NLRP3 inflammasome responses drive experimental severe, steroid-resistant asthma and are potential therapeutic targets in this disease.

Oxidative stress, specifically lipid peroxidation, is believed to contribute to the pathophysiology of asthma. This review highlights the pathways through which reactive oxygen species (ROS) may lead to lipid peroxidation. The potential of both the innate and acquired immune systems to activate inflammatory cells and release ROS that may overwhelm the host antioxidant defences and cause lipid peroxidation, accompanied by detrimental pathophysiological effects, are discussed.Despite the evidence demonstrating the importance of lipid peroxidation, systematic characterisation of oxidative stress and antioxidant defences has not been undertaken, largely due to the lack of appropriate biomarkers. This review discusses the emergence of isoprostanes (specifically 8-iso-prostaglandin F 2a ) as reliable, in vivo markers of lipid peroxidation, which provides an appropriate tool for studying oxidative stress. Furthermore, the development of techniques to study induced sputum and breath condensate, derived directly from the airway surface, enables the site of oxidative damage to be closely assessed.Evidence suggests that dietary changes that have occurred over recent years have increased susceptibility to lipid peroxidation, due to reduced antioxidant defences. To date, the limited number of long-term (w1 week) supplementation trials have been promising. However, the development of techniques to study isoprostanes in airwaylining fluid pave the way for further studies investigating the potential for antioxidant supplements to be used as routine therapy in asthma.

Chronic obstructive pulmonary disease (COPD) is the third commonest cause of death globally, and manifests as a progressive inflammatory lung disease with no curative treatment. The lung microbiome contributes to COPD progression, but the function of the gut microbiome remains unclear. Here we examine the faecal microbiome and metabolome of COPD patients and healthy controls, finding 146 bacterial species differing between the two groups. Several species, including Streptococcus sp000187445, Streptococcus vestibularis and multiple members of the family Lachnospiraceae, also correlate with reduced lung function. Untargeted metabolomics identifies a COPD signature comprising 46% lipid, 20% xenobiotic and 20% amino acid related metabolites. Furthermore, we describe a disease-associated network connecting Streptococcus parasanguinis_B with COPD-associated metabolites, including N-acetylglutamate and its analogue N-carbamoylglutamate. While correlative, our results suggest that the faecal microbiome and metabolome of COPD patients are distinct from those of healthy individuals, and may thus aid in the search for biomarkers for COPD.

Background: Prebiotic soluble fibers are fermented by beneficial bacteria in the colon to produce short-chain fatty acids (SCFAs), which are proposed to have systemic anti-inflammatory effects. Objective: This review examines the effect of SCFAs, prebiotics, and pre-and probiotic combinations (synbiotics) on systemic inflammation. Design: Relevant English language studies from 1947 to May 2017 were identified with the use of online databases. Studies were considered eligible if they examined the effects of SCFAs, prebiotics, or synbiotics; were delivered orally, intravenously, or per rectum; were on biomarkers of systemic inflammation in humans; and performed meta-analysis where possible. Results: Sixty-eight studies were included. Fourteen of 29 prebiotic studies and 13 of 26 synbiotic studies reported a significant decrease in $1 marker of systemic inflammation. Eight studies compared prebiotic and synbiotic supplementation, 2 of which reported a decrease in inflammation with synbiotics only, with 1 reporting a greater anti-inflammatory effect with synbiotics than with prebiotics alone. Meta-analyses indicated that prebiotics reduce C-reactive protein ( Conclusions: There is significant heterogeneity of outcomes in studies examining the effect of prebiotics and synbiotics on systemic inflammation. Approximately 50% of included studies reported a decrease in $1 inflammatory biomarker. The inconsistency in reported outcomes may be due to heterogeneity in study design, supplement formulation, dosage, duration, and subject population. Nonetheless, meta-analyses provide evidence to support the systemic anti-inflammatory effects of prebiotic and synbiotic supplementation.Am J Clin Nutr 2017;106:930-45.

Severe, steroid-resistant asthma is clinically and economically important since affected individuals do not respond to mainstay corticosteroid treatments for asthma. Patients with this disease experience more frequent exacerbations of asthma, are more likely to be hospitalized, and have a poorer quality of life. Effective therapies are urgently required, however, their development has been hampered by a lack of understanding of the pathological processes that underpin disease. A major obstacle to understanding the processes that drive severe, steroid-resistant asthma is that the several endotypes of the disease have been described that are characterized by different inflammatory and immunological phenotypes. This heterogeneity makes pinpointing processes that drive disease difficult in humans. Clinical studies strongly associate specific respiratory infections with severe, steroid-resistant asthma. In this review, we discuss key findings from our studies where we describe the development of representative experimental models to improve our understanding of the links between infection and severe, steroid-resistant forms of this disease. We also discuss their use in elucidating the mechanisms, and their potential for developing effective therapeutic strategies, for severe, steroid-resistant asthma. Finally, we highlight how the immune mechanisms and therapeutic targets we have identified may be applicable to obesity-or pollution-associated asthma.

In conclusion, this review suggests that higher intakes of fruit and vegetables lead to both a reduction in proinflammatory mediators and an enhanced immune cell profile.

Oxidlative stress is believed to play an important role in the pathophysiology of asthma. Recently discovered F2-isoprostanes, of which 8-iso-PGF2alpha is the most well-known isomer, have emerged as the most reliable marker of in vivo oxidative stress. The aim of this study was to examine 8-iso-PGF2alpha as a biomarker of oxidative stress in mild asthma in relation to endogenous and dietary antioxidant protection. Total (free and esterified) plasma 8-iso-PGF2alpha, plasma dietary antioxidants (vitamins E and C, Beta-carotene, Zn, and Se), and erythrocyte antioxidant enzyme activities (glutathione peroxidase and superoxide dismutase) were measured in 15 mild asthmatics and 15 age-and sex-matched controls. Total plasma 8-iso-PGF2alpha levels [median (quartile 1 - quartile 3)] were significantly increased in the asthmatics [213 pg/mL (122-455) vs. 139 pg/mL (109-174), P= 0.042]. The 8-iso PGF2alpha levels were found to be associated with clinical asthma severity (P = 0.044) and inhaled corticosteroid use (P = 0.027) in asthmatics. No differences were observed in the plasma dietary antioxidant vitamins. The asthmatics had significantly lower plasma levels of Zn (P = 0.027) and Se (P = 0.006). Plasma Se correlated negatively with 8-iso-PGF2alpha (r = -0.725, P= 0.002). No differences between the groups were observed for glutathione peroxidase or superoxide dismutase, however, superoxide dismutase activity was negatively associated with asthma severity (P = 0.042). In conclusion, oxidative stress is increased in mildly asthmatics, as reflected by increased plasma levels of 8-iso-PGF2alpha and a deficiency in plasma Zn and Se. The isoprostane 8-iso-PGF2alpha may provide a useful tool in intervention studies aimed at improving clinical status in asthma.

Whereas increased beta-carotene, selenium, and fatty acid concentrations are linked to improved lung function, increased plasma fatty acid concentrations are linked to oxidative stress. If oxidative stress is deemed to be important to the clinical outcome of CF patients, means of reducing oxidative stress while maintaining a high-fat, high-energy diet must be investigated.