Abstract
Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from the shrub Crotalaria spectabilis, induces in the lungs of many mammalian species severe hypertension and fibrosis. Previous work with MCT-induced lung disease in rats has shown that some of the steps to progressive fibrosis can be interrupted or decreased by intervention with retinoic acid (RA) or with the angiotensin converting enzyme inhibitor, captopril. This report emphasizes the pathology and cytokines present in lungs of rats in the MCT model of hypertension and fibrosis in 8 treatment groups, six per group: (1) controls, not treated; (2) captopril; (3) RA; (4) combined captopril and RA. Groups 5-8 replicated groups 1-4 and also received MCT subcutaneously. Tissues were harvested at 28 days for histopathology and measurement of cytokines TGFβ, TNFα, interleukin 6, and IFNα. TGFβ was depressed at 28 days by MCT, an effect reversed by a combination of captopril and RA. RA influences production of an important Th1 cytokine, IFNγ, and demonstrated the greatest limitation of MCTinduced TNFα. The MCT-induced lung pathology of vasculitis, interstitial pneumonia and fibrosis was limited by captopril. Smooth muscle actin was overexpressed in MCT treated animals receiving RA, an effect reduced with captopril. Overall, the study confirmed the existence of a protective effect for both captopril and RA from MCT-induced lung damage at 30 days. No synergistic or antagonistic activity was observed when the two drugs were administered together. Each of the drugs exerts different and particular effects on serum and tissue levels of various cytokines, suggesting that each drug is efficient at different points of attack in the control of lung fibrosis.
Keywords: transforming growth factor beta, Lung Tissue Supernatants, monocrotaline, inflammatory reaction, Interferon-gamma
Current Pharmaceutical Design
Title: Effects on Cytokines and Histology by Treatment with the Ace Inhibitor Captopril and the Antioxidant Retinoic Acid in the Monocrotaline Model of Experimentally Induced Lung Fibrosis
Volume: 13 Issue: 13
Author(s): Richard C. Baybutt, Betty L. Herndon, Joshua Umbehr, Jonathan Mein, Yuan Xue, Sara Reppert, Christine Van Dillen, Robin Kamal, Anirudha Halder and Agostino Molteni
Affiliation:
Keywords: transforming growth factor beta, Lung Tissue Supernatants, monocrotaline, inflammatory reaction, Interferon-gamma
Abstract: Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from the shrub Crotalaria spectabilis, induces in the lungs of many mammalian species severe hypertension and fibrosis. Previous work with MCT-induced lung disease in rats has shown that some of the steps to progressive fibrosis can be interrupted or decreased by intervention with retinoic acid (RA) or with the angiotensin converting enzyme inhibitor, captopril. This report emphasizes the pathology and cytokines present in lungs of rats in the MCT model of hypertension and fibrosis in 8 treatment groups, six per group: (1) controls, not treated; (2) captopril; (3) RA; (4) combined captopril and RA. Groups 5-8 replicated groups 1-4 and also received MCT subcutaneously. Tissues were harvested at 28 days for histopathology and measurement of cytokines TGFβ, TNFα, interleukin 6, and IFNα. TGFβ was depressed at 28 days by MCT, an effect reversed by a combination of captopril and RA. RA influences production of an important Th1 cytokine, IFNγ, and demonstrated the greatest limitation of MCTinduced TNFα. The MCT-induced lung pathology of vasculitis, interstitial pneumonia and fibrosis was limited by captopril. Smooth muscle actin was overexpressed in MCT treated animals receiving RA, an effect reduced with captopril. Overall, the study confirmed the existence of a protective effect for both captopril and RA from MCT-induced lung damage at 30 days. No synergistic or antagonistic activity was observed when the two drugs were administered together. Each of the drugs exerts different and particular effects on serum and tissue levels of various cytokines, suggesting that each drug is efficient at different points of attack in the control of lung fibrosis.
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Baybutt C. Richard, Herndon L. Betty, Umbehr Joshua, Mein Jonathan, Xue Yuan, Reppert Sara, Van Dillen Christine, Kamal Robin, Halder Anirudha and Molteni Agostino, Effects on Cytokines and Histology by Treatment with the Ace Inhibitor Captopril and the Antioxidant Retinoic Acid in the Monocrotaline Model of Experimentally Induced Lung Fibrosis, Current Pharmaceutical Design 2007; 13 (13) . https://dx.doi.org/10.2174/138161207780618803
DOI https://dx.doi.org/10.2174/138161207780618803 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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