Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain. Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells. Both GABAARs and the GABA synthetic enzyme glutamic acid decarboxylase (GAD) are expressed in pulmonary epithelial cells. Activation of GABAARs depolarized these cells. The expression of GAD in the cytosol and GABAARs in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD and GABAARs in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABAAR inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 in mice. These findings show that a previously unknown epithelial GABAergic system has an essential role in asthma.
Sputum consists of a mixture of mucus, inflammatory and epithelial cells, and cellular degradation products from the lower respiratory tract. In normal subjects, the inflammatory cells are mainly neutrophils and macrophages, with small numbers of lymphocytes, eosinophils, mast cells, and basophils. When expectorated the sputum is commonly contaminated with a variable amount of saliva, which has abundant squamous epithelial cells, and sometimes with secretions from the nasopharynx. These can be reduced by blowing the nose, rinsing the mouth, and swallowing water before expectoration. Contamination with saliva can be minimized by selecting the sputum from the expectorate and discarding the remainder. Selection of sputum (1) improves between-observer repeatability of differential cell counts (2,3) and allows standardization of measurements of total cell counts (expressed per gram of sputum) and fluid-phase mediators (by knowledge of the dilution factor of the processed sample).
RATIONALE:We have previously demonstrated that low dose repeated administration of silver nitrate (SN) can lead to effective pleurodesis, and that delivering a low dose of SN via a drug eluting catheter is effective in a small animal model. This study aimed to assess the effect of a SN eluting catheter in a large animal model of pleurodesis. METHODS: A catheter coating capable of eluting SN over 14 days was designed and tested in an in−vivo large animal pleurodesis model. Three groups of four animals (male Suffolk lambs) underwent placement of uncoated, 1g SN and 0.75g SN silicone catheters in the right pleural space. Catheters were aspirated regularly and removed on day 15 with necropsy performed on day 29. Efficacy of pleurodesis was assessed by an 8 point scoring system (1−normal, 8−pleural symphysis >50% hemithorax), with a score of 5 considered significant. RESULTS: One animal in the 0.75g group was ill and did not proceed with the experiment. One 1g catheter was accidentally removed at day 3 (score 4) but is included in the analysis. Two animals in the 1g group developed empyema, were excluded from analysis, and the experiment repeated in 2 additional animals. Mean pleurodesis scores on the treated side were 1, 6.7, and 6.5 for the uncoated, 0.75g and 1g groups respectively, and 1 for the untreated pleural space in all animals (Table).
word count: 216 21 Text word count: 8953 (Methods section is 3400) 22 Abstract 23Gut microbiomes make major contributions to the physiological and immunological 24 development of the host, but the relative importance of their bacterial and fungal components, 25 and how they interact, remain largely unknown. We applied carefully controlled experiments in 26 gnotobiotic mice colonized with defined communities of bacteria, fungi, or both to differentiate 27 the direct role of fungi on microbiome assembly, host development, and susceptibility to colitis 28 and airway inflammation. Our results revealed that fungal colonization alone was insufficient to 29 promote the intestinal anatomic and physiological changes seen in mice colonized by bacteria, 30 and had limited impact on the fecal metabolome. However, fungal colonization promoted major 31 shifts in bacterial microbiome ecology, and had an independent effect on the innate and adaptive 32 immune development in young mice. Fungi further exacerbated some aspects of the 33 inflammatory effects of the bacterial community during OVA-induced airway inflammation by 34 promoting macrophage infiltration in the airway. Our results demonstrate a dominant ecological 35 and physiological role of bacteria in gut microbiomes, but highlight fungi as an ecological factor 36 shaping the assembly of the bacterial community and a direct capacity to impact immune system 37 and modulate disease susceptibility. These findings demonstrate that studies focused on bacteria 38 alone provide an incomplete portrayal on microbiome ecology and functionality, and prompt for 39 the inclusion of fungi in human microbiome studies. 40 41 42 43 44 45 65 suggestive of fungal overgrowth by this common yeast18. As well, another common yeast, 66 Malassezia restricta, was present in the majority of patients carrying the IBD risk allele CARD9, 67 a molecule involved in fungal innate immunity19. Experimental colonization of mice with M. 68 4 restricta resulted in exacerbated Dextran Sodium Sulfate (DSS)-induced colitis, characterized by 69 CARD9-dependent Th1 and Th17 inflammation19. 70Early-life gut dysbiosis has also been linked to atopic asthma. We had previously shown 71 that early-life bacterial communities are altered in Canadian infants that later developed atopic-72 wheeze20. Fujimura et al. extended our findings and revealed an expansion of Candida sp. and 73 Rhodotorula sp. in stool samples from US infants that later developed atopy13. Similarly, we 74 detected mycobiome alterations in stool of rural Ecuadorian infants that developed atopic-75 wheeze at 5 years12. Differences in the fungal community were more strongly associated with 76 asthma risk than bacterial dysbiosis in the Ecuadorian study, in which we detected an 77 overrepresentation of total fungal sequences and an expansion of the yeast Pichia kudriavzevii in 78 children who later developed symptoms12. While these studies revealed interesting associations 79 between early-life mycobiome alterations and infant atopy and asthma, the causal...
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