 sulcus, 2 digitations), and class 2 (2 sulci, 3 digitations). MRIs with brain anomalies identified prenatally or postnatally, abnormal sulcation, or severe artifacts were excluded. Variant frequencies in both hemispheres were grouped by GA. Correspondence analysis and cumulative link mixed models were used to assess the association between GA and class distribution. RESULTS: Two hundred seventy-one fetuses were included, grouped into 8 GA categories. Overall frequencies were 33.6% for class 0, 48.9% for class 1, and 17.5% for class 2. With increasing GA, class 0 frequency decreased, while classes 1 and 2 increased. Between 23 and 25 weeks' GA, detection of more digitated HH variants rose sharply from 1% to 64%. Follow-up in 30 fetuses showed an increase in HH digitations, with no observed reductions. Regression analysis revealed greater digitation complexity in the right hemisphere. CONCLUSIONS: Digitations in the fetal HH begin to appear around 24 weeks' GA, reaching frequencies similar to those observed in adults by the later stages of gestation. The right hemisphere shows higher complexity, possibly reflecting faster growth. These findings contribute to the understanding of hippocampal development and may ser
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Journal articleSiddiqui S, Brooks L, Menzies-Gow A, et al., 2026, , Am J Respir Crit Care Med, Vol: 212, Pages: 2111-2112
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Journal articleMoffatt MF, Nishimura T, Cox MJ, et al., 2026, , American Journal of Respiratory and Critical Care Medicine, Vol: 212, Pages: 1962-1974, ISSN: 1073-449X
RationaleAsthma is characterized by disruption of the thoracic airway mucosae and loss of microbial diversity. Spatial profiling of the mucosal transcriptome may systematically discover mechanisms for microbial influences on immunity.ObjectivesWe investigated relationships between clinical measures, microbial communities, and the host mucosal transcriptome within different strata of bronchial biopsies in subjects with and without asthma.MethodsWe bronchoscoped 65 adult asthmatics and 44 healthy controls, quantifying bacterial operational taxonomic units (OTUs) in bronchial brushings by 16S rRNA gene amplicon sequences. Biopsy histologic features were scored blind to diagnosis. Following 16S rRNA in situ hybridization of 44 biopsies, bacterial foci were scored in epithelium, basement membrane and stroma. Global human gene expression was quantified in epithelial and stromal compartments using Digital Spatial Profiling.Measurements and main resultsClinical asthma was independently predicted by basement membrane abnormalities (BaseMA), endobronchial bacterial diversity and circulating eosinophil counts, but not by specific OTU abundances. 16S rRNA staining revealed bacteria within epithelium and mucosa of all biopsies. Intra-mucosal bacteria (IMCBs) counts correlated negatively with spatially organized co-expression networks encoding antigen-specific immunity, neutrophil functions, and matrix activation, whereas BaseMA correlated positively with the adaptive immunity module. Eosinophil counts correlated with epithelial bacterial counts and senescence pathways. Clinical asthma was accompanied by upregulation of a Treg cell network.ConclusionsAsthma and its related phenotypes are accompanied by complex mucosal events that extend beyond eosinophilic pathways. Components of diverse airway microbiota may modify immunity by beneficial interactions within the mucosa.
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Journal articleBush A, Chotirmall SH, Han MK, et al., 2026, , Am J Respir Crit Care Med, Vol: 212, Pages: 1879-1881
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Journal articleMassenet T, Stefanuto P-H, Peltrini R, et al., 2026, , Am J Respir Crit Care Med, Vol: 212, Pages: 2075-2078
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Journal articleBaraldi F, Mah JSY, Almuhanna A, et al., 2026, , Am J Respir Crit Care Med, Vol: 212, Pages: 2071-2074
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Journal articleBilska AG, Chaszczewska-Markowska M, Gajdanowicz P, et al., 2026, , Ecotoxicol Environ Saf, Vol: 322
Plastics continuously fragment into micro- and nanoplastics (MPs/NPs), which are increasingly recognized as emerging environmental contaminants of global concern. Human exposure to nanoplastics through air, food, and water is becoming unavoidable; however, their direct effects on human immune cells remain poorly understood. Due to their small size, NPs can enter the circulation and directly interact with immune cells, yet their cellular effects in humans remain poorly understood. In this study, we investigated the impact of polystyrene NPs on human peripheral blood mononuclear cells (PBMCs) using an integrated approach that combined imaging, mitochondrial stress testing, basophil activation assays, and single-cell RNA sequencing. Confocal microscopy confirmed efficient cytoplasmic internalization of 25-nm NPs. Optical diffraction tomography revealed that even short-term (1疲) exposure induced pronounced biophysical remodeling, including reduced cell volume and dry mass alongside increased intracellular density and refractive index. Seahorse metabolic profiling demonstrated substantial suppression of mitochondrial respiration across major immune subsets, reflected in reduced basal and maximal respiration, ATP-linked oxygen consumption, and spare respiratory capacity. Basophil activation remained unaffected by NP exposure. Single-cell transcriptomics identified a distinct NP-induced "stress-cell" population, characterized by upregulation of heat-shock and proteostasis pathways and concomitant downregulation of mitochondrial-encoded transcripts. Together, these data show that NPs rapidly disrupt mitochondrial function and activate proteotoxic stress programs in human immune cells. By situating these mechanisms within the One Health framework (human, animal and the planet health), our findings highlight how environmental nanoplastic pollution may translate into immune dysregulation and inform integrated environmental-public health risk assessments.
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Journal articlePiga NN, Portelli MA, Shrine N, et al., 2026, , ERJ Open Res, Vol: 12, ISSN: 2312-0541
BACKGROUND: In ∼10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. METHODS: We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10-6) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. RESULTS: In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). CONCLUSION: We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.
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Journal articleWang H, Fung NH, Aloe C, et al., 2026, , Clin Transl Allergy, Vol: 16, ISSN: 2045-7022
BACKGROUND: Severe asthma is a chronic inflammatory disease characterised by airway dysfunction, persistent immune activation and corticosteroid resistance. While macrophages are key regulators of lung immunity, how individual subsets, particularly interstitial macrophages (IMs), contribute to disease remains poorly understood. METHODS: Lung macrophages were profiled using single-cell RNA-sequencing (scRNA-seq) and flow cytometry in a C57BL/6 mouse model of severe asthma induced by Complete Freund's Adjuvant (CFA) and house dust mite (HDM). Human transcriptomic data from the U-BIOPRED asthma cohort were analyzed for translational validation. The dual CCR2/CCR5 antagonist Cenicriviroc (CVC) was used to evaluate the therapeutic potential of targeting pathogenic macrophages. RESULTS: CFA-HDM treatment led to marked depletion of resident alveolar macrophages (rAMs) and their replacement by recruited AMs (recAMs) associated with tissue remodeling. A distinct Lyve1loMHCIIhi IM subset emerged as the dominant inflammatory cell population, displaying high Ccr2 and Ccr5 expression, potent pro-inflammatory and antigen-presenting signatures, and extensive ligand-receptor communication with T cells, neutrophils and rAMs. Trajectory analysis demonstrated that both recAMs and Lyve1loMHCIIhi IMs arise from classical monocytes. Consistently, sputum transcriptomic data from the U-BIOPRED asthma cohort showed reduced AM-associated gene signatures and enrichment of IM/monocyte and CCR-chemokine programs in patients with severe disease. Pharmacological blockade of CCR2/CCR5 with CVC markedly reduced IM infiltration, limited T-cell and neutrophil recruitment, restored macrophage balance, and improved lung function. CONCLUSIONS: Lyve1loMHCIIhi IMs orchestrate airway inflammation in severe asthma. Dual CCR2/CCR5 antagonism inhibits their recruitment, restores macrophage balance, and halts disease progression, highlighting this pathway as a promising therapeutic target.
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Journal articleRoth-Walter F, Adcock IM, Benito-Villalvilla C, et al., 2026, , Allergy, Vol: 81, Pages: 3039-3070
In the last decades, critical advancements in research technology and knowledge on disease mechanisms steered therapeutic approaches for chronic inflammatory diseases towards unprecedented target specificity. For allergic and chronic lung diseases, biologic drugs pioneered this goal, acquiring on the way-through the clinical use of monoclonal antibodies-a deeper understanding of how inflammatory and immune pathways are configured in disease-specific patterns. In this biomarker-driven approach, synthetic small molecule drugs (SMDs) were perceived as lagging behind in innovation for their relative lack of specificity. This was, however, mostly due to a shift in focus towards biologics rather than true obsolescence of SMDs. In the same timeframe, in fact, advances in structural biology and medicinal chemistry, bioinformatics and artificial intelligence held steadily SMDs' innovation and relevance. The use of kinase inhibitors, well established in the treatment of cancer and rheumatological diseases, is now approved for some allergic skin diseases and is approaching asthma and COPD with several clinical trials; moreover, new therapeutics targeting mast cell receptors and molecules involved in innate immunity are entering preclinical and clinical testing. Alongside, the portfolio of biologics is harboring the expansion of RNA therapeutics, which gained global recognition during the COVID-19 pandemic due to RNA vaccines. Different types of RNA therapeutics, including those based on different non-coding RNAs, are advancing to agency approval and market, thanks to improvements in molecule stability and delivery systems. In summary, the evidence presented in this position paper illustrates that precision medicine is becoming a goal shared between synthetic SMDs and biologics, both protein/antibody-based and RNA therapeutics. We review the current state, unmet needs and opportunities within this evolving landscape, highlighting how small molecular species, both synthetic as S
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