The monocrotaline model of pulmonary hypertension in perspective.

Victoria Johnson Center for Obstructive Lung Disease Research, Virginia Commonwealth University, Richmond, 23298, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 3.52). 09/2011; 302(4):L363-9. DOI: 10.1152/ajplung.00212.2011
Source: PubMed

ABSTRACT Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

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    ABSTRACT: The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function.
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    ABSTRACT: Pulmonary hypertension (PH) is a disorder that develops as a result of remodeling of the pulmonary vasculature and is characterized by narrowing/obliteration of small pulmonary arteries, leading to increased mean pulmonary artery pressure and pulmonary vascular resistance. Subsequently, PH increases the right ventricular afterload, which leads to right ventricular hypertrophy and eventually right ventricular failure. The pathophysiology of PH is not fully elucidated, and current treatments have only a modest impact on patient survival and quality of life. Thus, there is an urgent need for improved treatments or a cure. The use of animal models has contributed extensively to the current understanding of PH pathophysiology and the investigation of experimental treatments. However, PH in current animal models may not fully represent current clinical observations. For example, PH in animal models appears to be curable with many therapeutic interventions, and the severity of PH in animal models is also believed to correlate poorly with that observed in humans. In this review, we discuss a variety of animal models in PH research, some of their contributions to the field, their shortcomings, and how these have been addressed. We highlight the fact that the constant development and evolution of animal models will help us to more closely model the severity and heterogeneity of PH observed in humans.
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    ABSTRACT: Sustained inflammation is associated with pulmonary vascular remodeling and arterial hypertension (PAH). Serum-glucocorticoid regulated kinase 1 (SGK1) has been shown to participate in vascular remodeling, but its role in inflammation-associated PAH remains unknown. In this study, the importance of SGK1 expression and activation was investigated on monocrotaline (MCT)-induced PAH, an inflammation-associated experimental model of PAH used in mice and rats. The expression of SGK1 in the lungs of rats with MCT-induced PAH was significantly increased. Furthermore, SGK1 knockout mice were resistant to MCT-induced PAH and showed less elevation of right ventricular systolic pressure and right ventricular hypertrophy and showed reduced pulmonary vascular remodeling in response to MCT injection. Administering the SGK1 inhibitor, EMD638683, to rats also prevented the development of MCT-induced PAH. The expression of SGK1 was shown to take place primarily in alveolar macrophages. EMD638683 treatment suppressed macrophage infiltration and inhibited the proliferation of pulmonary arterial smooth muscle cells (PASMCs) in the lungs of rats with MCT-induced PAH. Co-culture of bone marrow-derived macrophages (BMDMs) from wild-type (WT) mice promoted proliferation of PASMC in vitro, whereas BMDMs from either SGK1 knockout mice or WT mice with EMD638683 treatment failed to induce this response. Collectively, the present results demonstrated that SGK1 is important to the regulation of macrophage activation that contributes to the development of PAH; thus, SGK1 may be a potential therapeutic target for the treatment of PAH.
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