The Anti-fibrotic and Anti-inflammatory Potential of Bone Marrow-Derived Mesenchymal Stem Cells and Nintedanib in Bleomycin-Induced Lung Fibrosis in Rats.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive lung damage. Tyrosine kinase inhibitors are approved to treat people with IPF while bone marrow-derived mesenchymal stem cell therapy was previously suggested to inhibit pulmonary fibrosis through the alveolar epithelial cell repair. The present study aimed to evaluate the anti-inflammatory and anti-fibrotic effect of the bone marrow-derived mesenchymal stem cell (BM-MSC) therapy in comparison with nintedanib, a tyrosine kinase inhibitor, on improving survival in bleomycin-induced lung fibrosis in rats. Moreover, the combined therapy of BM-MSCs and nintedanib will be evaluated. In the present study, IPF was induced through intra-tracheal instillation of bleomycin (5 mg/kg) in rats then treatments were administered 14 days thereafter. Nintedanib (100 mg/kg, I.P.) was administered daily for 28 days, while BM-MSCs were injected once intravenously in tail vein in the dose 1 × 106 cells/ml/rat. In the present study, both treatment regimens effectively inhibited lung fibrosis through several pathways, suppressing tumor growth factor-ß (TGF-ß)/SMAD3 expression which is considered the master signaling pathway. Nintedanib and BLM-MSCs exerted their anti-inflammatory effect through minimizing the expression of TNF-α and IL-6. In addition, the histopathological examination of the lung tissue showed a significant decrease in the alveolar wall thickening, in the inflammatory infiltrate, and in the collagen fiber deposition in response to either nintedanib or BM-MSC and their combination. In conclusion, the therapeutic pulmonary anti-fibrotic activity of nintedanib or BM-MSC is mediated through their anti-inflammatory properties and inhibition of SMAD-3/TGF-ß expression.

Ischemic preconditioning and postconditioning alleviates hippocampal tissue damage through abrogation of apoptosis modulated by oxidative stress and inflammation during transient global cerebral ischemia-reperfusion in rats.

INTRODUCTION: It has been argued recently that ischemic preconditioning (IPre) and postconditioning (IPost) have beneficial effects in many ischemic disorders however; their effects on global ischemia/reperfusion (I/R) are poorly understood. Thus, the present work aimed to study the possible mechanisms underlying the neuroprotective effects of IPre and IPost. METHODS: Animals were randomly allocated into 4 groups (n = 30): (1) Sham operated (SO); (2) I/R group, animals were subjected to 15 min global ischemia followed by 60 min reperfusion; (3) IPre, animals were subjected to 3 episodes of 5 min ischemia followed by 10 min reperfusion before I/R; (4) IPost, animals were subjected to three episodes of 10s of ischemia and 10s of reperfusion after the period of ischemia followed by a 60 min reperfusion period. Lactate dehydrogenase activity, oxidative stress, inflammatory and apoptotic biomarkers, as well as neurotransmitters, infarct size and histopathological examination were assessed. RESULTS: I/R induced hippocampal damage through increasing oxidative stress, inflammatory, excitotoxic and apoptotic markers as well as lactate dehydrogenase activity and infarct size. Both, IPre and IPost attenuated most markers induced by I/R. CONCLUSIONS: IPre and IPost neuroprotective effects can be explained through their anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms.

Montelukast, a cysteinyl leukotriene receptor-1 antagonist protects against hippocampal injury induced by transient global cerebral ischemia and reperfusion in rats.

Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory and immune modulating lipid mediators involved in inflammatory diseases and were boosted in human brain after acute phase of cerebral ischemia. The antagonism of CysLTs receptors may offer protection against ischemic damage. Therefore it seemed interesting to study the possible neuroprotective effect of Montelukast, a CysLTR1 antagonist in global cerebral ischemia/reperfusion (IR) injury in rats. Global cerebral ischemia-reperfusion was induced by bilateral carotid artery occlusion for 15 min followed by 60 min reperfusion period. Animals were randomly allocated into three groups (n = 30 per group): Sham operated, I/R control and rats treated with montelukast (0.5 mg/kg, po) daily for 7 days then I/R was induced 1 h after the last dose of montelukast. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid), Cys-LTs contents and CysLT1 receptor expression; as well as total brain infarct size and histopathological examination of the hippocampus were assessed. Montelukast protected hippocampal tissue by reducing oxidative stress, inflammatory and apoptotic markers. Furthermore, it reduced glutamate and lactate dehydrogenase activity as well as infarct size elevated by I/R. These results were consistent with the histopathological findings. Montelukast showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms.