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The importance of airway and lung microbiome in the critically ill.
Martin-Loeches, I, Dickson, R, Torres, A, Hanberger, H, Lipman, J, Antonelli, M, de Pascale, G, Bozza, F, Vincent, JL, Murthy, S, et al
Critical care (London, England). 2020;(1):537
Abstract
During critical illness, there are a multitude of forces such as antibiotic use, mechanical ventilation, diet changes and inflammatory responses that could bring the microbiome out of balance. This so-called dysbiosis of the microbiome seems to be involved in immunological responses and may influence outcomes even in individuals who are not as vulnerable as a critically ill ICU population. It is therefore probable that dysbiosis of the microbiome is a consequence of critical illness and may, subsequently, shape an inadequate response to these circumstances.Bronchoscopic studies have revealed that the carina represents the densest site of bacterial DNA along healthy airways, with a tapering density with further bifurcations. This likely reflects the influence of micro-aspiration as the primary route of microbial immigration in healthy adults. Though bacterial DNA density grows extremely sparse at smaller airways, bacterial signal is still consistently detectable in bronchoalveolar lavage fluid, likely reflecting the fact that lavage via a wedged bronchoscope samples an enormous surface area of small airways and alveoli. The dogma of lung sterility also violated numerous observations that long predated culture-independent microbiology.The body's resident microbial consortia (gut and/or respiratory microbiota) affect normal host inflammatory and immune response mechanisms. Disruptions in these host-pathogen interactions have been associated with infection and altered innate immunity.In this narrative review, we will focus on the rationale and current evidence for a pathogenic role of the lung microbiome in the exacerbation of complications of critical illness, such as acute respiratory distress syndrome and ventilator-associated pneumonia.
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Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment.
Martín Giménez, VM, Inserra, F, Tajer, CD, Mariani, J, Ferder, L, Reiter, RJ, Manucha, W
Life sciences. 2020;:117808
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Abstract
COVID-19 pandemic has a high mortality rate and is affecting practically the entire world population. The leading cause of death is severe acute respiratory syndrome as a consequence of exacerbated inflammatory response accompanied by uncontrolled oxidative stress as well as the inflammatory reaction at the lung level. Until now, there is not a specific and definitive treatment for this pathology that worries the world population, especially the older adults who constitute the main risk group. In this context, it results in a particular interest in the evaluation of the efficacy of existing pharmacological agents that may be used for overcoming or attenuating the severity of this pulmonary complication that has ended the lives of many people worldwide. Vitamin D and melatonin could be good options for achieving this aim, taking into account that they have many shared underlying mechanisms that are able to modulate and control the immune adequately and oxidative response against COVID-19 infection, possibly even through a synergistic interaction. The renin-angiotensin system exaltation with consequent inflammatory response has a leading role in the physiopathology of COVID-19 infection; and it may be down-regulated by vitamin D and melatonin in many organs. Therefore, it is also essential to analyze this potential therapeutic association and their relation with RAS as part of this new approach.
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MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.
Bilezikian, JP, Bikle, D, Hewison, M, Lazaretti-Castro, M, Formenti, AM, Gupta, A, Madhavan, MV, Nair, N, Babalyan, V, Hutchings, N, et al
European journal of endocrinology. 2020;(5):R133-R147
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Abstract
The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation.
Jevnikar, Z, Östling, J, Ax, E, Calvén, J, Thörn, K, Israelsson, E, Öberg, L, Singhania, A, Lau, LCK, Wilson, SJ, et al
The Journal of allergy and clinical immunology. 2019;(2):577-590
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Abstract
BACKGROUND Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. OBJECTIVE We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. METHODS An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. RESULTS Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. CONCLUSIONS Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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Interactions between microbiome and lungs: Paving new paths for microbiome based bio-engineered drug delivery systems in chronic respiratory diseases.
Chellappan, DK, Sze Ning, QL, Su Min, SK, Bin, SY, Chern, PJ, Shi, TP, Ee Mei, SW, Yee, TH, Qi, OJ, Thangavelu, L, et al
Chemico-biological interactions. 2019;:108732
Abstract
BACKGROUND The human body is a home to thousands of microbiotas. It is defined as a community of symbiotic, commensal and pathogenic microorganisms that have existed in all exposed sites of the body, which have co-evolved with diet, lifestyle, genetic factors and immune factors. Human microbiotas have been studied for years on their effects with relation to health and diseases. METHODS Relevant published studies, literature and reports were searched from accessible electronic databases and related institutional databases. We used keywords, viz; microbiome, microbiota, microbiome drug delivery and respiratory disease. Selected articles were carefully read through, clustered, segregated into subtopics and reviewed. FINDINGS The traditional belief of sterile lungs was challenged by the emergence of culture-independent molecular techniques and the recently introduced invasive broncho-alveolar lavage (BAL) sampling method. The constitution of a lung microbiome mainly depends on three main ecological factors, which include; firstly, the immigration of microbes into airways, secondly, the removal of microbes from airways and lastly, the regional growth conditions. In healthy conditions, the microbial communities that co-exist in our lungs can build significant pulmonary immunity and could act as a barrier against diseases, whereas, in an adverse way, microbiomes may interact with other pathogenic bacteriomes and viromes, acting as a cofactor in inflammation and host immune responses, which may lead to the progression of a disease. Thus, the use of microbiota as a target, and as a drug delivery system in the possible modification of a disease state, has started to gain massive attention in recent years. Microbiota, owing to its unique characteristics, could serve as a potential drug delivery system, that could be bioengineered to suit the interest. The engineered microbiome-derived therapeutics can be delivered through BC, bacteriophage, bacteria-derived lipid vesicles and microbe-derived extracellular vesicles. This review highlights the relationships between microbiota and different types of respiratory diseases, the importance of microbiota towards human health and diseases, including the role of novel microbiome drug delivery systems in targeting various respiratory diseases.
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Association of Serum Vitamin D (25OHD) Level with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.
Islam, S, Sarkar, NK, Mujahid, AA, Bennoor, KS, Hossain, SS, Attar, MM, Jahan, R, Hossain, MA, Chowdhury, HA, Ali, L
Mymensingh medical journal : MMJ. 2019;(2):441-448
Abstract
Acute exacerbations of COPD is characterized by a change in the patients baseline dyspnoea, cough and/or sputum that is beyond normal day to day differences and guides to a change in standard medications in a patient with COPD. Vitamin D influences the innate & adaptive immune system, and exerts pleiotropic antimicrobial and anti-inflammatory responses. Vitamin D deficiency is frequent among COPD patients but its contributory role in disease exacerbations is widely debated. This study was aimed to assess relationship between reduced serum vitamin D (25-OHD) level with COPD severity and acute exacerbation. This observational cross-sectional study was carried out in the department of Respiratory Medicine, NIDCH, Mohakhali, Dhaka, Bangladesh from October 2016 to September 2017. Consecutive 80 hospital admitted patients with acute exacerbation of chronic obstructive pulmonary disease diagnosed on the basis of clinical history & pulmonary function tests and 78 age & sex matched controls were investigated for serum vitamin D (25-OHD) level. Among the COPD patients, 37% had Vitamin D deficiency (<20ng/ml) and 28.75% had Vitamin D insufficiency (20-29ng/ml). Mean vitamin D (25-OHD) level of COPD patients (25.82±10.62ngm/ml) was found to be significantly lower than healthy controls (32.57±11.32ngm/ml). Vitamin D deficiency was found, by Pearson correlation test, to be significantly associated with severity of COPD. Multivariate analysis showed that age (in years), FEV1 (percent predicted), frequent exacerbators (≥2 in the last year), and smoking (>40 pack year) were significantly associated with Vitamin D deficiency. Acute exacerbation of chronic obstructive pulmonary disease patients was found to have vitamin D deficiency and vitamin D deficiency was significantly associated with severity of COPD. Vitamin D deficiency was also associated with frequent disease exacerbation.
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Rapid diversification of Pseudomonas aeruginosa in cystic fibrosis lung-like conditions.
Schick, A, Kassen, R
Proceedings of the National Academy of Sciences of the United States of America. 2018;(42):10714-10719
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Abstract
Chronic infection of the cystic fibrosis (CF) airway by the opportunistic pathogen Pseudomonas aeruginosa is the leading cause of morbidity and mortality for adult CF patients. Prolonged infections are accompanied by adaptation of P. aeruginosa to the unique conditions of the CF lung environment, as well as marked diversification of the pathogen into phenotypically and genetically distinct strains that can coexist for years within a patient. Little is known, however, about the causes of this diversification and its impact on patient health. Here, we show experimentally that, consistent with ecological theory of diversification, the nutritional conditions of the CF airway can cause rapid and extensive diversification of P. aeruginosa Mucin, the substance responsible for the increased viscosity associated with the thick mucus layer in the CF airway, had little impact on within-population diversification but did promote divergence among populations. Furthermore, in vitro evolution recapitulated traits thought to be hallmarks of chronic infection, including reduced motility and increased biofilm formation, and the range of phenotypes observed in a collection of clinical isolates. Our results suggest that nutritional complexity and reduced dispersal can drive evolutionary diversification of P. aeruginosa independent of other features of the CF lung such as an active immune system or the presence of competing microbial species. We suggest that diversification, by generating extensive phenotypic and genetic variation on which selection can act, may be a key first step in the development of chronic infections.
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Tolerability of inhaled N-chlorotaurine in humans: a double-blind randomized phase I clinical study.
Arnitz, R, Stein, M, Bauer, P, Lanthaler, B, Jamnig, H, Scholl-Bürgi, S, Stempfl-Al-Jazrawi, K, Ulmer, H, Baumgartner, B, Embacher, S, et al
Therapeutic advances in respiratory disease. 2018;:1753466618778955
Abstract
BACKGROUND N-chlorotaurine (NCT), a long-lived oxidant produced by human leukocytes, can be synthesized chemically and used topically as a well-tolerated antiseptic to different body regions including sensitive ones. The aim of this study was to test the tolerability of inhaled 1% NCT in aqueous solution upon repeated application. METHODS The study was performed double-blind and randomized with a parallel test group (1% NCT) and control group (0.9% NaCl as placebo). There were two Austrian centres involved, the hospitals, Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each centre. A total of 12 patients were treated with NCT, and 12 with placebo, exactly half of each group from each centre. The single dose was 1.2 ml inhaled over a period of 10 min using an AKITA JET nebulizer. One inhalation was done every day for five consecutive days. The primary criterion of evaluation was the forced expiratory volume in 1 second (FEV1). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters). RESULTS All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV1 (100.83% ± 8.04% for NCT and 92.92% ± 11.35% for controls) remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment (98.75% ± 7.37% for NCT and 91.17% ± 9.46% for controls, p > 0.082 between time points within each group). The same was true for all other objective parameters. Subjective mild sensations with a higher frequency in the test group were chlorine taste ( p < 0.01) and occasional tickle in the throat ( p = 0.057). Taurine and methionine plasma concentrations did not change within 60 min after inhalation or later on. CONCLUSIONS Inhaled NCT is well tolerated as in other applications of different body regions. Side effects are mild, topical and transitory. The study was registered prospectively in the European Clinical Trials Database of the European Medicines Agency. The EudraCT number is 2012-003700-12.
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Potential Role of the Lung Microbiome in Shaping Asthma Phenotypes.
Chung, KF
Annals of the American Thoracic Society. 2017;(Supplement_5):S326-S331
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Abstract
The introduction of 16s ribosomal RNA sequencing as a nonculture technique has led to the discovery of the presence of microbiota in the lower airways of healthy individuals. These bacterial communities may originate from the mouth and nasopharynx or from the environment by inhalation. The microbial composition of the lower airways may be modulated by dietary factors, antibiotic therapy, and microbial infections, particularly in early life. In addition, circulatory products from gut microbiota may influence the lung microbiota to maintain mucosal immunity. Recent studies have revealed that, in asthma, the lower airway microbiota show reduced diversity and community composition that is linked to severity and inflammatory phenotype. There is also a greater prevalence of proteobacteria, including Haemophilus, in symptomatic asthma. Microbial dysbiosis may contribute to both the inception and progression of asthma in infants and children, and to corticosteroid resistance in asthma. A better understanding of the regulation of the lung and gut microbiota in asthma may pave the way for targeting microbiota to prevent and treat asthma.
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In utero alcohol effects on foetal, neonatal and childhood lung disease.
Gauthier, TW, Brown, LA
Paediatric respiratory reviews. 2017;:34-37
Abstract
Maternal alcohol use during pregnancy exposes both premature and term newborns to the toxicity of alcohol and its metabolites. Foetal alcohol exposure adversely effects the lung. In contrast to the adult "alcoholic lung" phenotype, an inability to identify the newborn exposed to alcohol in utero has limited our understanding of its effect on adverse pulmonary outcomes. This paper will review advances in biomarker development of in utero alcohol exposure. We will highlight the current understanding of in utero alcohol's toxicity to the developing lung and immune defense. Finally, we will present recent clinical evidence describing foetal alcohol's association with adverse pulmonary outcomes including bronchopulmonary dysplasia, viral infections such as respiratory syncytial virus and allergic asthma/atopy. With research to define alcohol's effect on the lung and translational studies accurately identifying the exposed offspring, the full extent of alcohol's effects on clinical respiratory outcomes of the newborn or child can be determined.