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Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats.

Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, Reiss I, Ghofrani HA, Weissmann N, Kuebler WM, Seeger W, Grimminger F, Schermuly RT - Respir. Res. (2011)

Bottom Line: Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved.However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT-rats.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Giessen Lung Centre, Giessen, Germany.

ABSTRACT

Background: Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.

Methods: Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.

Results: There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.

Conclusions: The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT-rats.

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Effects of inhibiting c-kit and MC degranulation on PH and right ventricular hypertrophy (RVH) of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), MC stabilizer (Cromolyn) or placebo from day 1 to 21 after MCT-injection. The rats in healthy group received saline injection instead of MCT. (A) Right ventricular systolic pressure (RVSP), (B) Right to left ventricular plus septum weight ratio (RV/(LV+S)) and (C) Systemic arterial pressure (SAP)are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.
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Figure 3: Effects of inhibiting c-kit and MC degranulation on PH and right ventricular hypertrophy (RVH) of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), MC stabilizer (Cromolyn) or placebo from day 1 to 21 after MCT-injection. The rats in healthy group received saline injection instead of MCT. (A) Right ventricular systolic pressure (RVSP), (B) Right to left ventricular plus septum weight ratio (RV/(LV+S)) and (C) Systemic arterial pressure (SAP)are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.

Mentions: We then investigated if inhibition of c-kit by PLX and of MC degranulation by CSS had any modulating effects on the development of MCT-induced PH and vascular remodeling. We found that MCT-rats receiving placebo developed significantly higher right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RV/(LV+S)) as compared to healthy rats, whereas rats treated with PLX and CSS revealed significantly reduced RVSP and RV/(LV+S) as compared to placebo group (Figure 3A, 3B). No significant change was observed in systemic arterial pressure (SAP) (Figure 3C).


Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats.

Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, Reiss I, Ghofrani HA, Weissmann N, Kuebler WM, Seeger W, Grimminger F, Schermuly RT - Respir. Res. (2011)

Effects of inhibiting c-kit and MC degranulation on PH and right ventricular hypertrophy (RVH) of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), MC stabilizer (Cromolyn) or placebo from day 1 to 21 after MCT-injection. The rats in healthy group received saline injection instead of MCT. (A) Right ventricular systolic pressure (RVSP), (B) Right to left ventricular plus septum weight ratio (RV/(LV+S)) and (C) Systemic arterial pressure (SAP)are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104382&req=5

Figure 3: Effects of inhibiting c-kit and MC degranulation on PH and right ventricular hypertrophy (RVH) of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), MC stabilizer (Cromolyn) or placebo from day 1 to 21 after MCT-injection. The rats in healthy group received saline injection instead of MCT. (A) Right ventricular systolic pressure (RVSP), (B) Right to left ventricular plus septum weight ratio (RV/(LV+S)) and (C) Systemic arterial pressure (SAP)are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.
Mentions: We then investigated if inhibition of c-kit by PLX and of MC degranulation by CSS had any modulating effects on the development of MCT-induced PH and vascular remodeling. We found that MCT-rats receiving placebo developed significantly higher right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RV/(LV+S)) as compared to healthy rats, whereas rats treated with PLX and CSS revealed significantly reduced RVSP and RV/(LV+S) as compared to placebo group (Figure 3A, 3B). No significant change was observed in systemic arterial pressure (SAP) (Figure 3C).

Bottom Line: Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved.However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT-rats.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Giessen Lung Centre, Giessen, Germany.

ABSTRACT

Background: Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.

Methods: Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.

Results: There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.

Conclusions: The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT-rats.

Show MeSH
Related in: MedlinePlus