Journalartikel

Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension


AutorenlisteDahal, Bhola Kumar; Cornitescu, Teodora; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Kosanovic, Djuro; Dumitrascu, Rio; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Voswinckel, Robert; Banat, Gamal-Andre; Seeger, Werner; Grimminger, Friedrich; Schermuly, Ralph Theo

Jahr der Veröffentlichung2010

Seiten158-167

ZeitschriftAmerican Journal of Respiratory and Critical Care Medicine

Bandnummer181

Heftnummer2

ISSN1073-449X

eISSN1535-4970

DOI Linkhttps://doi.org/10.1164/rccm.200811-1682OC

VerlagAmerican Thoracic Society


Abstract

Rationale: Epidermal growth factor (EGF) and its receptors play a role in cell proliferation and survival and are implicated in the pathobiology of pulmonary arterial hypertension (PAH).

Objectives: To study the role of EGF inhibition on experimental pulmonary hypertension.

Methods: We investigated (1) the effects of three clinically approved EGF receptor (EGFR) antagonists in vitro on rat pulmonary arterial smooth muscle cell proliferation and in vivo on experimental pulmonary hypertension (PH) induced by monocrotaline injection in rats and by chronic hypoxia in mice, and (2) the expression of EGFR in the lung tissues from experimental and clinical PH.

Measurements and Main Results: The EGFR inhibitors gefitinib, erlotinib, and lapatinib inhibited the EGF-induced proliferation of pulmonary arterial smooth muscle cells. In rats with established PH, gefitinib and erlotinib significantly reduced right ventricular systolic pressure and right ventricular hypertrophy. In addition, the medial wall thickness and muscularization of pulmonary arteries were improved. In contrast, lapatinib did not provide therapeutic benefit. These EGFR antagonists at their highest tolerable dose did not yield significant improvement in right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice with chronic hypoxic PH. Moreover, no significant alteration in the EGFR expression was detected in the lung tissues from patients with idiopathic PAH.

Conclusions: The partial therapeutic efficacy of the EGFR antagonists in animal models of pulmonary hypertension and the absence of significant alteration in EGFR expression in the lungs from patients with idiopathic PAH suggest that EGFRs do not represent a promising target for the treatment of pulmonary hypertension.




Zitierstile

Harvard-ZitierstilDahal, B., Cornitescu, T., Tretyn, A., Pullamsetti, S., Kosanovic, D., Dumitrascu, R., et al. (2010) Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension, American Journal of Respiratory and Critical Care Medicine, 181(2), pp. 158-167. https://doi.org/10.1164/rccm.200811-1682OC

APA-ZitierstilDahal, B., Cornitescu, T., Tretyn, A., Pullamsetti, S., Kosanovic, D., Dumitrascu, R., Ghofrani, H., Weissmann, N., Voswinckel, R., Banat, G., Seeger, W., Grimminger, F., & Schermuly, R. (2010). Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension. American Journal of Respiratory and Critical Care Medicine. 181(2), 158-167. https://doi.org/10.1164/rccm.200811-1682OC



Schlagwörter


BLOCKADEcardiotoxicityepidermal growth factor receptorFACTOR EXPRESSIONFACTOR RECEPTOR TRANSACTIVATIONIMATINIB MESYLATELAPATINIBMOLECULAR-MECHANISMSMONOCROTALINEPulmonary hypertension


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