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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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Prevalence of pulmonary MCs in MCT-rats. Lung tissue from healthy and MCT-rats (that received single injection of saline and monocrotaline, respectively) were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for MCs. (A) Representative photomicrographs of healthy (a) and MCT-injected (b) rat lungs are shown. (B) Total and (C) perivascular MC count of different vessel sizes are given. An IOG was determined for perivascular MCs and (D) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10). *p < 0.05 versus healthy rats/corresponding vessels of healthy rats. Scale = 20 μm.
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Figure 2: Prevalence of pulmonary MCs in MCT-rats. Lung tissue from healthy and MCT-rats (that received single injection of saline and monocrotaline, respectively) were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for MCs. (A) Representative photomicrographs of healthy (a) and MCT-injected (b) rat lungs are shown. (B) Total and (C) perivascular MC count of different vessel sizes are given. An IOG was determined for perivascular MCs and (D) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10). *p < 0.05 versus healthy rats/corresponding vessels of healthy rats. Scale = 20 μm.

Mentions: As in clinical PH, pulmonary MC count was increased in MCT-rats (p < 0.05 versus healthy rats) and they were distributed throughout the lungs including peribronchial, perivascular and septal areas (Figure 2A, 2B). Perivascular MCs, the MC population of interest, was prevalent in MCT-rats (p < 0.05 versus healthy rats). Interestingly, there was about 9-fold increase in the number of MCs around the intra-acinar vessels (20-50 μm in diameter), whereas about 5- and 2-fold increases were found around the pre-acinar vessels (50-150 and >150 μm, respectively) in MCT-rats as compared to healthy rats (Figure 2C). As observed in the IPAH lungs, majority of the perivascular MCs was activated as evident from 6.3 fold decrease of their IOG in MCT-rats as compared to healthy rats (Figure 2D).


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)

Prevalence of pulmonary MCs in MCT-rats. Lung tissue from healthy and MCT-rats (that received single injection of saline and monocrotaline, respectively) were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for MCs. (A) Representative photomicrographs of healthy (a) and MCT-injected (b) rat lungs are shown. (B) Total and (C) perivascular MC count of different vessel sizes are given. An IOG was determined for perivascular MCs and (D) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10). *p < 0.05 versus healthy rats/corresponding vessels of healthy rats. Scale = 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Prevalence of pulmonary MCs in MCT-rats. Lung tissue from healthy and MCT-rats (that received single injection of saline and monocrotaline, respectively) were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for MCs. (A) Representative photomicrographs of healthy (a) and MCT-injected (b) rat lungs are shown. (B) Total and (C) perivascular MC count of different vessel sizes are given. An IOG was determined for perivascular MCs and (D) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10). *p < 0.05 versus healthy rats/corresponding vessels of healthy rats. Scale = 20 μm.
Mentions: As in clinical PH, pulmonary MC count was increased in MCT-rats (p < 0.05 versus healthy rats) and they were distributed throughout the lungs including peribronchial, perivascular and septal areas (Figure 2A, 2B). Perivascular MCs, the MC population of interest, was prevalent in MCT-rats (p < 0.05 versus healthy rats). Interestingly, there was about 9-fold increase in the number of MCs around the intra-acinar vessels (20-50 μm in diameter), whereas about 5- and 2-fold increases were found around the pre-acinar vessels (50-150 and >150 μm, respectively) in MCT-rats as compared to healthy rats (Figure 2C). As observed in the IPAH lungs, majority of the perivascular MCs was activated as evident from 6.3 fold decrease of their IOG in MCT-rats as compared to healthy rats (Figure 2D).

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