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Background: Early-life inflammation has long been recognised as a key pathophysiological process in the evolution of cystic fibrosis (CF) lung disease. Despite this, no CF-specific anti-inflammatory treatments have been developed. This is crucial even in the era of highly effective modulator therapy as recent evidence suggests that modulators alter, but may not fully resolve, pulmonary inflammation.

Methods: In this study, we used clinical microbiology data, high-dimensional flow cytometry and multiplex immunoassays to compare pulmonary (bronchoalveolar lavage (BAL)) and systemic immunity in 70 preschool children with CF and a total of 32 age-matched preschool controls.

Results: We show that inflammation in the early-life CF lung is characterised by innate cell infiltration (neutrophils: 31.31 vs 1.8% of BAL in CF compared with controls, FDRp=0.0001; eosinophils: 0.55 vs 0.06%, FDRp=0.001, and monocytes: 1.91 vs 0.45%, FDRp=0.004) and widespread upregulation of both traditional and type 2 inflammatory soluble signatures (40 analytes significantly elevated in BAL of CF compared with controls, all FDRp<0.1). Key targetable features of this response included pulmonary interleukin (IL)-8 and IL-13 which were most significantly associated with neutrophilic and eosinophilic infiltration, respectively (IL-8 and neutrophils; Spearman rho=0.68, FDRp=0.002: IL-13 and eosinophils; Spearman rho=0.75, FDRp=0.01). Signatures of type 2 inflammation, as identified by REACTOME pathway analysis, including IL-4, IL-13 and FGF-2, were highly elevated in both the lungs and circulation in early CF. When exploring the efficacy of Cystic Fibrosis Transmembrane Conductance Regulator modulators to resolve pulmonary and systemic inflammation in early life, we showed that different classes of modulators have varying effects on inflammation, with ivacaftor showing a more significant effect in the lungs and circulation than lumacaftor/ivacaftor. Finally, we showed that CF children with pathogen colonisation had similar levels of pulmonary inflammation as CF children without pathogen colonisation (no significant differences), and that inflammation was evident during infancy even without evidence of colonisation (as observed by significant increases in levels of SDF-1alpha, M-CSF, IL-2, IL-9, IL-12p40, IL-17, MCP-1 and LIGHT/TNFSF14, all FDRp<0.1), highlighting a role for intrinsic dysregulation of inflammation that begins in early life.

Conclusions: We provide a rationale for targeted anti-inflammatory intervention in early-life CF.

A decreasing trend in asthma hospitalisations among Finnish and Swedish children has been reported. However, possible changes in asthma hospitalisations among adults are incompletely characterised. We aimed to investigate the incidence of adult asthma hospitalisations in Finland and Sweden from 2006 to 2022 using Finland's National Hospital Discharge Register and Sweden's National Patient Register. During the study period, the incidence of asthma hospitalisations decreased by 65.8% in Finland (from 84.9 to 29.0 per 100 000 person-years) and by 52.5% in Sweden (from 31.4 to 14.9 per 100 000 person-years). The incidences of asthma hospitalisations were distinctly higher in Finland compared with Sweden at the start of the study period but approached parity among both sexes.

Dietary nitrate supplementation, which improves skeletal muscle oxygen utilisation, vascular endothelial function and exercise capacity in people with chronic obstructive pulmonary disease, may benefit other lung conditions. In a double-blind, placebo-controlled, crossover study, in 19 adults with Group 3 pulmonary hypertension who desaturated during exercise, 140 mL of nitrate-rich beetroot juice improved endurance shuttle walk time compared with nitrate-depleted beetroot juice placebo (median (IQR) ESWT NR-BRJ 197 (140-273) s vs PL-BRJ 174 (107-229) s; median difference (MD) (95% CI) 30 (6.19 to 91.07) s, p=0.0281), endothelial function, flow-mediated dilatation (+3.40±5.47% vs -1.33±4.78; MD (95% CI) 4.73 (1.44 to 8.02), p=0.007) and lowered mean arterial blood pressure (-3.9 (-7.4 to -0.4) mm Hg, p=0.028).

Medical practice is built on the foundations of evidence-based medicine. Hence, the more common the clinical intervention, the more comprehensive the evidence on which that intervention should be based. Although the widespread adoption of a national early warning score in the UK has led to improvements in the delivery of care, it should be considered as providing a foundation that can be refined and developed, and there is still a need for critical reflection and evaluation of early warning scores, particularly for individuals with chronic respiratory disease, in order to optimise patient monitoring, predict deterioration and guide intervention.

Smoking cessation is more effective when supported by medicines. Data on the availability, cost and affordability of these treatments in low-income and middle-income countries (LMIC) are limited. Cross-sectional data for smoking cessation medications were collected from pharmacies, healthcare facilities and central medicine stores in 60 LMIC (2022-2023). Medications had varying availability, large price ranges and were essentially unaffordable. Enabling access to these medications is important in reducing tobacco consumption and associated disease. Strategies for integrating smoking cessation services into health systems are needed to reach Sustainable Development Goal targets.

Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome's initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.