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Life Sciences Jan 2024Pulmonary fibrosis (PF) is a chronic interstitial lung disease with an increasing incidence following the COVID-19 outbreak. Pirfenidone (Pirf), an FDA-approved...
AIMS
Pulmonary fibrosis (PF) is a chronic interstitial lung disease with an increasing incidence following the COVID-19 outbreak. Pirfenidone (Pirf), an FDA-approved pulmonary anti-fibrotic drug, is poorly tolerated and exhibits limited efficacy. Trigonelline (Trig) is a natural plant alkaloid with diverse pharmacological actions. We investigated the underlying prophylactic and therapeutic mechanisms of Trig in ameliorating bleomycin (BLM)-induced PF and the possible synergistic antifibrotic activity of Pirf via its combination with Trig.
MATERIALS AND METHODS
A single dose of BLM was administered intratracheally to male Sprague-Dawley rats for PF induction. In the prophylactic study, Trig was given orally 3 days before BLM and then for 28 days. In the therapeutic study, Trig and/or Pirf were given orally from day 8 after BLM until the 28th day. Biochemical assay, histopathology, qRT-PCR, ELISA, and immunohistochemistry were performed on lung tissues.
KEY FINDINGS
Trig prophylactically and therapeutically mitigated the inflammatory process via targeting NF-κB/NLRP3/IL-1β signaling. Trig activated the autophagy process which in turn attenuated alveolar epithelial cells apoptosis and senescence. Remarkably, Trig attenuated lung SPHK1/S1P axis and its downstream Hippo targets, YAP-1, and TAZ, with a parallel decrease in YAP/TAZ profibrotic genes. Interestingly, Trig upregulated lung miR-375 and miR-27a expression. Consequently, epithelial-mesenchymal transition in lung tissues was reversed upon Trig administration. These results were simultaneously associated with profound improvement in lung histological alterations.
SIGNIFICANCE
The current study verifies Trig's prophylactic and antifibrotic effects against BLM-induced PF via targeting multiple signaling. Trig and Pirf combination may be a promising approach to synergize Pirf antifibrotic effect.
Topics: Rats; Animals; Bleomycin; Inflammasomes; Hippo Signaling Pathway; NLR Family, Pyrin Domain-Containing 3 Protein; Rats, Sprague-Dawley; Lung; Pulmonary Fibrosis; Pneumonia; Alkaloids; MicroRNAs
PubMed: 37981228
DOI: 10.1016/j.lfs.2023.122272 -
International Journal of Biological... 2023Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of...
Silicosis is a common and ultimately fatal occupational disease, yet the limited therapeutic option remains the major clinical challenge. Apelin, an endogenous ligand of the G-protein-coupled receptor (APJ), is abundantly expressed in diverse organs. The apelin-APJ axis helps to control pathological and physiological processes in lung. The role of apelin in the pathological process and its possible therapeutic effects on silicosis have not been elucidated. In this study, we found that lung expression and circulating levels of apelin were markedly decreased in silicosis patients and silica-induced fibrotic mice and associated with the severity. Furthermore, data demonstrated that pre-treatment from day 3 and post-treatment from day 15 with apelin could both alleviate silica-induced pulmonary fibrosis in mice. Besides, apelin inhibited pulmonary fibroblast activation via transforming growth factor beta 1 (TGF-β1) signaling. Our study suggested that apelin could prevent and reverse silica-induced pulmonary fibrosis by inhibiting the fibroblast activation through TGF-β1 signaling pathway, thus providing a new potential therapeutic strategy for silicosis and other pulmonary fibrosis.
Topics: Animals; Mice; Apelin; Fibroblasts; Pulmonary Fibrosis; Silicon Dioxide; Silicosis; Transforming Growth Factor beta1
PubMed: 37705751
DOI: 10.7150/ijbs.81436 -
American Journal of Respiratory and... Aug 2019
Review
Topics: Humans; Idiopathic Pulmonary Fibrosis
PubMed: 31022351
DOI: 10.1164/rccm.201903-0542UP -
The Science of the Total Environment Oct 2021Environmental exposure to silica or particles is very common in natural, agricultural and industrial activities. Chronic silica exposure can lead to silicosis, which...
Environmental exposure to silica or particles is very common in natural, agricultural and industrial activities. Chronic silica exposure can lead to silicosis, which remains one of the most serious interstitial lung diseases all through the world, while viable therapeutic choices are restricted. Triiodothyronine (T3) has been shown to exert a defensive role in many pulmonary diseases, however, rare data are available regarding the role of T3 on silica-induced injury. We constructed an experimental silicosis mouse model and T3 was intraperitoneally administrated after instillation of silica to observe the effect of T3 on silica-induced lung inflammation and fibrosis. Our results showed that the silicosis mouse model was accompanied by changes in thyroid morphology and function, and T3 supplement reduced silica-induced lung damage, inflammation and collagen deposition. The protective properties of T3 on silica-induced lung injury could be partially mediated through thyroid hormone receptors. And the mechanism by which T3 treatment ameliorated silica-induced fibrosis appeared to be via the reduction of glycolysis. Also, T3 could sufficiently postpone the progression of pulmonary fibrosis in established silicosis. Our findings reveal that administration of T3 could down-regulate the inflammatory response, pulmonary fibrosis and other lung damage caused by silica. The reduction of glycolysis may be one of the mechanisms.
Topics: Animals; Fibrosis; Inflammation; Lung; Mice; Mice, Inbred C57BL; Pneumonia; Pulmonary Fibrosis; Silicon Dioxide; Triiodothyronine
PubMed: 34090168
DOI: 10.1016/j.scitotenv.2021.148041 -
Methods in Molecular Biology (Clifton,... 2021The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is...
The drug discovery pipeline, from discovery of therapeutic targets through preclinical and clinical development phases, to an approved product by health authorities, is a time-consuming and costly process, where a lead candidates' success at reaching the final stage is rare. Although the time from discovery to final approval has been reduced over the last decade, there is still potential to further optimize and streamline the evaluation process of each candidate as it moves through the different development phases. In this book chapter, we describe our preclinical strategies and overall decision-making process designed to evaluate the tolerability and efficacy of therapeutic candidates suitable for patients diagnosed with fibrotic lung disease. We also describe the benefits of conducting preliminary discovery trials, to aid in the selection of suitable primary and secondary outcomes to be further evaluated and assessed in subsequent internal and external validation studies. We outline all relevant research methodologies and protocols routinely performed by our research group and hope that these strategies and protocols will be a useful guide for biomedical and translational researchers aiming to develop safe and beneficial therapies for patients with fibrotic lung disease.
Topics: Animals; Bleomycin; Computational Biology; Decision Making; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Regulation; Gene Regulatory Networks; Humans; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis
PubMed: 34028751
DOI: 10.1007/978-1-0716-1382-5_21 -
Experimental & Molecular Medicine Jul 2023To date, pulmonary fibrosis remains an unmet medical need. In this study, we evaluated the potency of mesenchymal stromal cell (MSC) secretome components to prevent...
To date, pulmonary fibrosis remains an unmet medical need. In this study, we evaluated the potency of mesenchymal stromal cell (MSC) secretome components to prevent pulmonary fibrosis development and facilitate fibrosis resolution. Surprisingly, the intratracheal application of extracellular vesicles (MSC-EVs) or the vesicle-depleted secretome fraction (MSC-SF) was not able to prevent lung fibrosis when applied immediately after the injury caused by bleomycin instillation in mice. However, MSC-EV administration induced the resolution of established pulmonary fibrosis, whereas the vesicle-depleted fraction did not. The application of MSC-EVs caused a decrease in the numbers of myofibroblasts and FAPa progenitors without affecting their apoptosis. Such a decrease likely occurred due to their dedifferentiation caused by microRNA (miR) transfer by MSC-EVs. Using a murine model of bleomycin-induced pulmonary fibrosis, we confirmed the contribution of specific miRs (miR-29c and miR-129) to the antifibrotic effect of MSC-EVs. Our study provides novel insights into possible antifibrotic therapy based on the use of the vesicle-enriched fraction of the MSC secretome.
Topics: Mice; Animals; Pulmonary Fibrosis; MicroRNAs; Mesenchymal Stem Cells; Bleomycin; Apoptosis; Extracellular Vesicles
PubMed: 37394579
DOI: 10.1038/s12276-023-01017-w -
Journal of Biochemical and Molecular... Nov 2023Sesamol, a lignan obtained from roasted seeds of Sesamum indicum, has high antioxidant and anti-inflammatory activity. In this study, we have investigated the effect of...
Sesamol, a lignan obtained from roasted seeds of Sesamum indicum, has high antioxidant and anti-inflammatory activity. In this study, we have investigated the effect of sesamol on Bleomycin (BLM) induced pulmonary toxicity as well as fibrosis in Wistar rats. Lung toxicity was induced by administration of BLM, 0.015 U/g ip, twice weekly for 28 days whereas lung fibrosis was induced by BLM, 0.015 U/g ip, every 5th day for 49 days. Sesamol administration was started 7 days before first dose of BLM in both the models. It was observed that sesamol 50 mg/kg most effectively attenuated pulmonary toxicity by reducing oxidative stress, inflammation and apoptosis. This dose was further evaluated for its anti-fibrotic effect. It was observed that there was a significant reduction in fibrosis. Lung collagen content was markedly reduced. Furthermore, expression of pro-fibrotic proteins, TGF-β/SMAD and α-SMA, was reduced and that of anti-fibrotic protein, AMPK, was markedly increased. Even though the combination of sesamol with pirfenidone exhibited no additional protection than either drug alone, it is evident from our study that our test drug, sesamol is comparable in efficacy to pirfenidone. Thus, sesamol has promising therapeutic potential in treatment of pulmonary toxicity and fibrosis.
Topics: Rats; Animals; Bleomycin; Rats, Wistar; Pulmonary Fibrosis; Lung; Fibrosis
PubMed: 37462223
DOI: 10.1002/jbt.23472 -
Der Pathologe Feb 2020Idiopathic pulmonary fibrosis (IPF) plays a special role within the group of interstitial lung diseases (ILDs) due to its inexorable progression and its specific... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) plays a special role within the group of interstitial lung diseases (ILDs) due to its inexorable progression and its specific medical treatment. With a median survival of only 2-3 years from the time of diagnosis, the prognosis is worse than many carcinomas.In contrast to other ILDs, IPF does not respond to anti-inflammatory treatment with corticosteroids but rather demands a specific medical therapy. Even though this cannot cure the disease, it can prolong survival. Lung transplantation is the only cure for progressive lung fibrosis. The clinical course is individual and difficult to predict. Acute exacerbations accelerate the clinical course and lead to high mortality.The underlying pathomechanisms of IPF, with its complex immunological and inflammatory processes and external impacts, have been the focus of recent research. Lifestyle and environmental influences are held responsible for much of its natural history. Smoking, pneumotoxic medications, and inhalation of dusts are well-known risk factors. Likewise, genetic and hereditary factors play a crucial role.This short review focuses on the peculiarities of IPF within the group of ILDs, especially in relation to its underlying mechanisms and clinical progression.
Topics: Disease Progression; Humans; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Prognosis; Risk Factors
PubMed: 31993696
DOI: 10.1007/s00292-019-00747-x -
Molecular Biology Reports Dec 2022Pulmonary fibrosis is the key feature of majority of idiopathic interstitial pneumonias (IIPs) as well as many patients with post-COVID-19. The pathogenesis of pulmonary... (Review)
Review
Pulmonary fibrosis is the key feature of majority of idiopathic interstitial pneumonias (IIPs) as well as many patients with post-COVID-19. The pathogenesis of pulmonary fibrosis is a complex molecular process that involves myriad of cells, proteins, genes, and regulatory elements. The non-coding RNA mainly miRNA, circRNA, and lncRNA are among the key regulators of many protein coding genes and pathways that are involved in pulmonary fibrosis. Identification and molecular mechanisms, by which these non-coding RNA molecules work, are crucial to understand the molecular basis of the disease. Additionally, elucidation of molecular mechanism could also help in deciphering a potential diagnostic/prognostic marker as well as therapeutic targets for IIPs and post-COVID-19 pulmonary fibrosis. In this review, we have provided the latest findings and discussed the role of these regulatory elements in the pathogenesis of pulmonary fibrosis associated with Idiopathic Interstitial Pneumonia and Covid-19.
Topics: Humans; COVID-19; Idiopathic Interstitial Pneumonias; Pulmonary Fibrosis; RNA, Untranslated
PubMed: 36097114
DOI: 10.1007/s11033-022-07820-4 -
Pharmacology & Therapeutics Jul 2023Pulmonary fibrotic diseases are characterized by proliferation of lung fibroblasts and myofibroblasts and excessive deposition of extracellular matrix proteins.... (Review)
Review
Pulmonary fibrotic diseases are characterized by proliferation of lung fibroblasts and myofibroblasts and excessive deposition of extracellular matrix proteins. Depending on the specific form of lung fibrosis, there can be progressive scarring of the lung, leading in some cases to respiratory failure and/or death. Recent and ongoing research has demonstrated that resolution of inflammation is an active process regulated by families of small bioactive lipid mediators termed "specialized pro-resolving mediators." While there are many reports of beneficial effects of SPMs in animal and cell culture models of acute and chronic inflammatory and immune diseases, there have been fewer reports investigating SPMs and fibrosis, especially pulmonary fibrosis. Here, we will review evidence that resolution pathways are impaired in interstitial lung disease, and that SPMs and other similar bioactive lipid mediators can inhibit fibroblast proliferation, myofibroblast differentiation, and accumulation of excess extracellular matrix in cell culture and animal models of pulmonary fibrosis, and we will consider future therapeutic implications of SPMs in fibrosis.
Topics: Animals; Pulmonary Fibrosis; Lung; Fibrosis; Cell Differentiation; Inflammation; Lipids; Inflammation Mediators
PubMed: 37244406
DOI: 10.1016/j.pharmthera.2023.108460