Pulmonary Hypertension in Rats 2.

Miyata, Masayuki; Sakuma, Fumitaka; Yoshimura, Akiko; Ishikawa, Hidemasa; Nishimaki, Tomoe; Kasukawa, Reiji

doi:10.1159/000237166

Cited by 61 publications

(42 citation statements)

References 13 publications

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“…In transgenic mice, IL-6 overexpression induces PAH associated with downregulation of TGF-b signalling [52]. Consistent with previous studies [9,51], we found that MCT-induced PAH is also associated with increased IL-6 production. Kaposi's sarcoma-associated herpes virus, which may cause PAH in HIV-negative Castleman's disease, encodes a viral, constitutively active form of IL-6 [53].…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

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Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points.Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg?kg ) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression.Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1-14 and 1-28) and reversing PAH at late (day 14-28 and 21-35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro.Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

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Section: Discussionsupporting

confidence: 92%

“…The importance of IL-6 has been shown in several studies of PAH. Patients with PAH have increased circulating IL-6 levels [8] and IL-6 is capable, on its own, of causing growth of vascular smooth muscle cells [50] and PAH [51]. In transgenic mice, IL-6 overexpression induces PAH associated with downregulation of TGF-b signalling [52].…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Lc¹,

Montani²,

Tchérakian³

et al. 2010

Eur Respir J

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show abstract

“…Indeed, systemic manifestations of multicentric Castleman's disease and its biological markers of inflammation can be alleviated after anti-IL-6 receptor antibody therapy [10,11]. IL-6 may also play a role in angiogenesis and could play a role in human, as well as experimental models of pulmonary hypertension [10,12,13]. These facts raise the possibility of IL-6 being a common pathogenic factor in both PAH and Castleman's disease.…”

Section: Discussionmentioning

confidence: 99%

Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman's disease

Montani

Achouh²,

Marcelin³

et al. 2005

Eur Respir J

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The present study describes a case of pulmonary arterial hypertension (PAH) associated with multicentric Castleman's disease in a patient infected with HIV type 1 and human herpes virus 8.Therapy included highly active antiretroviral therapy, warfarin, diuretics, continuous i.v. epoprostenol and 12-monthly pulses of cyclophosphamide.The patient's condition improved dramatically with complete reversibility of PAH, allowing weaning of continuous i.v. epoprostenol therapy. After 5 yrs, both Castleman's disease and PAH have not relapsed. This supports the hypothesis that control of inflammation and retroviral replication may be of interest in the context of PAH, complicating the course of an inflammatory condition associated with viral infection.In conclusion, further studies should help in characterising the best candidates for antiinflammatory treatment in the setting of pulmonary arterial hypertension.

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“…Several animal models of secondary PAH, including chronic hypoxia (15,32), monocrotaline treatment (2,12), and chronic air embolism (23), are also associated with increased cytokine production, including increased IL-6, and injection of recombinant IL-6 caused PAH in rats (19). Kaposi's sarcoma-associated herpesvirus, which may cause PAH in human immunodeficiency virus (HIV)-negative Castleman's disease, encodes a viral, constitutively active, form of IL-6 (22).…”

mentioning

confidence: 99%

Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle

Hagen

Fagan²,

Steudel³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

144

127

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.-The majority of familial pulmonary arterial hypertension (PAH) cases are caused by mutations in the type 2 bone morphogenetic protein receptor (BMPR2). However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a "second hit." There is substantial evidence from the literature implicating dysregulated inflammation, in particular the cytokine IL-6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL-6 in pulmonary tissues and conversely that IL-6 regulates the BMP pathway. We tested this in vivo using transgenic mice expressing an inducible dominant negative BMPR2 in smooth muscle, using mice injected with an IL-6-expressing virus, and in vitro using small interfering RNA (siRNA) to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL-6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38 MAPK inhibitors. We also found that IL-6 in vivo caused a twofold increase in expression of the BMP signaling target Id1 and caused increased BMP activity in a luciferase-reporter assay in PA SMC. Thus we have shown both in vitro and in vivo a complete negative feedback loop between IL-6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit. pulmonary circulation and disease; growth factors/cytokines; bone morphogenetic protein

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Pulmonary Hypertension in Rats 2.

Cited by 61 publications

References 13 publications

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman's disease

Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle

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