الفهرس 
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Abstract
Bleomycin is a mixture of cytotoxic glycopeptide
antibiotics. It inhibits DNA synthesis and is used for the treatment of several neoplastic disorders. The clinical use of BLM has been precluded by its toxic effects, the most serious being pulmonary fibrosis. Recent studies suggest that oxidative
stress may play an important role in the pathogenesis of pulmonary fibrosis caused by BLM.
The current study attempts to ameliorate the pulmonary side effect of BLM without affecting its anticancer effect using rutin as well as its metabolite; QU which are flavonoids with
powerful antioxidant capacities.
Lung fibrosis was induced in mice by the subcutaneous injection of 10 mg/kg BLM 2 times/week for 6 successive weeks. Animals were sacrificed 5 days later after the last dose of
BLM. Rutin and QU were orally administered in dose of 20 and 200 mg/kg, respectively daily for 52 consecutive days starting 10
days before BLM administration.
The ability of rutin and QU to protect against fibrotic,
infammatory (hydroxyproline content, MPO, and TNF-α) and oxidative stress parameters (GSH, lipid peroxide, NO, GSH-Px, SOD, CAT) in lung tissues after BLM treatment as well as
histopathological examination were assessed. The anticancer effect was studied using the EAC tumor model which was induced by s.c. inoculation of 105 tumor cells into the right flank
of mice and assessing TGT.
Bleomycin elevated the pulmonary hydroxyproline content, the building block of collagen, by 77.7% indicating pulmonary fibrosis. Co-treatment with QU or rutin reduced the
pulmonary collagen content by 41.8 and 32.9 %, respectively. In addition, MPO enzyme, a neutrophilic infiltration marker was increased (194.7%) after BLM treatment and was hampered by the co-administration of either QU (21.3%) or rutin (16.4%).
Moreover, TNF-α, a proinflammatory mediator which plays an integral role in the pathogenesis of lung fibrosis, was elevated by 2-folds. Both QU and rutin mitigated this increment by 51 and
67%, respectively.
Administration of BLM in the current study reduced the lung content of GSH by about 43%, together with a reduction in antioxidant enzyme activities of GSH-Px, SOD, and CAT by
26%, 58% and 38%, respectively. On the contrary, it induced lipid peroxidation in lung tissue as evidenced by about 2-folds increase in TBARS together with a prominent increase in NO
content which mounted to 160%.
Though rutin and QU partly improved both GSH and TBARS without full normalization, both of them hampered the elevated NO content by 70.8% and 69.7%, respectively. Only QU ameliorated the reduced SOD activity by 72% as compared
to BLM-treated group. No improvement of GSH-Px or CAT activities was detected upon treatment with rutin or QU.
Morphological analysis of lung tissue sections following repeated exposure to a fibrogenic dose of BLM revealed severe lung injury manifested as congestion, edema, interalveolar inflammation, thickened alveolar wall, collapsed alveoli with
bronchial erosion and patchy cheesy fibrotic areas. Combined treatment of rutin or QU with BLM resulted in milder histopathological alterations as compared qualitatively to BLM
group.
Bleomycin treatment significantly prolonged the time required for TGT2, TGT3, TGT4 and TGT5 by 133, 99, 100 and 97%, respectively as compared to corresponding control. No
significant difference was detected in TGT after combined treatment with either rutin or QU.
In conclusion, rutin and QU ameliorate the fibrotic,inflammatory, oxidative stress, and pathological features of BLM induced idiopathic pulmonary fibrosis side effect without
significantly altering its anti-tumor efficacy and hence the study raises the possibility of using them as an adjuvant in BLM-based combination therapeutic modalities.