American journal of respiratory and critical care medicine最新文献

Rationale: Congenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known.

Objectives: To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology.

Methods: Fetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation. A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDH in vivo.

Measurements and main results: VEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls.

Conclusions: This innovative approach could have a significant impact on the treatment of CDH.

Rationale: Pediatric asthma is heterogeneous, with varied clinical presentations and treatment responses. Metabolomic profiling may uncover shared and unique biological mechanisms across clinical traits that characterize pediatric asthma.

Objectives: To characterize the varied clinical presentation of pediatric asthma by examining the metabolome's relationship with 22 clinical traits, categorized into 5 phenotypic domains: airway hyperresponsiveness (AHR), atopy, lung function (LF), blood eosinophil (B-EOS), and blood neutrophil (B-NEU).

Methods: Metabolomic profiling was conducted on plasma samples from children in the Childhood Asthma Management Program (CAMP) (n=953) and the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n=1,155) studies. We identified domain-specific and multi-domain metabolites using a fixed-effect meta-analysis of generalized linear models between metabolites and 22 clinical traits. Metabolomic Risk Scores (MRSs) were developed to summarize the metabolic processes for each domain at the patient level.

Measurements and main results: There were 154 unique metabolites significantly associated with at least one of 22 clinical traits (q-value<0.05). Histamine and kynurenine were significant across 4 domains, while 7 metabolites-12,13-diHOME, azelate, sebacate, PC(P-36:0)/PC(O-36:1), taurine, nudifloramide, and niacinamide-were significant across 3. Notable domain-specific metabolites include n-oleoyl dopamine for AHR, 9-cis-retinoic acid for lung function, phosphatidylcholines for B-EOS, and 2-hydroxybutyric acid for B-NEUT. We then applied the domain-specific MRSs to previously identified patient clusters, enabling a more comprehensive characterization of each endotype.

Conclusion: This study demonstrated the power of the metabolome to capture the heterogeneity in the clinical presentation of pediatric asthma and to develop clinically relevant MRSs that inform our understanding of specific metabotypes to guide targeted treatment approaches.

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown.

Objective: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history.

Methods: We analyzed data from COPDGene participants with ≥10 pack-years cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator forced expiratory volume in 1 second (FEV₁)/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FEV₁ ≥LLN. We examined whether respiratory exacerbations occurring between Visits 1 and the 5-year follow-up visit (Visit 2) were associated with FEV₁ decline, and all-cause mortality.

Measurements and main results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between visit 1 and 2 was associated with a 2.96 ml/year FEV₁ decline (95%CI 1.81 to 4.12; P<0.001) at Visit 2. Experiencing ≥1 severe exacerbation between Visits 1 and 2 was associated with 14.6 ml/year FEV₁ decline relative to those with no severe exacerbations (95% CI 8.56 to 20.6; P<0.001). Individuals with ≥1 severe exacerbation between Visits 1 and 2 had increased mortality compared to those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio 1.97;95% CI 1.40 to 2.77; P<0.001).

Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.