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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, right ventricular hypertrophy (RVH) and pulmonary vascular remodeling of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), mast cell stabilizer (Cromolyn) or placebo from day 21 to 35 after MCT-injection followed by hemodynamic and RVH measurement. 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 shown. Double immunostaining for von Willebrand factor and α-smooth muscle actin, and elastica staining were performed on the lung tissues followed by vascular morphometry. (D) Proportion of non- (N), partially (P) or fully (F) muscularized pulmonary arteries and their (E) medial wall thicknesses (%) are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo group.
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Figure 6: Effects of inhibiting c-kit and MC degranulation on PH, right ventricular hypertrophy (RVH) and pulmonary vascular remodeling of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), mast cell stabilizer (Cromolyn) or placebo from day 21 to 35 after MCT-injection followed by hemodynamic and RVH measurement. 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 shown. Double immunostaining for von Willebrand factor and α-smooth muscle actin, and elastica staining were performed on the lung tissues followed by vascular morphometry. (D) Proportion of non- (N), partially (P) or fully (F) muscularized pulmonary arteries and their (E) medial wall thicknesses (%) are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo group.

Mentions: The findings of the preventive study prompted us to investigate the effects of inhibition of c-kit and MC degranulation by a therapeutic approach. Surprisingly, we did not find any significant reduction of RVSP and RV/(LV+S) in MCT-rats treated with PLX and CSS as compared to placebo rats (Figure 6A, 6B and 6C). Moreover, the treatment did not impair the progression of pulmonary vascular remodeling as evident from the comparable degree of muscularization and medial wall thickness of distal pulmonary vessels in treated versus placebo rats (Figure 6D and 6E).


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, right ventricular hypertrophy (RVH) and pulmonary vascular remodeling of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), mast cell stabilizer (Cromolyn) or placebo from day 21 to 35 after MCT-injection followed by hemodynamic and RVH measurement. 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 shown. Double immunostaining for von Willebrand factor and α-smooth muscle actin, and elastica staining were performed on the lung tissues followed by vascular morphometry. (D) Proportion of non- (N), partially (P) or fully (F) muscularized pulmonary arteries and their (E) medial wall thicknesses (%) are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Effects of inhibiting c-kit and MC degranulation on PH, right ventricular hypertrophy (RVH) and pulmonary vascular remodeling of MCT-rats. Rats were treated with selective c-kit inhibitor (PLX), mast cell stabilizer (Cromolyn) or placebo from day 21 to 35 after MCT-injection followed by hemodynamic and RVH measurement. 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 shown. Double immunostaining for von Willebrand factor and α-smooth muscle actin, and elastica staining were performed on the lung tissues followed by vascular morphometry. (D) Proportion of non- (N), partially (P) or fully (F) muscularized pulmonary arteries and their (E) medial wall thicknesses (%) are given. Each bar represents Mean ± SEM (n = 8-10). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo group.
Mentions: The findings of the preventive study prompted us to investigate the effects of inhibition of c-kit and MC degranulation by a therapeutic approach. Surprisingly, we did not find any significant reduction of RVSP and RV/(LV+S) in MCT-rats treated with PLX and CSS as compared to placebo rats (Figure 6A, 6B and 6C). Moreover, the treatment did not impair the progression of pulmonary vascular remodeling as evident from the comparable degree of muscularization and medial wall thickness of distal pulmonary vessels in treated versus placebo rats (Figure 6D and 6E).

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