Die Rolle des Endothelin-B-Rezeptors in der pulmonalen TH2-Inflammation

"The role of the endothelin B receptor in the pulmonary Th2 inflammation"

Pulmonary arterial hypertension is a rare, deadly disease, which is characterized by endothelial dysfunction, pulmonary vasoconstriction, pulmonary vascular hyperresponsiveness and pulmonary arterial remodeling. The endothelin system plays a crucial role in the pathogenesis of PAH. Hence, the aims of this study were to examine the role of the endothelin system in Th2-induced PAH-associated pathologies as well as agedependent endothelin-1-mediated alterations of the pulmonary vasculature. Pulmonary Th2 inflammation was induced in mice by systemic ovalbumin sensitization followed by ovalbumin airway exposure (OVA/OVA). Isolated perfused and ventilated lungs of transgenic mice were investigated to determine the effects of endothelin receptor B deficiency (ETB-/-) and human prepro-endothelin-1 overexpression (ETtg) on mean pulmonary arterial pressure and pulmonary vascular (hyper-) responsiveness. In addition, pulmonary collagen deposition and perivascular inflammation were examined by comparative histological analyses. Right ventricular hypertrophy was determined by Fulton index. Cytokine analyses of bronchoalveolar lavage fluid (BALF) and messenger ribonucleic acid analyses of lung homogenate allowed a specific characterization of the inflammation and regulatory mechanisms in the respective groups.
ETB-/- mice showed pulmonary hypertension, including pulmonary vascular hyperresponsiveness and right ventricular hypertrophy. Pulmonary vascular hyperresponsiveness and right ventricular hypertrophy aggravated following induction of pulmonary Th2 inflammation. OVA/OVA-treated ETB-/- mice showed markedly increased perivascular leukocyte infiltration, pulmonary endothelin-1 expression and BALF IL-12p40 levels in comparison to their corresponding wildtype animals. In addition, the endothelin-1-mediated pulmonary vascular release of thromboxane was distinctly augmented in ETB-/- mice. While prepro-endothelin-1 overexpression led to pulmonary vascular hyperresponsiveness in young ETtg animals, highly aged ETtg mice showed a fixed pulmonary hypertonus accompanied by right ventricular hypertrophy.
In summary, due to pulmonary Th2 inflammation, ETB deficiency led to an increased pulmonary leukocyte influx with markedly increased IL-12p40 levels and an enhanced expression of endothelin-1. These alterations as well as an increased pulmonary vascular release of thromboxane might have contributed to the increase in right ventricular hypertrophy and pulmonary vascular hyperresponsiveness, observed after OVA/OVA treatment. The results of this study support the hypothesis that endothelin receptor B plays a protective role in the pulmonary vascular system. Moreover, they show that endothelin-1 alone is sufficient to induce PAH-associated alterations in the heart and pulmonary circulation. Further studies, including separate and simultaneous inhibition of endothelin receptor A and/ or ETB, are needed to determine whether separate inhibition of endothelin receptor A could be superior to dual blockade of both endothelin receptors in PAH therapy.