Inflammation in hypoxia- induced pulmonary hypertension - Disease Model and therapeutic targets

GIERHARDT, M; FAGUNDEZ, C; GHOFRANI, A; WEISSMANN, N; SELVAKUMAR, B; FUERTES, M; HEROLD, S; SEEGER, W; SCHAEFFER, JM; SCHERMULY, RT; SOMMER, N

Buenos Aires

Simposio; Frontiers in Biosciences 3; 2018

Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society

Pulmonary hypertension (PH) is clinically defined as an increased mean pulmonaryarterial pressure (mPAP) of ≥ 25 mmHg at rest, assessed by right heart catheterization.PH can be associated to other diseases or occur as idiopathic form. All precapillaryforms of PH are characterized by pulmonary vascular remodeling and can lead to rightventricular hypertrophy and death by right heart failure (Fig.1). Hypoxia can be amajor trigger of pulmonary vascular remodeling (Humbert et al. 2004), and persistentinflammation is thought to play a major pathophysiological role in hypoxia-induced PHand other forms of PH (Pugliese et al. 2015; Marsh et al. 2018).Results in experimental PH suggest altered immunity as a cause rather than aconsequence of the vascular disease (Fig. 2; Rabinovitch et al. 2014). Althoughpromising results have been found in different pre-clinical studies by modulatingdifferent inflammatory/immune modulatory pathways (e.g. Macrophages and IL-6), no promising therapeutic option for PH patients followed from these resultsyet. A reason might be the complexity of the immune response itself and itsinteraction with vascular cells, so that adressing singular factors in experimentalmodels might not reproduce sufficiently the inflammatory landscape in PAHpatients.Aim of Study:? Developing a more suitable murine model for PAH by combining exposure to chronic hypoxia with an inflammatory stimulus (lipopolysaccharides; LPS) upstream ofcytokine / chemokine release? Elucidation of the effect of inflammation (on pre-existing or later onset) PH? Elucidation of the role of inflammatory (and inflammation - resolving) pathways involved in pulmonary vascular remodeling