Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan
Introduction
Pulmonary fibrosis (PF) is a common end stage of interstitial lung diseases, which form an etiologically heterogeneous group of diffuse inflammatory disorders affecting the pulmonary parenchyma. (American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias, 2001). Currently, there is no adequate therapy available for patients with PF that significantly prolongs their poor life expectancy (Flaherty et al., 2003, Walter et al., 2006).
Besides the PF itself, the development of pulmonary hypertension (PH) is an important reason for mortality in patients with PF (Lettieri et al., 2006, Nadrous et al., 2005a, Nadrous et al., 2005b). The etiology of PH in PF is not well understood. Endothelin-1 (ET) is known to play a key role in the development of PH (Michel et al., 2003). The finding of increased ET-1 plasma levels in patients with PF and PH implies that endothelial dysfunction and the ET system also contributes to the development of PH in PF (Trakada et al., 2003). The ET-receptor antagonist Bosentan is a promising and approved therapy in idiopathic pulmonary arterial hypertension (Rubin et al., 2002). However, there are no studies available which have analyzed the effect of an ET receptor antagonist on PH in PF.
In addition, there is growing evidence that the ET system plays an important role in the genesis and disease progression of PF. Elevated ET-1 levels have been found in plasma and bronchoalveolar lavage fluids of PF patients (Ryu et al., 2007, Uguccioni et al., 1995). ET converting enzyme 1 and ET-1 immunohistochemical stainings of the lung correlates with disease activity of PF (Giaid et al., 1993, Saleh et al., 1997) and even precedes the development of PF (Mutsaers et al., 1998a). There is clear evidence that ET-1 can function as a profibrotic cytokine by stimulating fibroblast chemotaxis and proliferation in vitro (Mutsaers et al., 1998a, Teder and Noble, 2000). ET-1 stimulates collagen synthesis in fibroblasts in cell culture (Dawes et al., 1996). In ET-1 transgenic mice, a fibrotic alteration of lung architecture has been observed (Hocher et al., 2000). ET receptor antagonists have been shown to inhibit the effects of ET-1 on lung fibroblast proliferation (Cambrey et al., 1994), and collagen synthesis in vitro and in vivo (Dawes et al., 1996, Park et al., 1997, Rockey and Chung, 1996). A trend in delayed time to death or disease progression, and improvement in quality of life, was observed especially in patients with biopsy proven idiopathic pulmonary fibrosis treated with the unselective ET receptor antagonists Bosentan (King et al., 2008).
Thus far there have been no studies which have analyzed the effect of an ET receptor antagonist on exercise capacity and PH in PF, and conflicting results exist with respect to the effect of ET receptor antagonists on PF (Mutsaers et al., 1998b, Park et al., 1997). We, therefore, tested the hypothesis that, in rats with Bleomycin-induced PF, application of the unselective ET receptor antagonist Bosentan results in a functional improvement by reduction of the development of PH and PF.
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Experimental groups
Adult male Wistar rats (250 g; Charles River, Sulzfeld, Germany) were randomly assigned to one of the following groups: untreated animals (controls, n = 10), Bleomycin-induced PF (Bleomycin, cell-pharm-GmbH, Hannover, Germany, intratracheal 2 units/kg, n = 9), Bleomycin-induced PF treated with Bosentan (Bleomycin + Bosentan, Actelion, Basel, Switzerland, 100 mg/kg, n = 7). Bleomycin was instilled intratracheally in narcosis (Isofluran, Florene “R”, Abbott GmbH, Wiesbaden, Germany) once to induce lung
Hemodynamics and right ventricular hypertrophy
Right ventricular hypertrophy at 4 weeks was significantly higher in the Bleomycin group compared to controls, indicated by a higher RV/(LV + S) ratio (p = 0.001, Fig. 1b) accompanied by a significantly elevated RVSP (p = 0.003, Fig. 1a). Right ventricular hypertrophy was significantly attenuated in the Bleomycin + Bosentan group compared to the untreated Bleomycin group (p = 0.003) and there was a statistically non-significant trend towards lower RVSP (p = 0.41). RV/(LV + S) (p = 0.001) and RVSP (p = 0.003)
Discussion
The present study provides the first evidence that the ET receptor antagonist Bosentan improves exercise capacity in the model of Bleomycin-induced PF in rats. This significant improvement in exercise capacity in the Bosentan-treated, Bleomycin-induced PF animals was accompanied by a trend towards lower RVSP and significantly less right ventricular hypertrophy compared to untreated animals with PF. In addition, our study revealed a significant reduction in PF by Bosentan treatment of animals
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