Evaluating the ameliorative potential of plant flavonoids and their nanocomposites in bleomycin induced idiopathic pulmonary fibrosis

Abstract

Abstract-Introduction: Pulmonary Fibrosis can severely disrupt lung function. The cause of Idiopathic Pulmonary Fibrosis (IPF) is still unclear. The treatment currently available for IPF provides minimal benefits. Bleomycin is used in research to induce experimental pulmonary fibrosis in animals. Plant flavonoids such as fisetin and curcumin are known for their anti-inflammatory properties. The aim was to demonstrate the path of physiological changes in bleomycin induced IPF and to further evaluate the reversal and ameliorative potentials of some plant flavonoids and their nanocomposites. Bleomycin administration is known to damage the lung epithelial cells resulting in lower cell numbers. Methods: The Balb/c mice were used as models for bleo-induced IPF. Inflammation was measured by the generation of ROS, RONI, and histological assessment. Cell proliferation was measured by MTS assay and CFU assay. Results: Our colony-forming assay in BALF also demonstrated a reduction (1.65 fold) in colony-forming unit after bleomycin administration. The number of colonies increased upon treatment with fisetin(1.20 fold) and curcumin (1.13 fold) respectively. MTT proliferation assay demonstrated a significant increase in the number of viable cells upon treatment with curcumin (1.42 fold) and fisetin (1.74 fold) respectively, in the lung. The NBT assay demonstrated a significant effect of curcumin in BALF, lung and peripheral blood. A significant effect of fisetin was observed in BALF and peripheral blood. Conclusion: These findings were also supported by the histological analyses of the lung samples. Curcumin showed highest potential for the treatment of IPF and fisetin showed its ameliorative effect.

Protective effects and mechanism of curcumin in animal models of pulmonary fibrosis: a preclinical systematic review and meta-analysis

“…Eleven studies ( Xu et al, 2007 ; Chen et al, 2008 ; Zhang et al, 2011 ; Avasarala et al, 2013 ; Chen et al, 2018 ; Gouda and Bhandary, 2018 ; Shaikh et al, 2020b ; Durairaj et al, 2020 ; Shaikh and Prabhakar Bhandary, 2020 ; Shaikh et al, 2021b ; Fathimath Muneesa et al, 2022 ) which did not include primary or secondary outcome measures were excluded. In the end, there were 27 studies were included ( Punithavathi et al, 2000 ; Venkatesan, 2000 ; Punithavathi et al, 2003 ; Punithavathi et al, 2006 ; Zhou et al, 2006 ; Zhang et al, 2007 ; Zhao et al, 2008 ; Jiang et al, 2009 ; Lee et al, 2010 ; Smith et al, 2010 ; Hamdy et al, 2012 ; Cho et al, 2013 ; Tyagi et al, 2014 ; Banerjee et al, 2015 ; Li et al, 2015 ; Kar et al, 2016 ; Tyagi et al, 2016 ; Chen et al, 2017 ; Hu Y. et al, 2018 ; Chen et al, 2019 ; Gouda M. M. et al, 2020 ; Barsan et al, 2021 ; Durairaj et al, 2021 ; Hemmati et al, 2021 ; Hosseini et al, 2021 ; Miao et al, 2021 ; Kumari and Singh, 2022 ), two of them ( Smith et al, 2010 ; Miao et al, 2021 ) were included in this meta-analysis, each of which included two independent experiments, so this study included a total of 27 studies and 29 independent experiments.…”

“…The evaluation results are as follows: 2 studies ( Zhang et al, 2007 ; Chen et al, 2017 ) were identified as “low risk” because they used a random number table, while the remaining 25 studies were identified as “uncertain” in terms of random sequence generation and allocation of different groups. Among them, 12 studies ( Zhou et al, 2006 ; Zhao et al, 2008 ; Jiang et al, 2009 ; Cho et al, 2013 ; Tyagi et al, 2014 ; Li et al, 2015 ; Kar et al, 2016 ; Tyagi et al, 2016 ; Chen et al, 2019 ; Hemmati et al, 2021 ; Hosseini et al, 2021 ; Kumari and Singh, 2022 ) only described “randomization” without explaining the randomization method, and the rest of the studies lacked explanation on this aspect. Not all studies reported whether the distribution of relevant baseline levels was balanced between the experimental and control groups, so the “baseline characteristics” were “uncertain;” 10 studies ( Venkatesan, 2000 ; Punithavathi et al, 2006 ; Cho et al, 2013 ; Tyagi et al, 2014 ; Tyagi et al, 2016 ; Chen et al, 2019 ; Durairaj et al, 2021 ; Hosseini et al, 2021 ; Miao et al, 2021 ; Kumari and Singh, 2022 ) were rated as low risk because they detailed the consistency and randomness of the conditions and environment in which laboratory animals were kept; None of the included studies mentioned blinding animals during the implementation of the intervention; 7 studies ( Zhou et al, 2006 ; Zhao et al, 2008 ; Smith et al, 2010 ; Tyagi et al, 2014 ; Chen et al, 2017 ; Chen et al, 2019 ; Kumari and Singh, 2022 ) only described the “randomized” selection of experimental animals for result evaluation, without explaining the randomization method, and the other studies did not explain this aspect.…”

“…Four paired comparisons ( Hamdy et al, 2012 ; Tyagi et al, 2014 ; Kar et al, 2016 ; Kumari and Singh, 2022 ) reported the effect of CUR on NO, one was from BALF ( Kumari and Singh, 2022 ), two from serum ( Tyagi et al, 2014 ; Kar et al, 2016 ) and the rest were from lung tissue. And the fixed-effect model showed a significant reduction in CUR compared to the control group (SMD = −7.21; 95% CI = −9.05 to −5.37; heterogeneity χ2 = 5.59, df = 3, p = 0.133, I 2 = 46.3%, Figure 5D ).…”

Pulmonary fibrosis: Therapeutic and mechanistic insights into the role of phytochemicals

“…While the balance between apoptosis and fibroblast proliferation is tilted toward slowed apoptosis or accelerated proliferation of fibroblasts, the ECM accumulates, thereby resulting in fibrosis. 13,14 There are two routes for progression of diffuse pulmonary fibrosis: (a) the inflammatory pathway that is represented by non-IPF interstitial lung diseases, where there is a primary, clearly distinguishable alveolitis stage, and a late fibrotic stage, and (b) the epithelial pathway represented by idiopathic pulmonary fibrosis. 15,16 Various mechanistic studies have centered on the crosstalk, between damaged lung mesenchymal cells and epithelial cells.…”

Effect of CoCl2 or H2O2 pre-conditioned mesenchymal stem cells in a mouse model of pulmonary fibrosis

“…The MTT and NO assays were performed on the following day as described previously in section 2.4. Nitro Blue Tetrazolium (NBT) assay was performed as described elsewhere [15].…”