New therapeutic strategies for the treatment of experimental pulmonary hypertension : Role of the epidermal growth factor

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CornitescuTeodora_2011_09_09.pdf (1.18 MB)

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2010

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DOI:
http://dx.doi.org/10.22029/jlupub-13766

Abstract

Pulmonary arterial hypertension (PAH) is a severe condition associated, if left untreated, with a poor prognosis and a high mortality rate. Pulmonary vascular remodeling, the main cause and the key pathological feature of PAH, subsequently causes the progressive increase of pulmonary vascular resistance and pulmonary arterial pressure, leading to right ventricular failure and death. In the development of the cellular events leading to lung arterial remodeling, like increased proliferation, resistance to apoptosis and migration of pulmonary vascular cells, the involvement of growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) has been suggested. Recent studies showed that inhibition of EGFR by the dual EGFR/HER2 inhibitor PKI166, a test compound, could mediate vascular SMC apoptosis and improve survival in monocrotaline (MCT)-treated rats, suggesting the possible therapeutic effect of EGF pathway blockage. In the light of these results, our study has aimed to investigate in the MCT model of PAH the therapeutic efficacy of chronic administration of three EGFR inhibitors which have the advantage of being already approved for use in the clinical practice for cancer patients. Our results have shown that in rats with established PH, gefitinib and erlotinib dose-dependently reduced RVSP and right heart hypertrophy, and, in addition, improved the medial wall thickness and muscularization levels of small pulmonary arteries. Furthermore, our results demonstrate a positive average bodyweight change, an improvement of the distress score and an increase of survival after two weeks of treatment in both gefitinib and erlotinib groups, with gefitinib having the most potent effect. Surprisingly, in contrast with gefitinib and erlotinib, which are EGFR1 antagonists and exhibited a partial effect, lapatinib, a dual EGFR/HER2 inhibitor, provided the least significant therapeutic benefit, as demonstrated by the development of vascular remodeling, right heart hypertrophy and by the negative impact on bodyweight, distress score and survival in treated rats.To our knowledge, this is the first study to investigate the role of EGFR signaling inhibition using three clinically approved small-molecule inhibitors in an established animal model of PH, in a head-to-head experiment. Our findings may represent the basis for further investigation and for the development of new therapeutic directions, with potential direct clinical application in the field of the human PAH treatment.

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