الفهرس 
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Abstract
Lung fibrosis is the most severe adverse effect of bleomycin that occurs in the form of remodeling of lung architecture and loss of pulmonary function, leading to death. Bleomycin is metabolized in liver then inactivated by bleomycin hydrolase, which is present in small amount in the lungs, leading to lung toxicity. Pirfenidone is a pyridone derivative that ameliorates bleomycininduced lung injury and suppresses transforming growth factor-beta-1 (TGF- β1) that can induce fibrogenisis by myofibroplastic proliferation. Nanotechnology offers safe delivery of the therapeutic agents to the target organ or tissue, thus protecting them against rapid degradation and increasing their solubility. This new approach can avoid the disadvantages of traditional drugs like poor distribution, limited efficacy, unwanted adverse effects and absence of selectivity. Niosomes are biodegradable, biocompatible and non-immunogenic nanoparticles with special structure. The special structure of a niosome gives it the ability to load both hydrophilic and lipophilic drugs and the vesicular structure behaves like a reservoir, that releases drug in a strict way. Aim of the Work: The aim of the present work was to study the effect of nanoparticles (niosomes) loaded with pirfenidone on bleomycin-induced lung fibrosis in adult male albino rats. Material and Methods: Forty adult male albino rats were included in this study and were divided into six groups as follows: group I (control group): It included five rats. They were given no medications. group II (pirfenidone group): It included five rats. They were given 50 mg/kg of pirfenidone once daily via an oro-gastric tube for 10 days. group III (encapsulated-pirfenidone group): It included five rats. They were given 50 mg/kg of encapsulated-pirfenidone (niosomes loaded with pirfenidone) once daily via an oro-gastric tube for 10 days. group IV (bleomycin group): It included five rats. They were given 50 mg/kg of bleomycin intraperitoneally (IP) at 1, 5, 8, 11 and 15 days starting from the first day of the experiment and left without treatment for 10 days. group V (bleomycin-pirfenidone group): It included ten rats. They were given bleomycin as group IV. Then it was subdivided into two equal subgroups (5 rats/each) as follows: • Subgroup Va (bleomycin-pirfenidone a): They were given 30 mg/kg of pirfenidone once daily via an oro-gastric tube for 10 days. • Subgroup Vb (bleomycin-pirfenidone b): They were given 50 mg/kg of pirfenidone once daily via an oro-gastric tube for 10 days. group VI (bleomycin-encapsulated-pirfenidone group): It included ten rats. They were given bleomycin as group IV. Then it was subdivided into two equal subgroups (5 rats/each) as follows: • Subgroup VIa (bleomycin-encapsulated-pirfenidone a): They were given 30 mg/kg of encapsulated-pirfenidone (niosomes loaded with pirfenidone) once daily via an oro-gastric tube for 10 days. • Subgroup VIb (bleomycin-encapsulated-pirfenidone b): They were given 50 mg/kg of encapsulated-pirfenidone (niosomes loaded with pirfenidone) once daily via an oro-gastric tube for 10 days. Lung specimens were obtained and subjected to histological examination using H&E, Masson’s trichrome, anti-TGF-β1 and toluidine blue stain and examined also using transmission electron microscope. The mean area % of the stained collagen fibers, intensity of TGF-β1 immune-histochemical expression and the mean thickness of blood-air barrier in the lungs were assessed and were statistically analyzed. Results: I) Light microscopy: group IV (bleomycin group): H&E stained sections showed disrupted lung architecture, multiple areas of interstitial hemorrhage and intercellular inflammatory infiltration. In addition, bronchioles appeared with sloughing of the epithelial lining into the lumen with extensive peribronchial cellular infiltration. group V (bleomycin-pirfenidone group): Subgroups Va and Vb showed partial improvement in the form of more patent alveoli, some thin interalveolar septa with some areas of interstitial hemorrhage and intercellular infiltration. Bronchioles appeared with clear lumen and lined with simple columnar epithelium. group VI (bleomycin-encapsulated-pirfenidone group): Subgroups VIa and VIb showed better results in comparison with group V in the form of more patent alveoli, more thin interalveolar septa, few areas of interstitial hemorrhage and intercellular infiltration. The bronchioles had clear lumen and were lined with simple columnar ciliated epithelium. II) Transmission electron microscopic results: group IV (bleomycin group): This group showed apparent thickening of the basal lamina of bloodair barrier. Type I and II pneumocytes appeared with irregular nuclei with condensed chromatin, the cytoplasm of type II showed empty lamellar bodies and the free surface showed detached microvilli. group V (bleomycin-pirfenidone group): Subgroups Va and Vb showed apparent normal thickness of the basal lamina of blood-air barrier. Type II pneumocytes had regular nuclei with peripherally condensed chromatin, the cytoplasm showed lamellar bodies with some containing surfactant and the free surface showed few short microvilli. group VI (bleomycin-encapsulated-pirfenidone group): Subgroups VIa and VIb showed better improvement in comparison with group V in the form of less thickness of the basal lamina of blood-air barrier. Type II pneumocytes appeared with regular nuclei with peripherally condensed chromatin and the cytoplasm showed more lamellar bodies with surfactant. Results of morphometric study: Morphometric study of the mean area % of collagen fibers stained with Masson’s trichrome of bleomycin group (group IV) revealed highly significant increase in comparison with control group. Also, highly significant decrease was recorded for subgroups (Va and Vb) in comparison with group IV. Subgroup VIb showed highly significant decrease when compared with subgroup Vb, but showed non-significant decrease when compared with subgroup VIa. Morphometric study of the mean area % of intensity of immunehistochemical cells stained with anti-TGF-β1 of bleomycin group (group IV) showed highly significant increase from control group. Highly significant decrease was recorded for subgroups Va and Vb in comparison with group IV. Moreover, highly significant decrease was recorded for subgroup Vb when compared with Va. Also, highly significant decrease was recorded for subgroup VIb when compared with subgroup Vb. On the other hand, nonsignificant change was recorded for subgroup VIb in comparison with VIa. Morphometric study of the mean thickness of blood-air barrier of ultrathin sections of the lungs of group IV denoted highly significant increase in comparison with control group. Subgroup Va showed significant decrease in comparison with group IV. While, highly significant decrease was recorded for subgroup Vb in comparison with group IV and subgroup Va. In addition, subgroup VIb showed highly significant decrease in comparison with subgroup Vb and only significant decrease when compared with subgroup VIa.