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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 MC stabilizer and c-kit inhibitor on pulmonary mast cells in rats with MCT- induced PH. 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. The lung tissue sections were stained with toluidine blue (TB). The TB-stained MCs were counted throughout the tissue sections and (A) total MCs were determined. Perivascular MCs were examined to determine the index of granulation (IOG). (B) Index of granulation (in %) is given. Each bar represents Mean ± SEM (n = 6-8). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.
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Figure 5: Effects of MC stabilizer and c-kit inhibitor on pulmonary mast cells in rats with MCT- induced PH. 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. The lung tissue sections were stained with toluidine blue (TB). The TB-stained MCs were counted throughout the tissue sections and (A) total MCs were determined. Perivascular MCs were examined to determine the index of granulation (IOG). (B) Index of granulation (in %) is given. Each bar represents Mean ± SEM (n = 6-8). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.

Mentions: We investigated the effects of treatments on pulmonary MCs. The number of MCs in MCT-rats receiving placebo was increased as compared with the healthy rats, whereas there was a decrease of MCs in MCT-rats treated with PLX and CSS (p < 0.05 versus placebo) (Figure 5A). The perivascular MCs were then analyzed and their activation/degranulation status was determined. We found that the IOG of perivascular MCs was significantly decreased in placebo rats as compared to healthy rats. Treatment with PLX and CSS resulted in an increase in IOG (p < 0.05 versus placebo) (Figure 5B).


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 MC stabilizer and c-kit inhibitor on pulmonary mast cells in rats with MCT- induced PH. 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. The lung tissue sections were stained with toluidine blue (TB). The TB-stained MCs were counted throughout the tissue sections and (A) total MCs were determined. Perivascular MCs were examined to determine the index of granulation (IOG). (B) Index of granulation (in %) is given. Each bar represents Mean ± SEM (n = 6-8). *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 5: Effects of MC stabilizer and c-kit inhibitor on pulmonary mast cells in rats with MCT- induced PH. 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. The lung tissue sections were stained with toluidine blue (TB). The TB-stained MCs were counted throughout the tissue sections and (A) total MCs were determined. Perivascular MCs were examined to determine the index of granulation (IOG). (B) Index of granulation (in %) is given. Each bar represents Mean ± SEM (n = 6-8). *p < 0.05 versus healthy; †p < 0.05 versus MCT-placebo.
Mentions: We investigated the effects of treatments on pulmonary MCs. The number of MCs in MCT-rats receiving placebo was increased as compared with the healthy rats, whereas there was a decrease of MCs in MCT-rats treated with PLX and CSS (p < 0.05 versus placebo) (Figure 5A). The perivascular MCs were then analyzed and their activation/degranulation status was determined. We found that the IOG of perivascular MCs was significantly decreased in placebo rats as compared to healthy rats. Treatment with PLX and CSS resulted in an increase in IOG (p < 0.05 versus placebo) (Figure 5B).

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