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1.
Am J Respir Crit Care Med ; 210(6): 755-765, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-38598774

RESUMEN

Rationale: In asthma, sputum group 2 innate lymphoid cells (ILC2s) are activated within 7 hours after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2s colocalize to sensory neuronal termini expressing the neuropeptide neuromedin U (NMU), which stimulates type 2 (T2) cytokine secretion by ILC2s, with additive effects to alarmins in vitro. Objectives: To investigate the effect of the NMU/NMUR1 (NMU receptor 1) axis on early activation of ILC2s in asthma. Methods: Subjects with mild asthma (n = 8) were enrolled in a diluent-controlled allergen inhalation challenge study. Sputum ILC2 expression of NMUR1 and T2 cytokines was enumerated by flow cytometry, and airway NMU levels were assessed by ELISA. This was compared with samples from subjects with moderate to severe asthma (n = 9). Flow sort-purified and ex vivo-expanded ILC2s were used for functional assays and transcriptomic analyses. Measurements and Main Results: Significant increases in sputum ILC2s expressing NMUR1 were detected 7 hours after allergen versus diluent challenge whereby the majority of NMUR1+ ILC2s expressed IL-5/IL-13. Sputum NMUR1+ ILC2 counts were significantly greater in mild versus moderate to severe asthma, and NMUR1+ ILC2s correlated inversely with the dose of inhaled corticosteroid in the latter group. Coculturing with alarmins upregulated NMUR1 in ILC2s, which was attenuated by dexamethasone. NMU-stimulated T2 cytokine expression by ILC2s, maximal at 6 hours, was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase 1/2 and phosphoinositol 3-kinase but not the IL-33 signaling moiety MyD88 in vitro. Conclusions: The NMU/NMUR1 axis stimulates rapid effects on ILC2s and may be an important early activator of these cells in eosinophilic inflammatory responses in asthma.


Asunto(s)
Asma , Linfocitos , Neuropéptidos , Esputo , Asma/inmunología , Humanos , Femenino , Masculino , Neuropéptidos/metabolismo , Adulto , Linfocitos/inmunología , Linfocitos/metabolismo , Esputo/inmunología , Inmunidad Innata , Persona de Mediana Edad , Citocinas/inmunología , Citocinas/metabolismo , Receptores de Neurotransmisores
2.
Pharmacol Ther ; 253: 108578, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38103794

RESUMEN

The treatment of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), remains challenging as current available antifibrotic agents are not effective in halting disease progression. Connective tissue growth factor (CTGF), also known as cellular communication factor 2 (CCN2), is a member of the CCN family of proteins that regulates cell signaling through cell surface receptors such as integrins, the activity of cytokines/growth factors, and the turnover of extracellular matrix (ECM) proteins. Accumulating evidence indicates that CTGF plays a crucial role in promoting lung fibrosis through multiple processes, including inducing transdifferentiation of fibroblasts to myofibroblasts, epithelial-mesenchymal transition (EMT), and cooperating with other fibrotic mediators such as TGF-ß. Increased expression of CTGF has been observed in fibrotic lungs and inhibiting CTGF signaling has been shown to suppress lung fibrosis in several animal models. Thus, the CTGF signaling pathway is emerging as a potential therapeutic target in IPF and other pulmonary fibrotic conditions. This review provides a comprehensive overview of the current evidence on the pathogenic role of CTGF in pulmonary fibrosis and discusses the current therapeutic agents targeting CTGF using a systematic review approach.


Asunto(s)
Factor de Crecimiento del Tejido Conjuntivo , Fibrosis Pulmonar Idiopática , Animales , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Fibrosis , Fibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/patología , Factor de Crecimiento Transformador beta1 , Pulmón/metabolismo
5.
Dev Dyn ; 252(9): 1224-1239, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37227110

RESUMEN

BACKGROUND: Kidney development is regulated by cellular interactions between the ureteric epithelium, mesenchyme, and stroma. Previous studies demonstrate essential roles for stromal ß-catenin in kidney development. However, how stromal ß-catenin regulates kidney development is not known. We hypothesize that stromal ß-catenin modulates pathways and genes that facilitate communications with neighboring cell populations to regulate kidney development. RESULTS: We isolated purified stromal cells with wild type, deficient, and overexpressed ß-catenin by fluorescence-activated cell sorting and conducted RNA Sequencing. A Gene Ontology network analysis demonstrated that stromal ß-catenin modulates key kidney developmental processes, including branching morphogenesis, nephrogenesis and vascular formation. Specific stromal ß-catenin candidate target genes that may mediate these effects included secreted, cell-surface and transcriptional factors that regulate branching morphogenesis and nephrogenesis (Wnts, Bmp, Fgfr, Tcf/Lef) and secreted vascular guidance cues (Angpt1, VEGF, Sema3a). We validated established ß-catenin targets including Lef1 and novel candidate ß-catenin targets including Sema3e which have unknown roles in kidney development. CONCLUSIONS: These studies advance our understanding of gene and biological pathway dysregulation in the context of stromal ß-catenin misexpression during kidney development. Our findings suggest that during normal kidney development, stromal ß-catenin may regulate secreted and cell-surface proteins to communicate with adjacent cell populations.


Asunto(s)
Uréter , beta Catenina , beta Catenina/genética , beta Catenina/metabolismo , Riñón/metabolismo , Factores de Transcripción/metabolismo , Uréter/metabolismo , Transducción de Señal
6.
Commun Biol ; 6(1): 538, 2023 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-37202533

RESUMEN

During cancer development, tumor cells acquire changes that enable them to invade surrounding tissues and seed metastasis at distant sites. These changes contribute to the aggressiveness of metastatic cancer and interfere with success of therapy. Our comprehensive analysis of "matched" pairs of HNSCC lines derived from primary tumors and corresponding metastatic sites identified several components of Notch3 signaling that are differentially expressed and/or altered in metastatic lines and confer a dependency on this pathway. These components were also shown to be differentially expressed between early and late stages of tumors in a TMA constructed from over 200 HNSCC patients. Finally, we show that suppression of Notch3 improves survival in mice in both subcutaneous and orthotopic models of metastatic HNSCC. Novel treatments targeting components of this pathway may prove effective in targeting metastatic HNSCC cells alone or in combination with conventional therapies.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Animales , Ratones , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos
7.
Immunol Cell Biol ; 101(5): 412-427, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36862017

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.


Asunto(s)
Fibrosis Pulmonar Idiopática , Lesión Pulmonar , Ratones , Animales , Lesión Pulmonar/metabolismo , Factor de Transcripción Activador 6/metabolismo , Ratones Endogámicos C57BL , Macrófagos/metabolismo , Pulmón/patología , Fibrosis Pulmonar Idiopática/patología , Fibrosis , Bleomicina/efectos adversos , Bleomicina/metabolismo
8.
Am J Respir Crit Care Med ; 207(11): 1498-1514, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-36917778

RESUMEN

Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive lung scarring. IPF-related pulmonary vascular remodeling and pulmonary hypertension (PH) result in a particularly poor prognosis. Objectives: To study the pathogenesis of vascular remodeling in fibrotic lungs and its contribution to progression of fibrosis. Methods: We used an experimental model of lung fibrosis associated with PH by transient overexpression of active TGF-ß1 (transforming growth factor-ß1). Samples from patients with fibrotic lung diseases were analyzed in depth using immunostaining, gene expression, and gene mutations. Measurements and Main Results: We found a reduction in endothelial cells (ECs) and activation of vascular smooth muscle cells (VSMCs) in fibrotic lungs. Coculturing fibroblasts with VSMCs or ECs from fibrotic lungs induced fibrotic phenotypes in fibroblasts. IPF fibroblasts induced EC death and activation of VSMCs in coculture systems. Decreased concentrations of BMPR2 (bone morphogenic protein receptor 2) and its signaling were observed in ECs and VSMCs from fibrotic lungs in both rats and humans. On fibroblasts treated with media from VSMCs, BMPR2 suppression in VSMCs led to fibrogenic effects. Tacrolimus activated BMPR2 signaling and attenuated fibrosis and PH in rodent lungs. Whole-exome sequencing revealed rare mutations in PH-related genes, including BMPR2, in patients with IPF undergoing transplantation. A unique missense BMPR2 mutation (p.Q721R) was discovered to have dysfunctional effects on BMPR2 signaling. Conclusions: Endothelial dysfunction and vascular remodeling in PH secondary to pulmonary fibrosis enhance fibrogenesis through impaired BMPR2 signaling. Tacrolimus may have value as a treatment of advanced IPF and concomitant PH. Genetic abnormalities may determine the development of PH in advanced IPF.


Asunto(s)
Hipertensión Pulmonar , Fibrosis Pulmonar Idiopática , Humanos , Ratas , Animales , Remodelación Vascular , Células Endoteliales/metabolismo , Tacrolimus , Pulmón/patología , Fibrosis Pulmonar Idiopática/patología , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Fibroblastos/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética
9.
Biochem Pharmacol ; 211: 115501, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36921632

RESUMEN

Idiopathic pulmonary fibrosis (IPF) is the representative phenotype of interstitial lung disease where severe scarring develops in the lung interstitium. Although antifibrotic treatments are available and have been shown to slow the progression of IPF, improved therapeutic options are still needed. Recent data indicate that macrophages play essential pro-fibrotic roles in the pathogenesis of pulmonary fibrosis. Historically, macrophages have been classified into two functional subtypes, "M1″ and "M2," and it is well described that "M2″ or "alternatively activated" macrophages contribute to fibrosis via the production of fibrotic mediators, such as TGF-ß, CTGF, and CCL18. However, highly plastic macrophages may possess distinct functions and phenotypes in the fibrotic lung environment. Thus, M2-like macrophages in vitro and pro-fibrotic macrophages in vivo are not completely identical cell populations. Recent developments in transcriptome analysis, including single-cell RNA sequencing, have attempted to depict more detailed phenotypic characteristics of pro-fibrotic macrophages. This review will outline the role and characterization of pro-fibrotic macrophages in fibrotic lung diseases and discuss the possibility of treating lung fibrosis by preventing or reprogramming the polarity of macrophages. We also utilized a systematic approach to review the literature and identify novel and promising therapeutic agents that follow this treatment strategy.


Asunto(s)
Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Macrófagos/patología , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Fibrosis
10.
Biochem Biophys Res Commun ; 656: 53-62, 2023 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-36958255

RESUMEN

Type 1 alveolar epithelial cells (AT1s) and type 2 alveolar epithelial cells (AT2s) regulate the structural integrity and function of alveoli. AT1s mediate gas exchange, whereas AT2s serve multiple functions, including surfactant secretion and alveolar repair through proliferation and differentiation into AT1s as progenitors. However, mechanisms regulating AT2 proliferation and differentiation remain unclear. Here we demonstrate that Gremlin, an intrinsic inhibitor of bone morphogenetic protein (BMP), induces AT2 proliferation and differentiation. Transient overexpression of Gremlin in rat lungs by adenovirus vector delivery suppressed BMP signaling, induced proliferation of AT2s and the production of Bmp2, which in turn led to the recovery of BMP signaling and induced AT2 differentiation into AT1s. Bleomycin-induced lung injury upregulated Gremlin and showed a similar time course of biomarker expression comparable to the adenovirus model. TGF-ß and IL-1ß induced Gremlin expression in fibroblasts. Taken together, our findings implicate that Gremlin expression during lung injury leads to precisely timed inhibition of BMP signaling and activates AT2s, leading to alveolar repair.


Asunto(s)
Células Epiteliales Alveolares , Lesión Pulmonar , Ratas , Animales , Células Epiteliales Alveolares/metabolismo , Lesión Pulmonar/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular
11.
Am J Respir Crit Care Med ; 207(4): 427-437, 2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36287613

RESUMEN

Rationale: Localized autoimmune responses have been reported in patients with severe eosinophilic asthma, characterized by eosinophil degranulation and airway infections. Objective: To determine the presence of autoantibodies against macrophage scavenger receptors within the airways and their effects on macrophage function and susceptibility to infection. Methods: Anti-EPX (eosinophil peroxidase), anti-MARCO (macrophage receptor with collagenous structure) IgG titers, and T1 and T2 (type 1/2) cytokines were measured in 221 sputa from 143 well-characterized patients with severe asthma. Peripheral monocytes and MDMs (monocyte-derived macrophages) isolated from healthy control subjects were treated with immunoprecipitated immunoglobulins from sputa with high anti-MARCO titers or nonspecific IgG to assess uptake of Streptococcus pneumoniae or response to the bacterial product LPS. Measurements and Main Results: Anti-MARCO IgG was detected in 36% of patients, with significantly higher titers (up to 1:16) in patients with mixed granulocytic sputa, indicative of airway infections. Multivariate regression analysis confirmed increased frequency of degranulation (free eosinophil granules), increased blood eosinophils (indicative of high T2 burden), increased sputum total cell count, peripheral blood leukocytes (indicative of infection), and lymphopenia were associated with increased anti-MARCO IgG titers; IL-15 (odds ratio [OR], 1.79; confidence interval [CI], 1.19-2.70), IL-13 (OR, 1.06; CI, 1.02-1.12), and IL-12p70 (OR, 3.34; CI, 1.32-8.40) were the associated cytokines. Patients with anti-MARCO antibodies had higher chances of subsequent infective versus eosinophilic exacerbations (P = 0.01). MDMs treated with immunoprecipitated immunoglobulins (anti-MARCO+ sputa) had reduced bacterial uptake by 39% ± 15% and significantly reduced release of IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.05) in response to an LPS stimulus. Conclusions: Autoantibodies against macrophage scavenger receptors in eosinophilic asthma airways may impede effective host defenses and lead to recurrent infective bronchitis.


Asunto(s)
Asma , Bronquitis , Eosinofilia Pulmonar , Humanos , Autoanticuerpos , Lipopolisacáridos , Eosinófilos , Citocinas , Macrófagos , Inmunoglobulina G
12.
Eur Respir J ; 61(1)2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36137590

RESUMEN

BACKGROUND: Autoimmunity has been reported in patients with severe coronavirus disease 2019 (COVID-19). We investigated whether anti-nuclear/extractable-nuclear antibodies (ANAs/ENAs) were present up to a year after infection, and if they were associated with the development of clinically relevant post-acute sequalae of COVID-19 (PASC) symptoms. METHODS: A rapid-assessment line immunoassay was used to measure circulating levels of ANAs/ENAs in 106 convalescent COVID-19 patients with varying acute phase severities at 3, 6 and 12 months post-recovery. Patient-reported fatigue, cough and dyspnoea were recorded at each time point. Multivariable logistic regression model and receiver operating curves were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines. RESULTS: Compared to age- and sex-matched healthy controls (n=22) and those who had other respiratory infections (n=34), patients with COVID-19 had higher detectable ANAs at 3 months post-recovery (p<0.001). The mean number of ANA autoreactivities per individual decreased between 3 and 12 months (from 3.99 to 1.55) with persistent positive titres associated with fatigue, dyspnoea and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, area under the curve (AUC) 0.86) and dyspnoea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and C-reactive protein predicted the elevated ANAs at 12 months. TNF-α, D-dimer and interleukin-1ß had the strongest association with symptoms at 12 months. Regression analysis showed that TNF-α predicted fatigue (ß=4.65, p=0.004) and general symptomaticity (ß=2.40, p=0.03) at 12 months. INTERPRETATION: Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNF-α) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC.


Asunto(s)
Autoanticuerpos , COVID-19 , Humanos , Síndrome Post Agudo de COVID-19 , Factor de Necrosis Tumoral alfa , Tos , Anticuerpos Antinucleares , Citocinas , Fatiga
13.
Radiol Cardiothorac Imaging ; 5(6): e230054, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38166343

RESUMEN

Purpose To determine if proton (1H) MRI-derived specific ventilation is responsive to bronchodilator (BD) therapy and associated with clinical biomarkers of type 2 airway inflammation and airways dysfunction in severe asthma. Materials and Methods In this prospective study, 27 participants with severe asthma (mean age, 52 years ± 9 [SD]; 17 female, 10 male) and seven healthy controls (mean age, 47 years ± 16; five female, two male), recruited between 2018 and 2021, underwent same-day spirometry, respiratory oscillometry, and tidal breathing 1H MRI. Participants with severe asthma underwent all assessments before and after BD therapy, and type 2 airway inflammatory biomarkers were determined (blood eosinophil count, sputum eosinophil percentage, sputum eosinophil-free granules, and fraction of exhaled nitric oxide) to generate a cumulative type 2 biomarker score. Specific ventilation was derived from tidal breathing 1H MRI and its response to BD therapy, and relationships with biomarkers of type 2 airway inflammation and airway dysfunction were evaluated. Results Mean MRI specific ventilation improved with BD inhalation (from 0.07 ± 0.04 to 0.11 ± 0.04, P < .001). Post-BD MRI specific ventilation (P = .046) and post-BD change in MRI specific ventilation (P = .006) were greater in participants with asthma with type 2 low biomarkers compared with participants with type 2 high biomarkers of airway inflammation. Post-BD change in MRI specific ventilation was correlated with change in forced expiratory volume in 1 second (r = 0.40, P = .04), resistance at 5 Hz (r = -0.50, P = .01), resistance at 19 Hz (r = -0.42, P = .01), reactance area (r = -0.54, P < .01), and reactance at 5 Hz (r = 0.48, P = .01). Conclusion Specific ventilation evaluated with tidal breathing 1H MRI was responsive to BD therapy and was associated with clinical biomarkers of airways disease in participants with severe asthma. Keywords: MRI, Severe Asthma, Ventilation, Type 2 Inflammation Supplemental material is available for this article. © RSNA, 2023 See also the commentary by Moore and Chandarana in this issue.


Asunto(s)
Asma , Protones , Masculino , Humanos , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Asma/diagnóstico por imagen , Inflamación , Biomarcadores , Imagen por Resonancia Magnética/métodos
14.
Nat Immunol ; 23(12): 1687-1702, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36456739

RESUMEN

Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.


Asunto(s)
Vacuna BCG , Macrófagos Alveolares , Inmunidad Entrenada , Pulmón , Vacunación , Inmunidad Innata
15.
Gigascience ; 112022 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-36261217

RESUMEN

BACKGROUND: Beyond their specific experiment, video records of behavior have future value-for example, as inputs for new experiments or for yet unknown types of analysis of behavior-similar to tissue or blood sample banks in life sciences where clinically derived or otherwise well-described experimental samples are stored to be available for some unknown potential future purpose. FINDINGS: Research using an animal model of obsessive-compulsive disorder employed a standardized paradigm where the behavior of rats in a large open field was video recorded for 55 minutes on each test. From 43 experiments, there are 19,976 such trials that amount to over 2 years of continuous recording. In addition to videos, there are 2 video-derived raw data objects: XY locomotion coordinates and plots of animal trajectory. To motivate future use, the 3 raw data objects are annotated with a general schema-one that abstracts the data records from their particular experiment while providing, at the same time, a detailed list of independent variables bearing on behavioral performance. The raw data objects are deposited as 43 datasets but constitute, functionally, a library containing 1 large dataset. CONCLUSIONS: Size and annotation schema give the library high reuse potential: in applications using machine learning techniques, statistical evaluation of subtle factors, simulation of new experiments, or as educational resource. Ultimately, the library can serve both as the seed and as the test bed to create a machine-searchable virtual library of linked open datasets for behavioral performance in defined conditions.


Asunto(s)
Trastorno Obsesivo Compulsivo , Roedores , Ratas , Animales , Bibliotecas Digitales , Modelos Animales de Enfermedad , Encéfalo
16.
PLoS One ; 17(10): e0275864, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36206293

RESUMEN

Asthma, an inflammatory disorder of the airways, is one of the most common chronic illnesses worldwide and is associated with significant morbidity. There is growing recognition of an association between asthma and mood disorders including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Although there are several hypotheses regarding the relationship between asthma and mental health, there is little understanding of underlying mechanisms and causality. In the current study we utilized publicly available datasets of human blood mRNA collected from patients with severe and moderate asthma, MDD, and PTSD. We performed differential expression (DE) analysis and Gene Set Enrichment Analysis (GSEA) on diseased subjects against the healthy subjects from their respective datasets, compared the results between diseases, and validated DE genes and gene sets with 4 more independent datasets. Our analysis revealed that commonalities in blood transcriptomic changes were only found between the severe form of asthma and mood disorders. Gene expression commonly regulated in PTSD and severe asthma, included ORMDL3 a gene known to be associated with asthma risk and STX8, which is involved in TrkA signaling. We also identified several pathways commonly regulated to both MDD and severe asthma. This study reveals gene and pathway regulation that potentially drives the comorbidity between severe asthma, PTSD, and MDD and may serve as foci for future research aimed at gaining a better understanding of both the relationship between asthma and PTSD, and the pathophysiology of the individual disorders.


Asunto(s)
Asma , Trastorno Depresivo Mayor , Trastornos por Estrés Postraumático , Asma/genética , Comorbilidad , Depresión , Trastorno Depresivo Mayor/epidemiología , Humanos , ARN Mensajero , Trastornos por Estrés Postraumático/epidemiología , Transcriptoma
17.
Int J Mol Sci ; 23(17)2022 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-36077051

RESUMEN

Discovery of the microbiota-gut-brain axis has led to proposed microbe-based therapeutic strategies in mental health, including the use of mood-altering bacterial species, termed psychobiotics. However, we still have limited understanding of the key signaling pathways engaged by specific organisms in modulating brain function, and evidence suggests that bacteria with broadly similar neuroactive and immunomodulatory actions can drive different behavioral outcomes. We sought to identify pathways distinguishing two psychoactive bacterial strains that seemingly engage similar gut-brain signaling pathways but have distinct effects on behaviour. We used RNAseq to identify mRNAs differentially expressed in the blood and hippocampus of mice following Lacticaseibacillus rhamnosus JB-1, and Limosilactobacillus reuteri 6475 treatment and performed Gene Set Enrichment Analysis (GSEA) to identify enrichment in pathway activity. L. rhamnosus, but not L. reuteri treatment altered several pathways in the blood and hippocampus, and the rhamnosus could be clearly distinguished based on mRNA profile. In particular, L. rhamnosus treatment modulated the activity of interferon signaling, JAK/STAT, and TNF-alpha via NF-KB pathways. Our results highlight that psychobiotics can induce complex changes in host gene expression, andin understanding these changes, we may help fine-tune selection of psychobiotics for treating mood disorders.


Asunto(s)
Lacticaseibacillus rhamnosus , Probióticos , Afecto , Animales , Encéfalo/metabolismo , Hipocampo , Masculino , Ratones , Probióticos/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo
18.
Eur Respir J ; 60(6)2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35777765

RESUMEN

BACKGROUND: Local airway autoimmune responses may contribute to steroid dependence and persistent eosinophilia in severe asthma. Auto-IgG antibodies directed against granule proteins such as eosinophil peroxidase (EPX), macrophage scavenger receptor with collagenous structure (MARCO) and nuclear/extranuclear antigens (antinuclear antibodies (ANAs)) have been reported. Our objective was to describe the prevalence and clinical characteristics of asthmatic patients with airway autoreactivity, and to assess if this could be predicted from clinical history of autoreactivity. METHODS: We analysed anti-EPX, anti-MARCO and ANAs in 218 sputum samples collected prospectively from 148 asthmatic patients, and evaluated their association with lung function parameters, blood/airway inflammation, severity indices and exacerbations. Additionally, 107 of these patients consented to fill out an autoimmune checklist to determine personal/family history of systemic autoimmune disease and symptoms. RESULTS: Out of the 148 patients, 59 (40%) were anti-EPX IgG+, 53 (36%) were anti-MARCO IgG+ and 64 out of 129 (50%) had ≥2 nuclear/extranuclear autoreactivities. A composite airway autoreactivity score (CAAS) demonstrated that 82 patients (55%) had ≥2 airway autoreactivities (considered as CAAS+). Increased airway eosinophil degranulation (OR 15.1, 95% CI 1.1-199.4), increased blood leukocytes (OR 3.5, 95% CI 1.3-10.1) and reduced blood lymphocytes (OR 0.19, 95% CI 0.04-0.84) predicted CAAS+. A third of CAAS+ patients reported an exacerbation, associated with increased anti-EPX and/or anti-MARCO IgG (p<0.05). While no association was found between family history or personal diagnosis of autoimmune disease, 30% of CAAS+ asthmatic patients reported sicca symptoms (p=0.02). Current anti-inflammatory (inhaled/oral corticosteroids and/or adjunct anti-interleukin-5 biologics) treatment does not attenuate airway autoantibodies, irrespective of eosinophil suppression. CONCLUSION: We report 55% of moderate-severe asthmatic patients to have airway autoreactivity that persists despite anti-inflammatory treatment and is associated with exacerbations.


Asunto(s)
Asma , Enfermedades Autoinmunes , Humanos , Autoanticuerpos , Esputo/química , Eosinófilos , Antiinflamatorios/uso terapéutico , Inmunoglobulina G
19.
Eur Respir J ; 60(4)2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35273032

RESUMEN

BACKGROUND: Progressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiological, symptomatic and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain. METHODS: Patients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015 and 2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation or any two of: relative FVC decline ≥5% and <10%, worsening respiratory symptoms or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression. RESULTS: Of 2746 patients with fibrotic ILD (mean±sd age 65±12 years; 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD) and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared with IPF, time to progression was similar in patients with HP (hazard ratio (HR) 0.96, 95% CI 0.79-1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71-0.96) and CTD-ILD (HR 0.65, 95% CI 0.56-0.74). Background treatment varied across diagnostic subtypes, with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61% and 37% of patients with CHP, CTD-ILD and U-ILD, respectively. Increasing age, male sex, gastro-oesophageal reflux disease and lower baseline pulmonary function were independently associated with progression. CONCLUSIONS: Progression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies.


Asunto(s)
Alveolitis Alérgica Extrínseca , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Anciano , Alveolitis Alérgica Extrínseca/complicaciones , Alveolitis Alérgica Extrínseca/epidemiología , Canadá/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/epidemiología , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Sistema de Registros
20.
Eur Respir J ; 60(2)2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35058252

RESUMEN

BACKGROUND: Cigarette smokers are at increased risk of acquiring influenza, developing severe disease and requiring hospitalisation/intensive care unit admission following infection. However, immune mechanisms underlying this predisposition are incompletely understood, and therapeutic strategies for influenza are limited. METHODS: We used a mouse model of concurrent cigarette smoke exposure and H1N1 influenza infection, colony-stimulating factor (CSF)3 supplementation/receptor (CSF3R) blockade and single-cell RNA sequencing (scRNAseq) to investigate this relationship. RESULTS: Cigarette smoke exposure exacerbated features of viral pneumonia such as oedema, hypoxaemia and pulmonary neutrophilia. Smoke-exposed infected mice demonstrated an increase in viral (v)RNA, but not replication-competent viral particles, relative to infection-only controls. Interstitial rather than airspace neutrophilia positively predicted morbidity in smoke-exposed infected mice. Screening of pulmonary cytokines using a novel dysregulation score identified an exacerbated expression of CSF3 and interleukin-6 in the context of smoke exposure and influenza. Recombinant (r)CSF3 supplementation during influenza aggravated morbidity, hypothermia and oedema, while anti-CSF3R treatment of smoke-exposed infected mice improved alveolar-capillary barrier function. scRNAseq delineated a shift in the distribution of Csf3 + cells towards neutrophils in the context of cigarette smoke and influenza. However, although smoke-exposed lungs were enriched for infected, highly activated neutrophils, gene signatures of these cells largely reflected an exacerbated form of typical influenza with select unique regulatory features. CONCLUSION: This work provides novel insight into the mechanisms by which cigarette smoke exacerbates influenza infection, unveiling potential therapeutic targets (e.g. excess vRNA accumulation, oedematous CSF3R signalling) for use in this context, and potential limitations for clinical rCSF3 therapy during viral infectious disease.


Asunto(s)
Fumar Cigarrillos , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana , Animales , Fumar Cigarrillos/efectos adversos , Humanos , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Neutrófilos , Nicotiana
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