The air–liquid interface model

The airway epithelium lining the airways is in first contact with the inhaled environment, which contains allergens, gaseous pollutants, particulates, and pathogenic microorganisms. It forms an ion- and size-selective barrier between the inhaled environment and the underlying tissue by the formation of intercellular tight junctions and adhesion junctions. Additionally, the airway epithelium plays an important role in innate immune defense, expressing receptors that recognize molecular patterns from pathogenic microbes, parasites, fungi, and allergens and danger signals from damaged cells, directing proinflammatory processes. Chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, involve changes in airway epithelial function. For valuable insights into these changes, in vitro models should closely recapitulate human airway epithelial composition, three-dimensional structure, and function as an immunological barrier. The goal of this chapter is to review the literature on the use of air–liquid interface cultures to model the lung epithelium in health and disease.</p

Dynamic differences in dietary polyunsaturated fatty acid metabolism in sputum of COPD patients and controls

Introduction: Disturbances in onset and resolution of inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. Dietary polyunsaturated fatty acids (PUFAs) can be converted into lipid mediators here collectively named oxylipins. These include classical eicosanoids, but also pro-resolving mediators. A balanced production of pro-inflammatory and pro-resolving oxylipins is of importance for adequate inflammatory responses and subsequent return to homeostasis. Objectives: Here we investigated if PUFA metabolism is disturbed in COPD patients. Methods: Free PUFA and oxylipin levels were measured in induced sputum samples from the Bergen COPD cohort and COPD exacerbation study using liquid chromatography-mass spectrometry. Additionally, effects of whole cigarette smoke on PUFA metabolism in air-liquid interface cultures of primary bronchial epithelial cells were assessed. Results: Significantly lower levels of free alpha-linolenic acid, linoleic acid and eicosapentaenoic acid (EPA) were detected in sputum from stable COPD patients compared to controls. During acute exacerbation (AE), levels of free arachidonic acid and docosapentaenoic acid were higher than in stable COPD patients. Furthermore, levels of omega-3 EPA- and docosahexaenoic acid-derived oxylipins were lower in sputum from stable COPD patients compared to controls. Cyclooxygenase-2-converted mediators were mostly increased during AE. In vitro studies additionally showed that cigarette smoke exposure may also directly contribute to altered epithelial PUFA metabolism, and indirectly by causing airway epithelial remodelling. Conclusions: Our findings show significant differences in PUFA metabolism in COPD patients compared to controls, further changed during AE. Airway epithelial remodelling may contribute to these changes. These findings provide new insight in impaired inflammatory resolution in COPD.publishedVersio

Cigarette smoke differentially affects IL-13-induced gene expression in human airway epithelial cells

Allergic airways inflammation in asthma is characterized by an airway epithelial gene signature composed of POSTN, CLCA1, and SERPINB2 This Th2 gene signature is proposed as a tool to classify patients with asthma into Th2-high and Th2-low phenotypes. However, many asthmatics smoke and the effects of cigarette smoke exposure on the epithelial Th2 gene signature are largely unknown. Therefore, we investigated the combined effect of IL-13 and whole cigarette smoke (CS) on the Th2 gene signature and the mucin-related genes MUC5AC and SPDEF in air-liquid interface differentiated human bronchial (ALI-PBEC) and tracheal epithelial cells (ALI-PTEC). Cultures were exposed to IL-13 for 14 days followed by 5 days of IL-13 with CS exposure. Alternatively, cultures were exposed once daily to CS for 14 days, followed by 5 days CS with IL-13. POSTN, SERPINB2, and CLCA1 expression were measured 24 h after the last exposure to CS and IL-13. In both models POSTN, SERPINB2, and CLCA1 expression were increased by IL-13. CS markedly affected the IL-13-induced Th2 gene signature as indicated by a reduced POSTN, CLCA1, and MUC5AC expression in both models. In contrast, IL-13-induced SERPINB2 expression remained unaffected by CS, whereas SPDEF expression was additively increased. Importantly, cessation of CS exposure failed to restore IL-13-induced POSTN and CLCA1 expression. We show for the first time that CS differentially affects the IL-13-induced gene signature for Th2-high asthma. These findings provide novel insights into the interaction between Th2 inflammation and cigarette smoke that is important for asthma pathogenesis and biomarker-guided therapy in asthma

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Chapter 8 Lung-on-Chip

An increasing collection of cell culture techniques is currently available to model the lung microenvironment and study lung diseases, tissue, and tissue regeneration. In this chapter, developments in the field of organs-on-chips (OOC) are discussed with a specific focus on lung-on-chip. Features of airway and alveolus lung-on-chip models are described separately, with a focus on both the cell biology and bioengineering aspects. These include options to study crosstalk between various cell types and the extracellular matrix and the application of lung-specific mechanical forces that result from air and blood flow as well as stretch induced by breathing. Utilizing human induced pluripotent stem cell technology to generate lung cells for culture on-chip and coupling a lung-on-chip with other OOC increase their potential even further. The use of lung-on-chip models for disease modeling, inhalation toxicology, drug development, and screening is discussed as well as their potential for studying lung repair and regeneration

Dynamic postural stability differences between male and female players with and without ankle sprain

Objectives: To evaluate dynamic stability index (DSI) differences between males and females for different jump directions. To examine both preseason DSI differences between players with and without a history of ankle sprain, and between players with and without an ankle sprain during the subsequent season. Design: Prospective cohort design. Setting: Laboratory. Participants: 47 male (22.9 +/- 3.9 y) and 19 female (21.5 +/- 2.9 y) sub-elite and elite team sport players. Main outcome measures: Ankle sprain history was collected using an injury history questionnaire. DSI of a single-leg hop-stabilization task measured preseason was collected using force plates and calculated using a Matlab program. Ankle sprains were reported during the subsequent season. Results: Male players demonstrated larger DSI than female players on forward medial/lateral stability index (MLSI) and vertical stability index (VSI), diagonal VSI, and lateral anterior/posterior stability index (APSI) and VSI. Forward, diagonal and lateral dynamic postural stability indices (DPSI) were larger for males (p <0.001). No significant differences were found between players with and without a previous ankle sprain nor between players with and without an ankle sprain during the subsequent season. Conclusion: Male players showed larger DSI scores than female players, indicating lower dynamic stability. Sex-specific training sessions or prevention programs should be developed. (C) 2015 Elsevier Ltd. All rights reserved

Contribution of Host Defence Proteins and Peptides to Host-Microbiota Interactions in Chronic Inflammatory Lung Diseases

The respiratory tract harbours a variety of microorganisms, collectively called the respiratory microbiota. Over the past few years, alterations in respiratory and gut microbiota composition have been associated with chronic inflammatory diseases of the lungs. How these changes influence disease development and progression is an active field of investigation. Identifying and understanding host-microbiota interactions and factors contributing to these interactions could promote the development of novel therapeutic strategies aimed at restoring host-microbiota homeostasis. In this review, we discuss recent literature on host-microbiota interactions in the respiratory tract, with a specific focus on the influence of endogenous host defence peptides and proteins (HDPs) on the composition of microbiota populations in vivo and explore possible HDPs-related therapeutic approaches targeting microbiota dysbiosis in chronic inflammatory lung diseases

Contribution of Host Defence Proteins and Peptides to Host-Microbiota Interactions in Chronic Inflammatory Lung Diseases

The respiratory tract harbours a variety of microorganisms, collectively called the respiratory microbiota. Over the past few years, alterations in respiratory and gut microbiota composition have been associated with chronic inflammatory diseases of the lungs. How these changes influence disease development and progression is an active field of investigation. Identifying and understanding host-microbiota interactions and factors contributing to these interactions could promote the development of novel therapeutic strategies aimed at restoring host-microbiota homeostasis. In this review, we discuss recent literature on host-microbiota interactions in the respiratory tract, with a specific focus on the influence of endogenous host defence peptides and proteins (HDPs) on the composition of microbiota populations in vivo and explore possible HDPs-related therapeutic approaches targeting microbiota dysbiosis in chronic inflammatory lung diseases

The human lactoferrin-derived peptide hLF1-11 primes monocytes for an enhanced TLR-mediated immune response

Earlier we reported that the peptide corresponding to the first eleven N-terminal amino acids of human lactoferrin (hLF1-11) is active against multi-drug resistant pathogens in mice. The mechanisms underlying this anti-infective activity remain unclear. Since hLF1-11 is ineffective against pathogens at physiological salt concentrations and hLF1-11 directs differentiation of monocytes toward a macrophage subset with enhanced effector functions, we investigated the effects of hLF1-11 on human and murine monocytes. Results revealed that human and murine monocytes exposed for 1 h to hLF1-11 and then stimulated with the Toll-like receptor (TLR)-ligand LPS for 18 h, displayed enhanced cytokine and chemokine production as compared to control (peptide-treated) monocytes. We also found that expression of mRNA, cell-surface receptor expression, and NF-κB activation by hLF1-11-exposed human monocytes were enhanced as compared to control (peptide-treated) monocytes. Furthermore, the kinetics of the cytokine production was unchanged as mRNA levels and protein levels paralleled the enhanced response of hLF1-11-exposed monocytes to LPS. The cytokine production by human monocytes in response to TLR4, TLR5, and TLR7 stimulation, but not to TLR2 stimulation, was elevated by hLF1-11. In concordance, translocation of NF-κB subunits to the nucleus was enhanced in hLF1-11-exposed monocytes after TLR stimulation, except for TLR2, as compared to control (peptide-exposed) monocytes. In conclusion, monocytes were primed by hLF1-11 for an enhanced inflammatory response upon TLR4, TLR5, and TLR7 stimulation, but not TLR2 stimulation. Such effects of hLF1-11 on monocyte reactivity should be taken into account when considering the clinical development of this peptide for a therapeutic intervention in patients

The air–liquid interface model

The airway epithelium lining the airways is in first contact with the inhaled environment, which contains allergens, gaseous pollutants, particulates, and pathogenic microorganisms. It forms an ion- and size-selective barrier between the inhaled environment and the underlying tissue by the formation of intercellular tight junctions and adhesion junctions. Additionally, the airway epithelium plays an important role in innate immune defense, expressing receptors that recognize molecular patterns from pathogenic microbes, parasites, fungi, and allergens and danger signals from damaged cells, directing proinflammatory processes. Chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, involve changes in airway epithelial function. For valuable insights into these changes, in vitro models should closely recapitulate human airway epithelial composition, three-dimensional structure, and function as an immunological barrier. The goal of this chapter is to review the literature on the use of air–liquid interface cultures to model the lung epithelium in health and disease