RESUMEN
BACKGROUND: Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome. METHODS: Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α-diversity of mild-moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS). FINDINGS: Fifty-one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n = 16), followed by Actinobacillus unclassified (n = 10), Veillonella unclassified (n = 9), Haemophilus aegyptius (n = 9), Streptococcus pseudopneumoniae (n = 7), Propionibacterium acnes (n = 5), Moraxella catarrhalis (n = 5) and Tropheryma whipplei (n = 5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n = 9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF-κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6-transignalling signature and neutrophil activation. CONCLUSION: We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics.
Asunto(s)
Asma , Haemophilus influenzae , Neutrófilos , Esputo , Humanos , Asma/microbiología , Haemophilus influenzae/patogenicidad , Haemophilus influenzae/genética , Esputo/microbiología , Masculino , Femenino , Adulto , Neutrófilos/metabolismo , Persona de Mediana Edad , Fenotipo , Infecciones por Haemophilus/microbiologíaRESUMEN
BACKGROUND: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. OBJECTIVE: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma. METHODS: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort. RESULTS: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways. CONCLUSIONS: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Asma/tratamiento farmacológico , Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Interleucinas/antagonistas & inhibidores , Adulto , Anciano , Asma/genética , Asma/inmunología , Bronquios/inmunología , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Femenino , Humanos , Inmunoglobulina E/sangre , Interleucinas/genética , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Proteoma/efectos de los fármacos , Índice de Severidad de la Enfermedad , Piel/inmunología , Esputo/inmunología , Transcriptoma/efectos de los fármacos , Resultado del Tratamiento , Interleucina-22RESUMEN
Fibrates and omega-3 polyunsaturated acids are used for the treatment of hypertriglyceridemia but have not demonstrated consistent effects on cardiovascular (CV) risk. In this study, we investigate how these two pharmacological agents influence plasma levels of bioactive lipid mediators, aiming to explore their efficacy beyond that of lipid-lowering agents. Plasma from overweight patients with non-alcoholic fatty liver disease (NAFLD) and hypertriglyceridemia, participating in a randomized placebo-controlled study investigating the effects of 12 weeks treatment with fenofibrate or omega-3 free carboxylic acids (OM-3CA) (200 mg or 4 g per day, respectively), were analyzed for eicosanoids and related PUFA species, N-acylethanolamines (NAE) and ceramides. OM-3CA reduced plasma concentrations of proinflammatory PGE2 , as well as PGE1 , PGD1 and thromboxane B2 but increased prostacyclin, and eicosapentaenoic acid- and docosahexaenoic acid-derived lipids of lipoxygenase and cytochrome P450 monooxygenase (CYP) (e.g., 17-HDHA, 18-HEPE, 19,20-DiHDPA). Fenofibrate reduced plasma concentrations of vasoactive CYP-derived eicosanoids (DHETs). Although OM-3CA increased plasma levels of the NAE docosahexaenoyl ethanolamine and docosapentaenoyl ethanolamine, and fenofibrate increased palmitoleoyl ethanolamine, the effect of both treatments may have been masked by the placebo (olive oil). Fenofibrate was more efficacious than OM-3CA in significantly reducing plasma ceramides, pro-inflammatory lipids associated with CV disease risk. Neither treatment affected putative lipid species associated with NAFLD. Our results show that OM-3CA and fenofibrate differentially modulate the plasma mediator lipidome, with OM-3CA promoting the formation of lipid mediators with potential effects on chronic inflammation, while fenofibrate mainly reducing ceramides. These findings suggest that both treatments could ameliorate chronic inflammation with possible impact on disease outcomes, independent of triglyceride reduction.
Asunto(s)
Ácidos Carboxílicos , Ácidos Grasos Omega-3 , Fenofibrato , Hipertrigliceridemia/tratamiento farmacológico , Hipolipemiantes , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Adulto , Anciano , Ácidos Carboxílicos/administración & dosificación , Ácidos Carboxílicos/farmacología , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/farmacología , Femenino , Fenofibrato/administración & dosificación , Fenofibrato/farmacología , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Extracellular DNA (e-DNA) and neutrophil extracellular traps (NETs) are linked to asthmatics airway inflammation. However, data demonstrating the characterization of airway inflammation associated with excessive e-DNA production and its impact on asthma outcomes are limited. OBJECTIVE: To characterize the airway inflammation associated with excessive e-DNA production and its association with asthma control, severe exacerbations and pulmonary function, particularly, air trapping and small airway dysfunction. METHODS: We measured e-DNA concentrations in induced sputum from 134 asthma patients and 28 healthy controls. We studied the correlation of e-DNA concentrations with sputum neutrophils, eosinophils and macrophages and the fractional exhaled nitric oxide (FeNO). Lung function was evaluated using spirometry, body plethysmography, impulse oscillometry and inert gas multiple breath washout. We stratified patients with asthma into low-DNA and high-DNA to compare lung function impairments and asthma outcomes. RESULTS: Patients with severe asthma had higher e-DNA concentration (54.2 ± 42.4 ng/µl) than patients with mild-moderate asthma (41.0 ± 44.1 ng/µl) or healthy controls (26.1 ± 16.5 ng/µl), (all p values < 0.05). E-DNA concentrations correlated directly with sputum neutrophils (R = 0.49, p < 0.0001) and negatively with sputum macrophages (R = - 0.36, p < 0.0001), but neither with sputum eosinophils (R = 0.10, p = 0.26), nor with FeNO (R = - 0.10, p = 0.22). We found that 29% of asthma patients (n = 39) had high e-DNA concentrations above the upper 95th percentile value in healthy controls (55.6 ng /µl). High-DNA was associated with broad lung function impairments including: airflow obstruction of the large (FEV1) and small airways (FEF50%, FEF25-75), increased air trapping (RV, RV/TLC), increased small airway resistance (R5-20, sReff), decreased lung elasticity (X5Hz) and increased ventilation heterogeneity (LCI), (all P values < 0.05). We also found that high e-DNA was associated with nearly three-fold greater risk of severe exacerbations (OR 2·93 [95% CI 1.2-7.5]; p = 0·012), worse asthma control test (p = 0.03), worse asthma control questionnaire scores (p = 0.01) and higher doses of inhaled corticosteroids (p = 0.026). CONCLUSION: Increased production of extracellular DNA in the airway characterizes a subset of neutrophilic asthma patients who have broad lung function impairments, poor symptom control and increased risk of severe exacerbations.
Asunto(s)
Asma/metabolismo , ADN/metabolismo , Líquido Extracelular/metabolismo , Volumen Espiratorio Forzado/fisiología , Pulmón/fisiopatología , Neutrófilos/patología , Esputo/metabolismo , Adulto , Asma/patología , Asma/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Prospectivos , Pruebas de Función Respiratoria , Esputo/citologíaRESUMEN
While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.
Asunto(s)
Antiinflamatorios/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neumonía/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Antiinflamatorios/farmacología , COVID-19/epidemiología , COVID-19/inmunología , Ensayos Clínicos como Asunto/métodos , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Sistema de Señalización de MAP Quinasas/fisiología , Neumonía/epidemiología , Neumonía/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Síndrome de Dificultad Respiratoria/epidemiología , Síndrome de Dificultad Respiratoria/inmunologíaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Increasing age alters innate immune-mediated responses; however, the mechanisms underpinning these changes in humans are not fully understood. Using a human dermal model of acute inflammation, we found that, although inflammatory onset is similar between young and elderly individuals, the resolution phase was substantially impaired in elderly individuals. This arose from a reduction in T cell immunoglobulin mucin receptor-4 (TIM-4), a phosphatidylserine receptor expressed on macrophages that enables the engulfment of apoptotic bodies, so-called efferocytosis. Reduced TIM-4 in elderly individuals was caused by an elevation in macrophage p38 mitogen-activated protein kinase (MAPK) activity. Administering an orally active p38 inhibitor to elderly individuals rescued TIM-4 expression, cleared apoptotic bodies and restored a macrophage resolution phenotype. Thus, inhibiting p38 in elderly individuals rejuvenated their resolution response to be more similar to that of younger people. This is the first resolution defect identified in humans that has been successfully reversed, thereby highlighting the tractability of targeting pro-resolution biology to treat diseases driven by chronic inflammation.
Asunto(s)
Inflamación/etiología , Inflamación/metabolismo , Fagocitosis/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Factores de Edad , Anciano , Animales , Apoptosis , Vesícula/inmunología , Vesícula/metabolismo , Vesícula/patología , Cantaridina , Expresión Génica , Humanos , Inmunidad Innata , Inflamación/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Receptores de Superficie Celular/metabolismo , Transducción de SeñalRESUMEN
The house dust mite allergen Dermatophagoides pteronyssinus (Der p) is a major driver of allergic asthma. Studies from our group demonstrated anti-eosinophilic effects of ethanolic extract of Lafoensia pacari stem bark (and ellagic acid, isolated from L. pacari extract), used as traditional medicine in Brazil to naturally treat inflammatory conditions. Here, we extended these results through performing phytochemical analysis of the constituents of L. pacari using liquid chromatography-mass spectrometry and evaluating the anti-inflammatory effects of both L. pacari and ellagic acid in the human BEAS-2B bronchial epithelial cell line stimulated with Der p. Ellagic acid (major constituent), gallic acid, ferulic acid, chlorogenic acid and rosmarinic acid, but not flavonoids (rutin, kaempferol, luteolin and quercetin), were found in the L. pacari. Pro-inflammatory mediators, IL-6, IL-8 and CCL-2 production were increased in BEAS-2B stimulated with Der p (10 µg/mL, 24 h) compared to control. L. pacari (250 µg/mL) and ellagic acid (100 µM) significantly reduced the concentration of these mediators. L. pacari increased the production of the anti-inflammatory cytokine, IL-10. These results were associated with the downregulation of NF-κB and STAT3 pathways. These findings indicate a novel anti-inflammatory action for L. pacari and ellagic acid in the airways allergic inflammatory response.
Asunto(s)
Antiinflamatorios/farmacología , Bronquios/metabolismo , Citocinas/metabolismo , Ácido Elágico/farmacología , Células Epiteliales/metabolismo , Mediadores de Inflamación/metabolismo , Lythraceae , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Pyroglyphidae/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Animales , HumanosRESUMEN
Across a majority of cancer types tumor-associated neutrophils (TAN) are linked with poor prognosis. However, the underlying mechanisms, especially the intratumoral behavior of TAN, are largely unknown. Using intravital multiphoton imaging on a mouse model with neutrophil-specific fluorescence, we measured the migration of TAN in distinct compartments of solid tumor cell lesions in vivo. By longitudinally quantifying the infiltration and persistence of TAN into growing tumors in the same animals, we observed cells that either populated the peripheral stromal zone of the tumor (peritumoral TAN) or infiltrated into the tumor core (intratumoral TAN). Intratumoral TAN showed prolonged tumor-associated persistence and reduced motility compared to peritumoral TAN, whose velocity increased with tumor progression. Selective pharmacological blockade of CXCR2 receptors using AZD5069 profoundly inhibited recruitment of TAN into peritumoral regions, while intratumoral infiltration was only transiently attenuated and rebounded at later time points. Our findings unravel distinct spatial dynamics of TAN that are partially and differentially regulated via the CXCR2 signaling pathway.
Asunto(s)
Neoplasias Experimentales/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Neoplasias Cutáneas/inmunología , Animales , Línea Celular Tumoral , Ratones , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/patología , Pirimidinas/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/inmunología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Sulfonamidas/farmacologíaRESUMEN
Neutrophils play a central role in innate immunity, inflammation, and resolution. Unresolving neutrophilia features as a disrupted inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD) and severe asthma. The extent to which this may be linked to disease pathobiology remains obscure and could be further confounded by indication of glucocorticoids or concomitant respiratory infections. The formation of neutrophil extracellular traps (NETs) represents a specialized host defense mechanism that entrap and eliminate invading microbes. NETs are web-like scaffolds of extracellular DNA in complex with histones and neutrophil granular proteins, such as myeloperoxidase and neutrophil elastase. Distinct from apoptosis, NET formation is an active form of cell death that could be triggered by various microbial, inflammatory, and endogenous or exogenous stimuli. NETs are reportedly enriched in neutrophil-dominant refractory lung diseases, such as COPD and severe asthma. Evidence for a pathogenic role for respiratory viruses (e.g., Rhinovirus), bacteria (e.g., Staphylococcus aureus) and fungi (e.g., Aspergillus fumigatus) in NET induction is emerging. Dysregulation of this process may exert localized NET burden and contribute to NETopathic lung inflammation. Disentangling the role of NETs in human health and disease offer unique opportunities for therapeutic modulation. The chemokine CXCR2 receptor regulates neutrophil activation and migration, and small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways. NET-stabilizing agents using CXCR2 antagonists are being investigated in proof-of-concept studies in patients with COPD to provide mechanistic insights. Clinical validation of this type could lead to novel therapeutics for multiple CXCR2-related NETopathologies. In this Review, we discuss the emerging role of NETs in the clinicopathobiology of COPD and severe asthma and provide an outlook on how novel NET-stabilizing therapies via CXCR2 blockade could be leveraged to disrupt NETopathic inflammation in disease-specific phenotypes.
Asunto(s)
Asma/etiología , Asma/metabolismo , Trampas Extracelulares/inmunología , Neutrófilos/inmunología , Neutrófilos/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Animales , Asma/patología , Biomarcadores , Trampas Extracelulares/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Neutrófilos/patología , Enfermedad Pulmonar Obstructiva Crónica/patología , Receptores de Interleucina-8B/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVES: To evaluate the efficacy and safety of AZD1981, a potent, specific antagonist of the CRTh2 receptor, as add-on therapy to inhaled corticosteroids (ICS) and long-acting ß2-agonists (LABA), in patients with persistent asthma with an allergic component. PATIENTS AND METHODS: In this placebo-controlled, parallel-group Phase IIb study, patients with persistent atopic asthma on ICS and LABA were randomized to receive 12 weeks of treatment with placebo or AZD1981 (80 mg daily, 200 mg daily, and 10 mg, 40 mg, 100 mg, or 400 mg twice daily [BID]). The primary end point was the mean change from baseline in predose, prebronchodilator forced expiratory volume in 1 second (FEV1) averaged over weeks 2, 4, 8, and 12 in the AZD1981-treatment group vs the placebo group. Secondary end points included other measures of lung function, symptoms, and asthma control, as well as standard measures of safety. RESULTS: In total, 1,140 patients (99.7%) received study treatment. There were improvements in the primary end point across all treatment groups over 12 weeks of treatment. However, the improvement for the highest AZD1981 dose (400 mg BID) vs placebo was not statistically significant (0.02 L, P=0.58), preventing interpretation of statistical testing for the lower doses. AZD1981 was well tolerated, and the incidence of adverse events was comparable across placebo and treatment groups. CONCLUSION: In patients with allergic asthma receiving ICS and LABA therapy, the addition of AZD1981 at doses up to 400 mg BID failed to produce a clinically relevant improvement in lung function or any other measured end point, but appeared to have an acceptable safety profile. This clinical study is registered with ClinicalTrials.gov (NCT01197794).
Asunto(s)
Acetatos/farmacología , Corticoesteroides/farmacología , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Indoles/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Acetatos/administración & dosificación , Administración por Inhalación , Corticoesteroides/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Antiasmáticos/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana EdadAsunto(s)
Trampas Extracelulares/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Pirimidinas/uso terapéutico , Receptores de Interleucina-8B/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Anciano , Humanos , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Esputo/citologíaRESUMEN
The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kδ/Akt (IC-87114) respectively, or an inhibitor of NF-κB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.
Asunto(s)
Asma/genética , FN-kappa B/metabolismo , Ovalbúmina/efectos adversos , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Activación Transcripcional , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Asma/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Regulación hacia Abajo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Indoles/administración & dosificación , Indoles/farmacología , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos BALB C , Fosforilación/efectos de los fármacos , Quinazolinas/administración & dosificación , Quinazolinas/farmacología , Transducción de Señal , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , Tirfostinos/administración & dosificación , Tirfostinos/farmacologíaRESUMEN
Neutrophils are important effector cells of antimicrobial immunity in an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), there is excessive infiltration and activation of neutrophils, subsequent production of reactive oxygen species, and release of serine proteases, matrix metalloproteinases, and myeloperoxidase-resulting in collateral damage as the cells infiltrate into the tissue. Increased neutrophil survival through dysregulated apoptosis facilitates continued release of neutrophil-derived mediators to perpetuate airway inflammation and tissue injury. Several target mechanisms have been investigated to address pathologic neutrophil biology and thereby provide a novel therapy for respiratory disease. These include neutrophil influx through inhibition of chemokine receptors CXCR2, CXCR1, and PI3Kγ signaling and neutrophil weaponry by protease inhibitors, targeting matrix metalloproteinases and neutrophil serine proteases. In addition, neutrophil function can be modulated using selective PI3Kδ inhibitors. This review highlights the latest advances in targeting neutrophils and their function, discusses the opportunities and risks of neutrophil inhibition, and explores how we might better develop future strategies to regulate neutrophil influx and function for respiratory diseases in dire need of novel effective therapies.
Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/terapia , Neutrófilos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Sistema Respiratorio/inmunología , Animales , Antiinflamatorios/farmacología , Asma/inmunología , Movimiento Celular , Humanos , Mediadores de Inflamación/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8B/antagonistas & inhibidores , Transducción de SeñalAsunto(s)
Asma/tratamiento farmacológico , Infiltración Neutrófila/efectos de los fármacos , Pirimidinas/farmacología , Receptores de Interleucina-8B/antagonistas & inhibidores , Sulfonamidas/farmacología , Adulto , Asma/fisiopatología , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Proyectos PilotoAsunto(s)
Interleucina-8/inmunología , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Pirimidinas/farmacología , Receptores de Interleucina-8B/inmunología , Estallido Respiratorio/efectos de los fármacos , Sulfonamidas/farmacología , Administración Oral , Animales , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Esquema de Medicación , Femenino , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Inmunidad Innata/efectos de los fármacos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-8/agonistas , Interleucina-8/genética , Recuento de Leucocitos , Macaca fascicularis , Masculino , Neutrófilos/citología , Neutrófilos/inmunología , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/genética , Transducción de Señal , Pruebas de Toxicidad Crónica , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
OBJECTIVES: This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. MATERIAL: We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. RESULTS: Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. CONCLUSION: We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.