Crucial role for lung iron level and regulation in the pathogenesis and severity of asthma.

Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1 s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.

Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report.

"Treatable traits" have been proposed as a new paradigm for the management of airway diseases, particularly complex disease, which aims to apply personalised medicine to each individual to improve outcomes. Moving new treatment approaches from concepts to practice is challenging, but necessary. In an effort to accelerate progress in research and practice relating to the treatable traits approach, the Treatable Traits Down Under International Workshop was convened in Melbourne, Australia in May 2018. Here, we report the key concepts and research questions that emerged in discussions during the meeting. We propose a programme of research that involves gaining international consensus on candidate traits, recognising the prevalence of traits, and identifying a potential hierarchy of traits based on their clinical impact and responsiveness to treatment. We also reflect on research methods and designs that can generate new knowledge related to efficacy of the treatable traits approach and consider multidisciplinary models of care that may aid its implementation into practice.

Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured airway epithelial cells.

Long-chain n-3 PUFA (LCn-3PUFA) including DHA and EPA, are known to decrease inflammation by inhibiting arachidonic acid (AA) metabolism to eicosanoids, decreasing the production of pro-inflammatory cytokines and reducing immune cell function. The aim of this study was to determine if EPA and DHA reduced the release of inflammatory mediators from airway epithelial cells infected with rhinovirus (RV). Airway epithelial cells (Calu-3) were incubated with EPA, DHA and AA for 24 h, followed by rhinovirus infection for 48 h. IL-6, IL-8 and interferon-gamma-induced protein-10 (IP-10) released by cells were measured using ELISA. Viral replication was measured by serial titration assays. The fatty acid content of cells was analysed using GC. Cellular viability was determined by visual inspection of cells and lactate dehydrogenase release. DHA (400 microm) resulted in a significant 16% reduction in IL-6 release after RV-43 infection, 29% reduction in IL-6 release after RV-1B infection, 28% reduction in IP-10 release after RV-43 infection and 23 % reduction in IP-10 release after RV-1B infection. Cellular DHA content negatively correlated with IL-6 and IP-10 release. None of the fatty acids significantly modified rhinovirus replication. DHA supplementation resulted in increased cellular content of DHA at the cost of AA, which may explain the decreased inflammatory response of cells. EPA and AA did not change the release of inflammatory biomarkers significantly. It is concluded that DHA has a potential role in suppressing RV-induced airway inflammation.

Lycopene enrichment of cultured airway epithelial cells decreases the inflammation induced by rhinovirus infection and lipopolysaccharide.

Rhinovirus infection results in increased release of inflammatory mediators from airway epithelial cells in asthma. As an antioxidant, lycopene offers protection from adverse effects of inflammation. The aim of this study was to find an appropriate method of lycopene enrichment of airway epithelial cells and to determine the effects of lycopene enrichment on the inflammatory response of cells infected by rhinovirus or exposed to lipopolysaccharide. Lycopene enrichment of airway epithelial cells using solubilisation in tetrahydrofuran versus incorporation in liposomes was compared. After determining that solubilisation of lycopene in tetrahydrofuran was the most suitable method of lycopene supplementation, airway epithelial cells (Calu-3) were incubated with lycopene (dissolved in tetrahydrofuran) for 24 h, followed by rhinovirus infection or lipopolysaccharide exposure for 48 h. The release of interleukin-6, interleukin-8 and interferon-gamma induced protein-10 (IP-10) and their messenger RNA levels were measured using enzyme linked immunosorbent assay and reverse transcription polymerase chain reaction, respectively. Viral replication was measured by tissue culture infective dose of 50% assay. Lycopene concentration of cells and media were analysed using high-performance liquid chromatography. Preincubation of airway epithelial cells with lycopene (dissolved in tetrahydrofuran) delivered lycopene into the cells and resulted in a 24% reduction in interleukin-6 after rhinovirus-1B infection, 31% reduction in IP-10 after rhinovirus-43 infection and 85% reduction in rhinovirus-1B replication. Lycopene also decreased the release of IL-6 and IP-10 following exposure to lipopolysaccharide. We conclude that lycopene has a potential role in suppressing rhinovirus induced airway inflammation.