Journal Article

Role of Epidermal Growth Factor Inhibition in Experimental Pulmonary Hypertension

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

2010

Overview

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

• Publisher: Am Thoracic Soc,American Thoracic Society,Oxford University Press
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Antineoplastic Agents - pharmacology / Biological and medical sciences / Cardiotoxicity / Cell Division - drug effects / Cell growth / Cell Survival - drug effects / Disease Models, Animal / Dose-Response Relationship, Drug / Epidermal growth factor / Epidermal Growth Factor - antagonists & inhibitors / Epidermal Growth Factor - genetics / Erlotinib Hydrochloride / Gene Expression - drug effects / Hemodynamics / Humans / Hypertension, Pulmonary - pathology / Hypertension, Pulmonary - physiopathology / Hypoxia / Intensive care medicine / Kinases / Lung diseases / Male / Medical sciences / Mice / Muscle, Smooth, Vascular - drug effects / Muscle, Smooth, Vascular - pathology / Patients / Pneumology / Polymerase Chain Reaction / Protein Kinase Inhibitors - pharmacology / Pulmonary arteries / Pulmonary hypertension / Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases / Pulmonary Wedge Pressure - drug effects / Quinazolines - pharmacology / Rats / Rats, Sprague-Dawley / RNA, Messenger - genetics / Smooth muscle / Vascular Resistance - drug effects / Veins & arteries