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Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension

¹ University of Giessen Lung Centre (UGLC), Giessen, Germany; ² Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany; and ³ University of Giessen, Department of Hematology and Oncology, Giessen, Germany

Correspondence and requests for reprints should be addressed to Ralph T. Schermuly, Ph.D., Max Planck Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany. E-mail: ralph.schermuly{at}mpi-bn.mpg.de

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.

Key Words: epidermal growth factor receptor • pulmonary hypertension • monocrotaline • hypoxia

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Epidermal growth factor (EGF) and its receptors (EGFR) are implicated in the pathobiology of pulmonary arterial hypertension (PAH). What This Study Adds to the Field The small response of three clinically approved EGF receptor antagonists in experimental PH and the absence of significant changes in lung EGFR expression in clinical PAH suggest that targeting EGF signaling may not be a promising therapeutic approach for pulmonary hypertension.