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	Horst OLSCHEWSKI, MD, PhD Characterization of the vascular phenotype in COPD: Are there gender differences?
Department of Medicine, Division of Pulmonology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz; phone: +43-316-385 80631, fax: +43-316-385 13578, ✉ e-mail
websites: [RESPImmun]
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Horst Olschewski is a leading physician in the field of PH. He possesses a strong background in the mechanisms of pulmonary and vascular diseases. In recent years he characterized the clinical usefulness – and the related pharmacological mechanisms – of targeting the endothelin system, phosphodiesterases and prostanoid receptors in the management of PH. He has designed and performed the international study on inhaled iloprost for the treatment of severe PH. Within RESPImmun he closely collaborates with Gerald Höfler (histologic analysis), Leigh Marsh (inflammatory profiling), Grażyna Kwapiszewska (molecular signaling).

Project

Project 7: Characterization of the vascular phenotype in COPD: are there gender differences?
Co-PI: Slaven Crnković

Background

Chronic obstructive pulmonary disease (COPD) is a multifaceted disease with a high morbidity and mortality. One subgroup of patients develops an out-of-proportion pulmonary arterial pressure (PAP) increase, or "pulmonary vascular phenotype" which is associated with a very poor prognosis. Better identification of this phenotype and understanding the pathologic mechanisms might open new therapeutic options. The prototype pulmonary vascular disease is idiopathic PAH which is strongly associated to female gender suggesting that gender-related mechanisms play a big role in pulmonary vascular remodeling. We have recently investigated the expression of p22phox in explanted lungs of patients with end-stage COPD. P22phox codes for a critical component of NADPH oxidases, serving as oxygen sensors in PAs. This appears to be regulated by TMEM16A. In addition, free radical species from NADPH oxidase mediate cell signalling processes that elicit inflammatory responses. P22phox expression was reduced in patients with predominant bronchitic disease and preserved in those with predominant vascular disease. This suggests that preserved p22phox expression may be a predisposing factor for a vascular phenotype in severe COPD.

Hypothesis and objectives

We hypothesize that

the pulmonary epithelial expression of p22phox is correlated with the pulmonary vascular phenotype in COPD;
the vascular phenotype is associated with specific changes in the cell composition in the bronchoalveolar lavage (BAL), with changes in biomarkers, inflammatory mediators / metabolites in the blood;
the association between the PAP / FEV₁ ratio, the DLCO / FEV₁ ratio, and the clinically defined pulmonary vascular phenotype on the one hand, and biomarkers, inflammatory mediators, metabolites, ECG, echocardiogram, and invasive pulmonary hemodynamics on the other hand are gender-dependent.

Methodology

The clinical work-up including right heart catheterization and bronchoscopy will be performed at the Clinical Division of Pulmonology (Med Uni Graz). Severe COPD patients will be characterized by a broad spectrum of clinical parameters and the vascular phenotype will be defined based on pulmonary hemodynamics derived from right heart catheterization (RHC). We will determine p22phox expression from probes of the bronchial epithelium and will take probes from BAL samples for FACS analysis. In year 1– 2, the PhD student will co-ordinate the clinical investigations, probe sampling and processing, manage ethics submission including informed consent forms, enter the data into a RDA databank structure, perform FACS analysis from BAL probes and gene arrays and analyse the cellular landscape by clinical phenotypes. In year 2 – 3, the PhD student will perform analysis of the results using artificial intelligence methods in order to recognize the vascular phenotype and to specify the relation between p22phox expression and that phenotype, taking care of gender as an important co-variate. In year 3 – 4, the PhD student will finalize data entry of clinical and laboratory data, prepare presentations for international conferences and at least one full paper as first author.

Input from collaborations within the RESPImmun programme

Grażyna Kwapiszewska will perform gene array analysis and determination of p22phox expression.
Leigh Marsh will support analysis of BAL samples.
Gerald Höfler will provide standardized histologic analysis and quantification of p22phox expression in the bronchial biopsies.
Andrea Olschewski will support with her expertise in lung physiology.