Immunosuppressive Activity of Goat Kefir in a Rat Model with Bleomycin-induced Pulmonary Fibrosis (original) (raw)
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High Doses of Kefir Accelerate Lung-Injury Progression in Bleomycin-Induced Pneumonitis in Rats
Jundishapur Journal of Natural Pharmaceutical Products, 2021
Background: Bleomycin-induced pneumonitis (BIP) is a common consequence of bleomycin (BLE) use during chemotherapy. Kefir is a probiotic with many health benefits. Many cancer patients in Indonesia consume kefir as a complementary traditional medicine alongside standard chemotherapy. Objectives: This study aimed to investigate the effects of high-dose kefir consumption on BIP in a rat model. Methods: Wistar male rats were given 0.3 mg of BLE via intranasal inhalation for 6 days with a daily intragastric administration of either phosphate buffered saline (PBS) or kefir at dosages of 2.5 mL, 3.5 mL, and 4.5 mL per day for 30 days. On day 30, lung sections were obtained and stained with hematoxylin and eosin for histological examinations. Immunohistochemistry tests were carried out to determine the activity levels of matrix metalloproteinase (MMP)-1, signal transducer, and activator of transcription (STAT)-3. TNF-α and IL-6 concentrations in plasma were also evaluated. Results: Histolo...
The Egyptian Journal of Anatomy, 2011
The possible protective effect of Losartan, an angiotensin II receptor 1 antagonist, on bleomycininduced rat lung fibrosis was evaluated using histological and immunohistochemical techniques. Twenty adult male albino rats were divided into 4 groups each of five rats: Group I (control) given saline both I.V and orally, Group II given bleomycin 10mg/Kg/day I.V., Group III given losartan 10 mg/Kg/day orally and Group IV given both bleomycin and losartan. Lung sections were taken at the 28 th day of the experiment, stained with H&E, Masson's trichrome, Orcein and immunohistochemical stain for α-SMA. This was followed by morphometric measurements and statistical analysis. The present study showed that bleomycin induced fibrotic changes in the lung in the form of thickened interalveolar septa filled with proliferated type II pneumocytes, fibroblasts and inflammatory cells with significant increase in collagen and elastic fibres deposition and in α-SMA immunoreactivity. It was found that concomitant treatment with losartan (Group IV) showed significant reduction in these fibrotic changes. The changes in α-SMA immunoreactivity in different groups showed the same pattern as those of collagen and elastic fibres. Thus, it could be concluded that myofibroblasts might play a pivotal role in induction of lung fibrosis and they could be a target of future therapeutic strategies.
Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGF1-induced expression of alpha smooth muscle actin (SMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGF1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and SMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGF1-induced collagen and SMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation.
Evaluation of the Effects of Nicotinamide on the Bleomycin-induced Pulmonary Fibrosis in Rat
2011
Fibrosis is the abnormal production of collagen fibers following tissue damage. This accounts for the formation of scar tissue. Lung fibrosis is one of the typical ways in which the lung reacts to damaging stimuli. In this study we tried to investigate the involving phenomena during the process of bleomycin-induced fibrosis in murine lung. We have evaluated this process at three levels, namely, at (1) cellular level (cells with contraction activity of pulmonary tissue), (2) intercellular signaling agents (e.g., IL-8, TNF-", TGF-$), tissue index factors (collagen, hydroxyproline) and some inorganic elements which may hypothetically be engaged as efficient enzymatic cofactors (e.g., copper), (3) pathophysiological or exaggerated physiological processes (inflammation and fibrosis). The pharmacological agent which have been selected for evaluating in this study is Nicotinamide, which their selection rationale will be discussed in detail separately in the discussion section. Bleomycin-induced pulmonary fibrosis is a widely used animal model for lung injury and fibrosis. After single dose instillation of intratracheal bleomycin, the fibrotic responses were studied by biochemical measurement of collagen deposition and analysis of pathological lung changes in different treatment groups. The results of this study showed that administrated agents in different doses, had satisfactorily healing effects on fibrosis process, ranging from good to moderate, through significant decreasing in lung collagen content (p<0.05).
Therapeutic effect of a peptide inhibitor of TGF-� on pulmonary fibrosis
Cytokine, 2011
Pulmonary fibrosis encompasses several respiratory diseases characterized by epithelial cell injury, inflammation and fibrosis. Transforming growth factor (TGF)-β1 is one of the main profibrogenic cytokines involved in the pathogenesis of lung fibrosis. It induces fibroblast differentiation into myofibroblasts, which produce high levels of collagen and concomitantly loss of lung elasticity and reduction of the respiratory function.In the present study, we have investigated the effects of P17 (a TGF-β inhibitor peptide) on IMR-90 lung fibroblast differentiation in vitro, as well as on the inhibition of the development of bleomycin-induced pulmonary fibrosis in mice.It was found that in IMR-90 cells, P17 inhibited TGF-β1-induced expression of connective tissue growth factor and α-smooth muscle actin. In vivo, treatment of mice with P17 2 days after bleomycin administration decreased lung fibrosis, areas of myofibroblast-like cells and lymphocyte infiltrate. P17 also reduced mRNA expression of collagen type I, fibronectin and the fibronectin splice isoform EDA in the lung, and increased the expression of IFN-γ mRNA. Finally, therapeutic treatment with P17 in mice with already established fibrosis was able to significantly attenuate the progression of lung fibrosis.These results suggest that P17 may be useful in the treatment of pulmonary fibrosis.
Effects of erdosteine on bleomycin-induced lung fibrosis in rats
Molecular and Cellular Biochemistry, 2006
This study was designed to examine the effects of erdosteine on bleomycin (BLM)-induced lung fibrosis in rats. Thirty-three Sprague-Dawley rats were divided randomly into three groups, bleomycin alone (BLM), bleomycin + erdosteine (BLM + ERD), and saline alone (control). The BLM and BLM + ERD groups, were given 2.5 mg/kg BLM intratracheally. The first dose of oral erdosteine (10 mg/kg/day) in the BLM + ERD group was started 2 days before BLM administration and continued until animals were sacrificed. Animals were sacrificed 14 days after intratracheal instillation of BLM. The effect of erdosteine on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and biochemical measurements of lung tissue superoxide dismutase (SOD) and glutathione (GSH) as antioxidants, malondialdehyde (MDA) as an index for lipid peroxidation, and nitrite/nitrate levels. Bleomycin-induced lung fibrosis as determined by lung histology was prevented with erdosteine (grades of fibrosis were 4.9, 2.3, and 0.2 in BLM, BLM + ERD, and control groups, respectively). Erdosteine also prevented bleomycin-induced increase in MDA (MDA levels were 0.50 ± 0.15, 0.11 ± 0.02, and 0.087 ± 0.03 nmol/mg protein in BLM, BLM + ERD, and control groups, respectively) and nitrite/nitrate (nitrite/nitrate levels were 0.92 ± 0.06, 0.60 ± 0.09, and 0.56 ± 0.1 µmol/mg protein in BLM, BLM + ERD, and control groups respectively) levels. Bleomycin-induced decrease in GSH and SOD levels in the lung tissue also prevented by erdosteine [(GSH levels were 213.5 ± 12.4, 253.2 ± 25.2, and 287.9 ± 34.4 nmol/mg protein) (SOD levels were 1.42 ± 0.12, 1.75 ± 0.17, and 1.89 ± 0.09 U/mg protein) in BLM, BLM + ERD, and control groups respectively]. Erdosteine prevented bleomycin-induced increases in total cell number and neutrophil content of the BAL fluid. In conclusion, oral erdosteine is effective in prevention of BLM-induced lung fibrosis in rats possibly via the repression of neutrophil accumulation, inhibition of lipid peroxidation, and maintenance of antioxidant and free radical scavenger properties. (Mol Cell Biochem 281: [129][130][131][132][133][134][135][136][137] 2006) known and unknown etiology. The progression of fibrosis is closely controlled by a complicated network consisting of many cytokines, chemical mediators, growth factors, and biophysical peptides derived from inflammatory immune cells, endothelial cells, and alveolar type II cells. It has generally
Therapeutic effect of a peptide inhibitor of TGF-β on pulmonary fibrosis
Cytokine, 2011
Pulmonary fibrosis encompasses several respiratory diseases characterized by epithelial cell injury, inflammation and fibrosis. Transforming growth factor (TGF)-b1 is one of the main profibrogenic cytokines involved in the pathogenesis of lung fibrosis. It induces fibroblast differentiation into myofibroblasts, which produce high levels of collagen and concomitantly loss of lung elasticity and reduction of the respiratory function.
American Journal of Respiratory Cell and Molecular Biology, 2005
Pulmonary fibrosis is the result of abnormal processes of repair that occur after lung injury. Transforming growth factor (TGF)- is a key molecule in the progression of pulmonary fibrosis. Although clinical use of interferon (IFN)- did not improve survival in patients with idiopathic pulmonary fibrosis, because some preclinical studies have suggested that IFN- is a potent inhibitor of fibrogenesis, beneficial effects of IFN- have been expected. We therefore attempted to determine effects of IFN- and investigated the mechanism of action of IFN- in bleomycin-induced pulmonary fibrosis. Bleomycin at Day 0 and IFN- for 4 wk were administered intravenously to ICR mice. At 28 d after bleomycin injection, histologic and chemical analysis was performed for evaluation of effects of IFN-. Tissue distribution and amounts of TGF-1 and thrombospondin (TSP)-1/2 were analyzed. IFN- attenuated prolylhydroxylase activity, resulting in inhibition of pulmonary fibrosis. Bleomycin-induced increase in TGF-1 in epithelial cells and extracellular matrix was attenuated by IFN-. TSP-1/2 was limited in platelets of control mice, but was present in foamy cells in fibrotic regions induced by bleomycin. These findings suggest that the antifibrotic effect of IFN- is inhibition of TGF- and its activation via decrease in TSP-1/2 in lung tissue and change in location of TSP-1/2 from platelets to foamy cells.
An Experimental Model to Induce Homogeneous and Progressive Pulmonary Fibrosis in Rats
Indian Journal of Pharmaceutical Education and Research, 2021
Background: This study aims to develop a new experimental model of pulmonary fibrosis (PF) as an alternative to conventional bleomycin model to overcome its limitations and effectively screened the therapeutic agents. Similarity of new experimental model to human lung fibrosis particularly as uniform and continuous progression has encouraged us to evaluate the usefulness of this system by assessment of anti-fibrotic drug pirfenidone parallel with bleomycin induced PF. Materials and Methods: In new model, ovalbumin (OVA) related asthma induced rats were set to inhaled nebulized formaldehyde solution (0.5% v/v, 30 min) subsequent with cigarettes smoke exposure twice daily for 14, 28 or 42 days and designated as AFC treated rats. However, bleomycin (BLM) treated rats were administered (5 IU/kg) single dose intratracheal injection. The pulmonary associated effects were assessed through cells permeation study, biochemical evaluation, physical and physiological parameters, survival analysis and histopathological examination. Results: Overall, pulmonary associated effects induced by new as well as conventional bleomycin model exhibited almost similar results. Though, new model developed homogeneous and time dependent advancement in pulmonary severity with enhanced survival ratio as compared to bleomycin model. Comparatively, new model also represented low extent of normalization with pirfenidone treatment due to establishment of progressive fibrosis. Conclusion: This study reflects the role of formaldehyde and cigarette smoke in reinforcement of PF particularly during the lung inflammatory condition. Also, it provides novel idea to induce homogeneous and progressive PF in rats, which could resembles human lung fibrosis more specifically than conventionally induced by intratracheal bleomycin instillation.