Background The lung has a diverse microbiome that is modest in biomass. This microbiome differs in asthmatic patients compared to control subjects, but the effects of clinical characteristics on the microbial community composition and structure are not clear. Objectives We examined whether the composition and structure of the lower airway microbiome correlated with clinical characteristics of chronic, persistent asthma including airflow obstruction, use of corticosteroid medications, and presence of airway eosinophilia. Methods DNA was extracted from endobronchial brushings and bronchoalveolar lavage fluid collected from 39 asthmatic and 19 control subjects, along with negative control samples. 16S rRNA V4 amplicon sequencing was employed to compare the relative abundance of bacterial genera to clinical characteristics. Results Differential feature selection analysis revealed significant differences in microbial diversity between asthmatic and control brush and lavage samples. Lactobacillus, Pseudomonas, and Rickettsia were significantly enriched in asthmatic samples; while Prevotella, Streptococcus, and Vellonella were enriched in the control brushing samples. Generalized linear models (GLM) on brush samples demonstrated oral corticosteroid usage as an important factor affecting the relative abundance of the taxa significantly enriched in asthmatic patients. In addition, bacterial alpha-diversity in brush samples from asthmatic subjects was correlated with FEV1 and with the proportion of lavage eosinophils. Conclusion The diversity and composition of the bronchial airway microbiome of asthmatic patients is distinct from that of control, non-asthmatic patients and is influenced by worsening airflow obstruction and corticosteroid usage.

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Rationale: Bronchial thermoplasty is an alternative treatment for patients with severe, uncontrolled asthma in which the airway smooth muscle is eliminated using radioablation. Although this emerging therapy shows promising outcomes, little is known about its effects on airway inflammation.Objectives: We examined the presence of bronchoalveolar lavage cytokines and expression of smooth muscle actin in patients with severe asthma before and in the weeks after bronchial thermoplasty.Methods: Endobronchial biopsies and bronchoalveolar lavage samples from 11 patients with severe asthma were collected from the right lower lobe before and 3 and 6 weeks after initial bronchial thermoplasty. Samples were analyzed for cell proportions and cytokine concentrations in bronchoalveolar lavage and for the presence of a-SMA in endobronchial biopsies.Measurements and Main Results: a-SMA expression was decreased in endobronchial biopsies of 7 of 11 subjects by Week 6. In bronchoalveolar lavage fluid, both transforming growth factor-b 1 and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5 were substantially decreased 3 and 6 weeks post bronchial thermoplasty in all patients. The cytokine tumor-necrosisfactor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in several cell types, was increased in concentration both 3 and 6 weeks post bronchial thermoplasty.Conclusions: Clinical improvement and reduction in a-SMA after bronchial thermoplasty in severe, uncontrolled asthma is associated with substantial changes in key mediators of inflammation. These data confirm the substantial elimination of airway smooth muscle post thermoplasty in the human asthmatic airway and represent the first characterization of significant changes in airway inflammation in the first weeks after thermoplasty.

Background: Noscapine is a safe orally available anticough medicine also known to bind microtubules and induce cancer cell death. Results: Noscapine inhibits myofibroblast differentiation and pulmonary fibrosis through prostaglandin receptors and activation of PKA. Conclusion: Noscapine is an antifibrotic drug acting through PKA activation via EP 2 prostaglandin receptors. Significance: This study describes a novel antifibrotic function and novel mechanism of action of noscapine.

Development of the nephron tubules, the functional units of the kidney, requires the differentiation of a renal progenitor population of mesenchymal cells to epithelial cells. This process requires an intricate balance between self-renewal and differentiation of the renal progenitor pool. Sall1 is a transcription factor necessary for renal development which is expressed in renal progenitor cells (cap mesenchyme). Sall1 recruits the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex to regulate gene transcription. We deleted Mi2β, a component of the NuRD complex, in cap mesenchyme (CM) to examine its role in progenitor cells during kidney development. These mutants displayed significant renal hypoplasia with a marked reduction in nephrons. Markers of renal progenitor cells, Six2 and Cited1 were significantly depleted and progenitor cell proliferation was reduced. We also demonstrated that Sall1 and Mi2β exhibited a strong in vivo genetic interaction in the developing kidney. Together these findings indicate that Sall1 and NuRD act cooperatively to maintain CM progenitor cells.