respimmun.at

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Heinemann ⏩
• Höfler
• Kargl
• Kwapiszewska
• Leithner
• Marsche
• Marsh
• Moissl-Eichinger
• Olschewski A
• Olschewski H
• Strobl
• Sturm
• Tomazic

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The RESPImmun Faculty

Ákos HEINEMANN, MD

Short chain fatty acids and pulmonary endothelial function

Otto Loewi Research Centre, Division of Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz;
phone: +43-316-385 74112, fax: +43-316-385 79613,  e-mail
websites: [RESPImmun] [DK-MOLIN] [MOLMED]
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Ákos Heinemann is an immunopharmacologist who focuses his research on the regulation of leukocyte trafficking as a fundamental principle of tissue inflammation. Recently, he has explored the role of chemokines and eicosanoids in the modulation of immune cell function and has characterized a panel of novel pharmacological tools that served as starting points for the clinical development of anti-inflammatory drugs. His primary aim is to characterize novel mediators and pathways that regulate the function and interaction of endothelial cells, granulocytes and macrophages, and might hence serve as promising therapeutic targets for inflammation including asthma and acute lung injury. Within RESPImmun he closely collaborates with Gerald Höfler (pathology), Eva Sturm, Julia Kargl and Leigh Marsh (animal models), and Grażyna Kwapiszewska and Horst Olschewski (human cell systems / patients samples). He is the coordinator of the MOLIN.

Project

Project 3: Short chain fatty acids and pulmonary endothelial function
Co-PI: Thomas Bärnthaler

Background

Short chain fatty acids (SCFA) such as acetate, propionate and butyrate, are produced in high concentration via fermentation in the human gut by commensal bacteria and are taken up into the bloodstream. SCFA have been shown to have strong anti-inflammatory properties by the production of mediators like PGE2 and inhibition of cytokine release. Accordingly, allergic germ-free mice show exaggerated airway eosinophilia and increased levels of TH2 cytokines when compared to recolonized mice and nutrient fiber content strongly correlates with the extent of allergic inflammation and lung eosinophilia, which was also alleviated by treatment with propionate in a mouse model of house-dust mite allergy. SCFA are natural ligands for the free fatty acid receptors FFA2 (GPR43) and FFA3 (GPR41), which belong to the family of seven transmembrane spanning G protein-coupled receptors. SCFA have also been shown to regulate gene transcription via the inhibition of histone deacatylase (HDAC) activity. Their anti-inflammatory properties are at least partially mediated by NFκB inhibition and subsequent repression of related cytokines.

Hypothesis and objectives

Based on preliminary data from our laboratory we hypothesize that SCFA are capable of regulating endothelial function which translates to an anti-inflammatory action. We will further characterize the effects of SCFA on pulmonary microvascular and arterial endothelial cells regarding barrier function, expression of adhesion molecules, intracellular signaling pathways and interaction of the endothelium with immune cells. Proof-of-concept studies will be performed in diverse mouse models of asthma and asthma exacerbations.

Methodology

Year 1: The PhD student will learn how to isolate leukocytes from peripheral blood of human volunteers and patients and how to cultivate endothelial cells from lungs. FFA2 and FFA3 expression will be quantified by real-time PCR, Western blot, fluorescence microscopy and multi-colour flow cytometry. Year 2: Endothelial barrier function will be investigated by electrical impedance measurements (ECIS), transendothelial diffusion assays, VE-cadherin / actin staining of monolayers and systems of isolated whole lung perfusion. Cytokine profiles will be determined by multiplex ELISA. Lipid mediators will be determined by LC-MS. Year 3: Moreover, the student will investigate the role of SCFA and their receptors in experimental mouse models for allergic asthma and non-allergic Fra-2 transgenic asthma mouse model that are already available within the consortium and international collaborators. Year 4: The occurrence of SCFA-producing microbiota strains in stool samples of animal models and patients with chronic asthma will be investigated.

Input from collaborations within the RESPImmun programme