Role of airway epithelial cell miRNAs in asthma

The airway epithelial cells and overlying layer of mucus are the first point of contact for particles entering the lung. The severity of environmental contributions to pulmonary disease initiation, progression, and exacerbation is largely determined by engagement with the airway epithelium. Despite the cellular cross-talk and cargo exchange in the microenvironment, epithelial cells produce miRNAs associated with the regulation of airway features in asthma. In line with this, there is evidence indicating miRNA alterations related to their multifunctional regulation of asthma features in the conducting airways. In this review, we discuss the cellular components and functions of the airway epithelium in asthma, miRNAs derived from epithelial cells in disease pathogenesis, and the cellular exchange of miRNA-bearing cargo in the airways

Airway remodeling: The Drosophila model permits a purely epithelial perspective

Airway remodeling is an umbrella term for structural changes in the conducting airways that occur in chronic inflammatory lung diseases such as asthma or chronic obstructive pulmonary disease (COPD). The pathobiology of remodeling involves multiple mesenchymal and lymphoid cell types and finally leads to a variety of hardly reversible changes such as hyperplasia of goblet cells, thickening of the reticular basement membrane, deposition of collagen, peribronchial fibrosis, angiogenesis and hyperplasia of bronchial smooth muscle cells. In order to develop solutions for prevention or innovative therapies, these complex processes must be understood in detail which requires their deconstruction into individual building blocks. In the present manuscript we therefore focus on the role of the airway epithelium and introduce Drosophila melanogaster as a model. The simple architecture of the flies’ airways as well as the lack of adaptive immunity allows to focus exclusively on the importance of the epithelium for the remodeling processes. We will review and discuss genetic and environmentally induced changes in epithelial structures and molecular responses and propose an integrated framework of research for the future

Cigarette Smoke Affects Dendritic Cell Populations, Epithelial Barrier Function, and the Immune Response to Viral Infection With H1N1

Smokers with apparently "healthy" lungs suffer from more severe and frequent viral respiratory infections, but the mechanisms underlying this observation are still unclear. Epithelial cells and dendritic cells (DC) form the first line of defense against inhaled noxes such as smoke or viruses. We therefore aimed to obtain insight into how cigarette smoke affects DCs and epithelial cells and how this influences the response to viral infection. Female C57BL/6J mice were exposed to cigarette smoke (CS) for 1 h daily for 24 days and then challenged i.n. with the viral mimic and Toll-like receptor 3 (TLR3) ligand poly (I:C) after the last exposure. DC subpopulations were analyzed 24 h later in whole lung homogenates by flow cytometry. Calu-3 cells or human precision-cut lung slices (PCLS) cultured at air-liquid interface were exposed to CS or air and subsequently inoculated with influenza H1N1. At 48 h post infection cytokines were analyzed by multiplex technology. Cytotoxic effects were measured by release of lactate dehydrogenase (LDH) and confocal imaging. In Calu-3 cells the trans-epithelial electrical resistance (TEER) was assessed. Smoke exposure of mice increased numbers of inflammatory and plasmacytoid DCs in lung tissue. Additional poly (I:C) challenge further increased the population of inflammatory DCs and conventional DCs, especially CD11b(+) cDCs. Smoke exposure led to a loss of the barrier function in Calu-3 cells, which was further exaggerated by additional influenza H1N1 infection. Influenza H1N1-induced secretion of antiviral cytokines (IFN-alpha 2a, IFN-lambda, interferon-gamma-induced protein 10 [IP-10]), pro-inflammatory cytokine IL-6, as well as T cell-associated cytokines (e.g., I-TAC) were completely suppressed in both Calu-3 cells and human PCLS after smoke exposure. In summary, cigarette smoke exposure increased the number of inflammatory DCs in the lung and disrupted epithelial barrier functions, both of which was further enhanced by viral stimulation. Additionally, the antiviral immune response to influenza H1N1 was strongly suppressed by smoke. These data suggest that smoke impairs protective innate mechanisms in the lung, which could be responsible for the increased susceptibility to viral infections in "healthy" smokers