Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part II: Evaluation of IL-10-loaded Microparticles for the Treatment of Lung Inflammation

Hittinger, Marius; Mell, Nico Alexander; Huwer, Hanno; Loretz, Brigitta; Schneider-Daum, Nicole; Lehr, Claus Michael

doi:10.1177/026119291604400405

Cited by 11 publications

(11 citation statements)

References 38 publications

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“…Particle clearance was addressed by co-culturing epithelial cells with human primary alveolar macrophages. The issue of potential macrophage activation during the isolation or culturing processes was addressed in additional experiments that are described in the accompanying paper (20). However, it must be noted that most of the donor lungs came from smokers, which leads to implications during imaging as a result of already internalised particles.…”

Section: Discussionmentioning

confidence: 99%

“…However, experiments to characterise cytokine release in the model have already been performed (23). In the accompanying paper, on the characterisation of the autologous co-culture (20), we describe how the suitability of the system as a tool for studying the efficacy of a new anti-inflammatory dry powder formulation was investigated. We show how typical inflammatory markers, such as IL-6 and TNFα, were studied in the non-activated, activated and the treated co-cultures, in order to improve our understanding of this new in vitro system.…”

Section: Discussionmentioning

confidence: 99%

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Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part I: Model Characterisation

Hittinger

Janke

Huwer³

et al. 2016

Altern Lab Anim

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CitationAutologous co-culture of primary human alveolar macrophages and epithelial cells for investigating aerosol medicines. Part I: model characterisation. 2016, 44 (4):337-347 Altern Lab Anim Journal Alternatives to laboratory animals : ATLA Download date 10/07/2020 16:43:37 Item License http://creativecommons.org/licenses/by-nc-sa/4.0/ Link to ItemSummary -The development of new formulations for pulmonary drug delivery is a challenge on its own. New in vitro models which address the lung are aimed at predicting and optimising the quality, efficacy and safety of inhaled drugs, to facilitate the more rapid translation of such products into the clinic.Reducing the complexity of the in vivo situation requires that such models reproducibly reflect essential physiological factors in vitro. The choice of cell types, culture conditions and the experimental set-up, can affect the outcome and the relevance of a study. In the alveolar space of the lung, epithelial cells and alveolar macrophages are the most important cell types, forming an efficient cellular barrier to aerosols. Our aim was to mimic this barrier with primary human alveolar cells. Cell densities of alveolar macrophages and epithelial cells, isolated from the same human donor, were optimised, with a focus on barrier properties. The combination of 300,000 epithelial cells/cm 2 together with 100,000 macrophages/cm 2 showed a functional barrier (transepithelial electrical resistance > 500Ω.cm 2 ). This cell model was combined with the Pharmaceutical Aerosol Deposition Device on Cell Cultures. The functionality of the in vitro system was investigated with spray-dried fluorescently labelled poly(lactic-co-glycolic) acid particles loaded with ovalbumin as a model drug.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part I: Model Characterisation

Hittinger

Janke

Huwer³

et al. 2016

Altern Lab Anim

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“…It is difficult, for instance to recapitulate the complete architecture of the alveolar epithelium in vitro and findings are limited to interactions with two cell types in the current study. Moreover, early host-pathogen interactions are not limited to the epithelium; numerous in vivo and ex vivo studies such as those above have demonstrated that an equally important role is played by various components of the immune system, in particular alveolar macrophages, as recently studied in human co-culture models of the alveolus 69– 72 . Such studies also highlight the potential of co-culture models for studying interaction of the host epithelium with nanoparticles and aerosol medicines, in addition to disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

A co-culture model of the bovine alveolus

Lee

Chambers

2019

F1000Res

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The epithelial lining of the lung is often the first point of interaction between the host and inhaled pathogens, allergens and medications. Epithelial cells are therefore the main focus of studies which aim to shed light on host-pathogen interactions, to dissect the mechanisms of local host immunity and study toxicology. If these studies are not to be conducted exclusively in vivo, it is imperative that in vitro models are developed with a high in vitro- in vivo correlation. We describe here a co-culture model of the bovine alveolus, designed to overcome some of the limitations encountered with mono-culture and live animal models. Our system includes bovine pulmonary arterial endothelial cells (BPAECs) seeded onto a permeable membrane in 24 well Transwell format. The BPAECs are overlaid with immortalised bovine alveolar type II epithelial cells and cultured at air-liquid interface for 14 days before use; in our case to study host-mycobacterial interactions. Characterisation of novel cell lines and the co-culture model have provided compelling evidence that immortalised bovine alveolar type II cells are an authentic substitute for primary alveolar type II cells and their co-culture with BPAECs provides a physiologically relevant in vitro model of the bovine alveolus. The co-culture model may be used to study dynamic intracellular and extracellular host-pathogen interactions, using proteomics, genomics, live cell imaging, in-cell ELISA and confocal microscopy. The model presented in this article enables other researchers to establish an in vitro model of the bovine alveolus that is easy to set up, malleable and serves as a comparable alternative to in vivo models, whilst allowing study of early host-pathogen interactions, currently not feasible in vivo. The model therefore achieves one of the 3Rs objectives in that it replaces the use of animals in research of bovine respiratory diseases.

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“…With respect to human lung models, mono-and multicellular models, primary or cell line-derived, have been developed to mimic human airway epithelia and the alveolar epithelialendothelial tissue barrier (Hermanns et al, 2004;Steimer et al, 2005;Bur and Lehr, 2008;Haghi et al, 2015;Hittinger et al, 2016;Yonker et al, 2017;Costa et al, 2019;Artzy-Schnirman et al, 2020). These models have been employed in investigations of lung inflammation to study various lung diseases and disorders, such as cystic fibrosis (Castellani et al, 2018), chronic obstructive pulmonary disorder (Haghi et al, 2015;Zhou et al, 2019), and acute respiratory distress syndrome (Viola et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…These models have been employed in investigations of lung inflammation to study various lung diseases and disorders, such as cystic fibrosis (Castellani et al, 2018), chronic obstructive pulmonary disorder (Haghi et al, 2015;Zhou et al, 2019), and acute respiratory distress syndrome (Viola et al, 2019). Also, these models have been employed to investigate the safety and efficacy of aerosolized and dry powder formulations for pulmonary drug delivery (Hittinger et al, 2016), including that of steroid drugs (Bur and Lehr, 2008;Haghi et al, 2015). Finally, an in vitro human airway model differentiated from primary human bronchial cells has been proposed for pharmacokinetics studies (Rivera-Burgos et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

An Inflamed Human Alveolar Model for Testing the Efficiency of Anti-inflammatory Drugs in vitro

Drašler

Karakoçak

Tankus

et al. 2020

Front. Bioeng. Biotechnol.

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A large number of prevalent lung diseases is associated with tissue inflammation. Clinically, corticosteroid therapies are applied systemically or via inhalation for the treatment of lung inflammation, and a number of novel therapies are being developed that require preclinical testing. In alveoli, macrophages and dendritic cells play a key role in initiating and diminishing pro-inflammatory reactions and, in particular, macrophage plasticity (M1 and M2 phenotypes shifts) has been reported to play a significant role in these reactions. Thus far, no studies with in vitro lung epithelial models have tested the comparison between systemic and direct pulmonary drug delivery. Therefore, the aim of this study was to develop an inflamed human alveolar epithelium model and to test the resolution of LPS-induced inflammation in vitro with a corticosteroid, methylprednisolone (MP). A specific focus of the study was the macrophage phenotype shifts in response to these stimuli. First, human monocyte-derived macrophages were examined for phenotype shifts upon exposure to lipopolysaccharide (LPS), followed by treatment with MP. A multicellular human alveolar model, composed of macrophages, dendritic cells, and epithelial cells, was then employed for the development of inflamed models. The models were used to test the anti-inflammatory potency of MP by monitoring the secretion of pro-inflammatory mediators (interleukin [IL]-8, tumor necrosis factorα [TNF-α], and IL-1β) through four different approaches, mimicking clinical scenarios of inflammation and treatment. In macrophage monocultures, LPS stimulation shifted the phenotype towards M1, as demonstrated by increased release of IL-8 and TNF-α and altered expression of phenotype-associated surface markers (CD86, CD206). MP treatment of inflamed macrophages reversed the phenotype towards M2. In multicellular models, increased pro-inflammatory reactions after LPS exposure were observed, as demonstrated by protein secretion and gene expression measurements. In all scenarios, among the tested mediators the most pronounced anti-inflammatory effect of MP was observed for IL-8. Our findings demonstrate that our inflamed multicellular human lung model is a promising tool for the evaluation of anti-inflammatory potency of drug candidates in vitro. With the presented setup, our model allows a meaningful comparison of the systemic vs. inhalation administration routes for the evaluation of the efficacy of a drug in vitro.

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Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part II: Evaluation of IL-10-loaded Microparticles for the Treatment of Lung Inflammation

Abstract: Citation Autologous co-culture of primary human alveolar macrophages and epithelial cells for investigating aerosol medicines. Part II: evaluation of IL-10-loaded microparticles for the treatment of lung inflammation. 2016, 44 (4):349-360 Altern Lab Anim

Cited by 11 publications

References 38 publications

Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part I: Model Characterisation

Autologous Co-culture of Primary Human Alveolar Macrophages and Epithelial Cells for Investigating Aerosol Medicines. Part I: Model Characterisation

A co-culture model of the bovine alveolus

An Inflamed Human Alveolar Model for Testing the Efficiency of Anti-inflammatory Drugs in vitro

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