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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 IPAH patients. Lung tissues from donors and IPAH patients were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for the TB-stained MCs. (A) Representative photomicrographs of lung sections from donor (a) and patients (b) are shown. (B) Total and (C) perivascular MC count of different vessel size are given. (D) Perivascular MCs were further analyzed to identify granulated (a) and degranulated (b) MCs, and an index of granulation (IOG) was determined. (E) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10-15). *p < 0.05 versus donor/corresponding vessels of donor. Scale = 20 μm.
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Figure 1: Prevalence of pulmonary MCs in IPAH patients. Lung tissues from donors and IPAH patients were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for the TB-stained MCs. (A) Representative photomicrographs of lung sections from donor (a) and patients (b) are shown. (B) Total and (C) perivascular MC count of different vessel size are given. (D) Perivascular MCs were further analyzed to identify granulated (a) and degranulated (b) MCs, and an index of granulation (IOG) was determined. (E) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10-15). *p < 0.05 versus donor/corresponding vessels of donor. Scale = 20 μm.

Mentions: Toluidine blue staining showed that MCs were scattered throughout the lung tissues including peribronchial, septal and perivascular areas (Figure 1A). We counted the MCs and found that MC population was about 8 fold higher in IPAH patients as compared to the donors (Figure 1B). There was a preponderance of perivascular MCs in IPAH lungs (p < 0.05 versus donor lungs). Moreover, about 3 and 4 fold increases in MCs were observed around resistance (20-50 and 50-150 μm in diameter) and the larger (> 150 μm) vessels, respectively in the lungs of IPAH patients as compared to the donors (Figure 1C). We categorized perivascular MCs as granulated and degranulated (Figure 1D) and calculated the index of granulation (IOG) to examine their activation status. Interestingly, there was a 5.7 fold decrease of IOG in IPAH lungs (Figure 1E), suggesting that majority of the perivascular MCs were degranulated/activated.


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 IPAH patients. Lung tissues from donors and IPAH patients were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for the TB-stained MCs. (A) Representative photomicrographs of lung sections from donor (a) and patients (b) are shown. (B) Total and (C) perivascular MC count of different vessel size are given. (D) Perivascular MCs were further analyzed to identify granulated (a) and degranulated (b) MCs, and an index of granulation (IOG) was determined. (E) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10-15). *p < 0.05 versus donor/corresponding vessels of donor. Scale = 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Prevalence of pulmonary MCs in IPAH patients. Lung tissues from donors and IPAH patients were stained with toluidine blue (TB). The arrow indicates the positive signal (purple/violet stain) for the TB-stained MCs. (A) Representative photomicrographs of lung sections from donor (a) and patients (b) are shown. (B) Total and (C) perivascular MC count of different vessel size are given. (D) Perivascular MCs were further analyzed to identify granulated (a) and degranulated (b) MCs, and an index of granulation (IOG) was determined. (E) IOG (in %) is shown. Each bar represents Mean ± SEM (n = 10-15). *p < 0.05 versus donor/corresponding vessels of donor. Scale = 20 μm.
Mentions: Toluidine blue staining showed that MCs were scattered throughout the lung tissues including peribronchial, septal and perivascular areas (Figure 1A). We counted the MCs and found that MC population was about 8 fold higher in IPAH patients as compared to the donors (Figure 1B). There was a preponderance of perivascular MCs in IPAH lungs (p < 0.05 versus donor lungs). Moreover, about 3 and 4 fold increases in MCs were observed around resistance (20-50 and 50-150 μm in diameter) and the larger (> 150 μm) vessels, respectively in the lungs of IPAH patients as compared to the donors (Figure 1C). We categorized perivascular MCs as granulated and degranulated (Figure 1D) and calculated the index of granulation (IOG) to examine their activation status. Interestingly, there was a 5.7 fold decrease of IOG in IPAH lungs (Figure 1E), suggesting that majority of the perivascular MCs were degranulated/activated.

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