The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats

Abstract

Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease.In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg?kg -1 ?day -1 ) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by highperformance liquid chromatographic quantitation of hydroxyproline.In animals given bleomycin and drug vehicle, total lung collagen was increased by 182¡11% (mean¡SEM) compared with saline controls at 14 days (pv0.001). The increase in lung-collagen accumulation was reduced by 75¡12% (pv0.01) in animals given SDZ RAD and was accompanied by a concomitant 56¡6% (pv0.001) reduction in lung weight.SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.

Extending Myringotomy Patency with Topical Everolimus in Rats

“…The dose of everolimus tested in the study is based on the dose used in topical applications of everolimus in experimental keratoplasty [27], and it is far less than the dose used to elicit immunosuppressive effects in rats (1.0 to 3.0 mg/kg/day Table 2. Histological assessment of fibrosis and inflammation in the lamina propria of tympanic membranes orally) [16][17][18]25]. The hypothesis was confirmed:…”

“…Everolimus has been reported to inhibit fibroblast proliferative capabilities and to reduce lung-collagen accumulation in bleomycin-induced pulmonary fibrosis [25]. Everolimus-coated coronary stents have been shown to effectively prevent intimal hyperplasia following stent implantation and to control restenosis [19,20].…”

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

“…8 In addition to immunosuppressive effects, rapamycin also showed to be effective in preventing fibrogenesis in animal models. [11][12][13] However, the exact molecular mechanisms underlying the effects of rapamycin on preventing organ fibrosis remain poorly understood. Furthermore, the antifibrotic effect of rapamycin was seriously challenged by other studies, which showed that rapamycin had no significant improvements on fibrotic process.…”

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…Liu et al, 1993), Ginkgo biloba (Daba et al, 2002;Iraz et al, 2006), Moxibustion (R. Li et al, 2005), Fufang (Kong et al, 2005) etc. ), Immunosuppressants (Cyclosporin-A (Lossos, Or, Goldstein, Conner, & Breuer, 1996), Rapamycin analogue SDZ RAD (Simler et al, 2002)), Corticosteroids (Dexamethasone (F. Chen et al, 2006;Dik et al, 2003;H. P. Li, Li, He, Yi, & Kaplan, 2004), Methylprednisolone (Phan, Thrall, & Williams, 1981), Prednisolone (Chaudhary, Schnapp, & Park, 2006;Entzian et al, 1998) 1986) etc.…”

“…Pirfenidone early (Schelegle, Mansoor, & Giri, 1997) Decorin early (Shimizukawa et al, 2003) 16 7 SDZ RAD early (Simler et al, 2002) 16 8…”