RESUMO
Specialized proresolving mediators (SPMs) decrease NF-κB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-κB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-κB regulators A20 and single Ig IL-1R-related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) receptor-dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-κB-induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-κB activity and to establish mechanisms for NF-κB regulation by SPMs for pneumonia resolution.
Assuntos
Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Graxos Insaturados/imunologia , Mediadores da Inflamação/imunologia , Lipoxinas/imunologia , NF-kappa B/imunologia , Pneumonia Bacteriana/imunologia , Animais , Linhagem Celular , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Lipoxinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia Bacteriana/metabolismo , Receptores de Interleucina-1/agonistas , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismoRESUMO
RATIONALE: Acute respiratory distress syndrome (ARDS) is a devastating illness with limited therapeutic options. A better understanding of early biochemical and immunological events in ARDS could inform the development of new preventive and treatment strategies. OBJECTIVES: To determine select peripheral blood lipid mediator and leukocyte responses in patients at risk for ARDS. METHODS: Patients at risk for ARDS were randomized as part of a multicenter, double-blind clinical trial of aspirin versus placebo (the LIPS-A [Lung Injury Prevention Study with Aspirin] trial; NCT01504867). Plasma thromboxane B2 (TXB2), aspirin-triggered lipoxin A4 (15-epi-LXA4, ATL), and peripheral blood leukocyte number and activation were determined on enrollment and after treatment with either aspirin or placebo. MEASUREMENTS AND MAIN RESULTS: Thirty-three of 367 subjects (9.0%) developed ARDS after randomization. Baseline ATL levels, total monocyte counts, intermediate monocyte counts, and monocyte-platelet aggregates were associated with the development of ARDS. Peripheral blood neutrophil count and monocyte-platelet aggregates significantly decreased over time. Of note, nine subjects developed ARDS after randomization yet before study drug initiation, including seven subjects assigned to aspirin treatment. Subjects without ARDS at the time of first dose demonstrated a lower incidence of ARDS with aspirin treatment. Compared with placebo, aspirin significantly decreased TXB2 and increased the ATL/TXB2 ratio. CONCLUSIONS: Biomarkers of intravascular monocyte activation in at-risk patients were associated with development of ARDS. The potential clinical benefit of early aspirin for prevention of ARDS remains uncertain. Together, results of the biochemical and immunological analyses provide a window into the early pathogenesis of human ARDS and represent potential vascular biomarkers of ARDS risk. Clinical trial registered with www.clinicaltrials.gov (NCT01504867).
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Transtornos Plaquetários/etiologia , Transtornos Plaquetários/fisiopatologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/tratamento farmacológico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Children with chronic medical conditions, including heart disease, have increased susceptibility to behavioral health concerns. We sought to evaluate the feasibility and parental opinion of anxiety screening in pediatric cardiology clinic. The PROMIS Pediatric Anxiety v2.0 Short Form 8a (PA2-S8) questionnaire was administered to 48 patients presenting to pediatric cardiology clinic for follow-up care. Parents/caregivers were asked their opinion on anxiety screening in cardiology clinic. The survey was completed by 47 out of 48 participants (median age 13, range 9-17). Fourteen (30%) participants had scores suggestive of increased anxiety symptomatology. No trends were identified between PA2-S8 score and age at diagnosis (P = .13), age at survey administration (P = .28), number of lifetime procedures (P = .89), number of noncardiac specialists (P = .13), or underlying cardiac diagnoses (P = .55). Most families (76%) were in favor of the screening effort. This study suggests that anxiety screening in cardiology clinic is both feasible and well-received by families.
Assuntos
Cardiologia , Cuidadores , Criança , Humanos , Adolescente , Projetos Piloto , Estudos de Viabilidade , Ansiedade/diagnósticoRESUMO
BACKGROUND: In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS: ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47]). RESULTS: Bronchoalveolar lavage (BAL) fluid LXA4 and 15-epi-LXA4 were decreased and SAA was increased in SA relative to NSA. BAL macrophage ALX expression was increased in SA. Subjects with LXA4loSAAhi levels had increased BAL neutrophils, more asthma symptoms, lower lung function, increased relative risk for asthma exacerbation, sinusitis, and gastroesophageal reflux disease, and were assigned more frequently to SA clinical clusters. SAA and aliquots of LXA4loSAAhi BAL fluid induced IL-8 production by lung epithelial cells expressing ALX receptors, which was inhibited by coincubation with 15-epi-LXA4. CONCLUSIONS: Together, these findings have established an association between select ALX receptor ligands and asthma severity that define a potentially new biochemical endotype for asthma and support a pivotal functional role for ALX signaling in the fate of lung inflammation. TRIAL REGISTRATION: Severe Asthma Research Program-3 (SARP-3; ClinicalTrials.gov NCT01606826)FUNDING Sources. National Heart, Lung and Blood Institute, the NIH, and the German Society of Pediatric Pneumology.