RESUMO
BACKGROUND: Pulmonary hypertension (PH) in patients with bronchopulmonary dysplasia (BPD) results from vasoconstriction and/or vascular remodeling, which can be regulated by mitogen-activated protein kinases (MAPKs). MAPKs are deactivated by dual-specificity phosphatases (DUSPs). We hypothesized that single-nucleotide polymorphisms (SNPs) in DUSP genes could be used to predict PH in BPD. METHODS: Preterm infants diagnosed with BPD (n = 188) were studied. PH was defined by echocardiographic criteria. Genomic DNA isolated from patient blood samples was analyzed for 31 SNPs in DUSP genes. Clinical characteristics and minor allele frequencies were compared between BPD-PH (cases) and BPD-without PH (control) groups. Biomarker models to predict PH in BPD using clinical and SNP data were tested by calculations of area under the ROC curve. RESULTS: In our BPD cohort, 32% (n = 61) had PH. Of the DUSP SNPs evaluated, DUSP1 SNP rs322351 was less common, and DUSP5 SNPs rs1042606 and rs3793892 were more common in cases than in controls. The best fit biomarker model combines clinical and DUSP genetic data with an area under the ROC curve of 0.76. CONCLUSION: We identified three DUSP SNPs as potential BPD-PH biomarkers. Combining clinical and DUSP genetic data yields the most robust predictor for PH in BPD.
Assuntos
Displasia Broncopulmonar/genética , Fosfatase 1 de Especificidade Dupla/genética , Fosfatases de Especificidade Dupla/genética , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/diagnóstico , Displasia Broncopulmonar/enzimologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/enzimologia , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the molecular mechanism of reactive nitrogen species (RNS) in the pathogenesis of asthma and examine the use of fractional exhaled nitric oxide (FENO) measurements in close conjunction with standard clinical assessments of asthma. DATA SOURCES: Through PubMed, Google Scholar, and Medline databases, a broad medical literature review was performed in the following areas of asthma pathobiology and management: allergic asthma, RNS, nitric oxide (NO), airway inflammation, and FENO. STUDY SELECTIONS: Studies were selected based on the physiologic and pathophysiologic roles of RNS in relation to allergic asthma. Current evaluations on clinical applications of FENO in asthma treatment also were selected. RESULTS: At the onset of an asthma attack, an enhanced production of NO strongly correlates with increase inducible NO synthase (NOS) activity, whereas endothelial NOS and neuronal NOS regulate primarily normal metabolic functions in the central and peripheral airways. During allergic inflammatory responses, NO and superoxide form peroxynitrite, which has deleterious effects in the respiratory tract. RNS directly accentuates airway inflammation and cytotoxicity through nitrosative stress. Moreover, the use of FENO to monitor eosinophilic-mediated airway inflammation is a potentially valuable assessment that supplements standard procedures to monitor the progression of asthma. CONCLUSION: This review examines recent evidence implicating the molecular mechanisms of NO and NO-derived RNS in the pathobiology of asthma and suggests that monitoring FENO may markedly contribute to asthma diagnosis.
