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Study of the possible therapeutic effect of LCZ696 in chemotherapy induced pulmonary fibrosis in rats / by Mai Abdelhalim Mohamed Abdelhalim ; the Supervision of Dr. Dalaal Moustafa Abdallah, Dr. Noha Nagah Nassar, Dr. Gehan Sobhy Georgy.

By: Contributor(s): Material type: TextTextLanguage: English Summary language: English, Arabic Producer: 2023Description: 176 pages : illustrations ; 25 cm. + CDContent type:
  • text
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  • / فى التليف الرئوى الناتج عن العلاج الكيميائى فى الجرذان LCZ696دراسة التأثير العلاجي المحتمل ل [Added title page title]
Subject(s): DDC classification:
  • 615.1
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  • Issues also as CD.
Dissertation note: Thesis (M.Sc.)-Cairo University, 2023. Summary: Introduction: Pulmonary fibrosis (PF) is a progressively devastating lung disease with no definitive therapeutic strategy. Several factors may precipitate PF including chemotherapy, environmental agents, and infection (as Coronavirus). Disruption of the lung oxidant/antioxidant status along with increased activation of inflammatory and apoptotic mediators are considered as major findings implicated in PF pathogenesis. This study investigated the prospect therapeutic effect of valsartan alone or combined with sacubitril (LCZ696) in chemotherapy-induced PF. Methods: Rats were randomly allocated into four groups; normal control, methotrexate (MTX)-induced PF (once weekly for 2 consecutive weeks), MTX-induced PF treated with valsartan or LCZ696 administered for 28 days initiated 2 weeks after PF induction. Lung histopathological examinations (H&E and Masson’s trichome) and immunohistochemical determination of α-smooth muscle actin (α-SMA) were performed. Additionally, pro-fibrotic, inflammatory, apoptotic, and oxidative stress biomarkers were assayed in lung tissues. Results: LCZ696 exhibited inhibition of the pro-fibrotic biomarker transforming growth factor-1β (TGF-1β) along with Smad7 increment with marked suppression of caspase-3, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) compared to valsartan. Though valsartan showed partial improvement, LCZ696 normalized α-SMA and oxidative/nitroactive stress biomarkers (catalase and nitric oxide). Furthermore, histopathological examination of LCZ696 treated group considerably inhibited inflammation and fibrosis in addition to remarkable reduction of collagen deposition. Conclusion and discussion: Collectively, the combined therapy LCZ696 showed superior effects to single valsartan regimen and may be considered as a promising therapeutic modality for chemotherapy-induced PF. Summary: تم تصميم الدراسة الحالية بهدف أساسي لتوضيح الإمكانية العلاجية لمثبط مستقبلات الأنجيوتنسين وكابح النيبريليسين الأول في فئته (ساكيوبتريل/فالسارتان) كنظام علاجي مشترك مقارنة بالعلاج الفردي فالسارتان في نموذج تليف الرئة الناجم عن الميثوتريكسيت. الدراسة تهدف إلى تمييز الآليات الجزيئية المعقدة واستقصاء تأثيراتها على الأحداث الرئيسية مثل الإجهاد التأكسدي، والالتهاب، والموت المبرمج، والتليف. علاوةً على ذلك، توسع الاستفسار ليشمل استكشاف مسار Neprilysin/Natriuretic peptides/ TGF-β1/Smad3 من أجل تحقيق هذه الأهداف، خضعت الدراسة الحالية لتقسيم إلى مرحلتين: المرحلة التجريبية والمرحلة الأساسية. تمت المرحلة التجريبية لتحديد الجرعة الفعّالة المثلى للنظام العلاجي المشترك ساكيوبيتريل/فالسارتان.
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Thesis Thesis قاعة الرسائل الجامعية - الدور الاول المكتبة المركزبة الجديدة - جامعة القاهرة Cai01.08.09.M.Sc.2023.Ma.S (Browse shelf(Opens below)) Not for loan 01010110089534000

Thesis (M.Sc.)-Cairo University, 2023.

Bibliography: pages 143-176.

Introduction: Pulmonary fibrosis (PF) is a progressively devastating lung disease with no definitive therapeutic strategy. Several factors may precipitate PF including chemotherapy, environmental agents, and infection (as Coronavirus). Disruption of the lung oxidant/antioxidant status along with increased activation of inflammatory and apoptotic mediators are considered as major findings implicated in PF pathogenesis. This study investigated the prospect therapeutic effect of valsartan alone or combined with sacubitril (LCZ696) in chemotherapy-induced PF. Methods: Rats were randomly allocated into four groups; normal control, methotrexate (MTX)-induced PF (once weekly for 2 consecutive weeks), MTX-induced PF treated with valsartan or LCZ696 administered for 28 days initiated 2 weeks after PF induction. Lung histopathological examinations (H&E and Masson’s trichome) and immunohistochemical determination of α-smooth muscle actin (α-SMA) were performed. Additionally, pro-fibrotic, inflammatory, apoptotic, and oxidative stress biomarkers were assayed in lung tissues. Results: LCZ696 exhibited inhibition of the pro-fibrotic biomarker transforming growth factor-1β (TGF-1β) along with Smad7 increment with marked suppression of caspase-3, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) compared to valsartan. Though valsartan showed partial improvement, LCZ696 normalized α-SMA and oxidative/nitroactive stress biomarkers (catalase and nitric oxide). Furthermore, histopathological examination of LCZ696 treated group considerably inhibited inflammation and fibrosis in addition to remarkable reduction of collagen deposition. Conclusion and discussion: Collectively, the combined therapy LCZ696 showed superior effects to single valsartan regimen and may be considered as a promising therapeutic modality for chemotherapy-induced PF.

تم تصميم الدراسة الحالية بهدف أساسي لتوضيح الإمكانية العلاجية لمثبط مستقبلات الأنجيوتنسين وكابح النيبريليسين الأول في فئته (ساكيوبتريل/فالسارتان) كنظام علاجي مشترك مقارنة بالعلاج الفردي فالسارتان في نموذج تليف الرئة الناجم عن الميثوتريكسيت. الدراسة تهدف إلى تمييز الآليات الجزيئية المعقدة واستقصاء تأثيراتها على الأحداث الرئيسية مثل الإجهاد التأكسدي، والالتهاب، والموت المبرمج، والتليف. علاوةً على ذلك، توسع الاستفسار ليشمل استكشاف مسار
Neprilysin/Natriuretic peptides/ TGF-β1/Smad3
من أجل تحقيق هذه الأهداف، خضعت الدراسة الحالية لتقسيم إلى مرحلتين: المرحلة التجريبية والمرحلة الأساسية. تمت المرحلة التجريبية لتحديد الجرعة الفعّالة المثلى للنظام العلاجي المشترك ساكيوبيتريل/فالسارتان.

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