Lung fibrosis is a severe, chronic pulmonary disease with a grim prognosis. The pathogenesis of lung fibrosis involves the distortion of pulmonary architecture due to lung injury and inflammation. Central to this process are the Transforming Growth Factor-β1 (TGF-β1)/Smad signaling pathway and oxidative stress. The Smad protein family acts as signal transducers for TGF-β receptors. When TGF-β binds to its receptors, it forms a dimer that phosphorylates and activates intracellular Smad-3. Inside the nucleus, phosphorylated Smad-3 promotes the gene transcription of several proteins that enhance collagen synthesis, contributing to lung fibrosis.
The COVID-19 pandemic has exacerbated the challenges posed by lung fibrosis, with a significant increase in cases. COVID-19 patients have exhibited evidence of lung scars during and after recovery. As of now, there are no available treatments specifically for COVID-19-induced lung fibrosis, despite the international medical community’s efforts. The limited options for managing lung fibrosis primarily aim to reduce symptoms or slow disease progression, but none can reverse the pathology. Therefore, developing a cost-effective therapeutic modality that can reverse lung fibrosis or improve lung function is of utmost importance.
Bleomycin (BLM), an antibiotic and chemotherapeutic drug produced by Streptomyces verticillus, is used to treat a variety of tumors, including carcinomas and lymphomas. However, lung fibrosis is one of the most well-known side effects of BLM. Single delivery of BLM directly into the lungs of mice or rats is commonly used to create experimental models to investigate pulmonary fibrogenesis and assess the efficacy of therapeutic antifibrotic approaches. The intratracheal mode of administration is preferred, as it allows the drug to exert a direct toxic effect on lung tissue. BLM models are advantageous due to their availability, ease of handling, and their ability to meet crucial requirements for an appropriate animal model. These models have significantly advanced our understanding of the pathophysiological functions of growth factors, cytokines, and signaling pathways related to lung fibrosis. However, some researchers argue that BLM-induced lung fibrosis is self-limiting, contrasting with the progressive nature of chronic lung fibrosis observed in clinical instances.
Vitamin E, a fat-soluble vitamin and natural component of the cell membrane lipid bilayer, plays a crucial role in reducing membrane damage and lipid peroxidation by donating hydrogen atoms to free radicals such as superoxide and hydroxyl radicals. It also aids in the detoxification of electrophilic compounds produced by lipid peroxidation and inhibits the oxidation of protein cysteine residues, thus maintaining membrane integrity. Furthermore, vitamin E suppresses the transduction of inflammatory pathways and the production of inflammatory cytokines.
Vitamin E is also linked to neurological and DNA repair functions. It may alleviate and treat certain chronic disorders, particularly in tissues requiring its anti-inflammatory properties and defense against lipid peroxidation. Vitamin E has shown promise in treating fatty liver disease symptoms and is increasingly associated with better brain and eye health. There is a strong correlation between dietary vitamin E intake and the amelioration of chronic heart disease and cancer. Previous epidemiological studies have shown a significant decrease in the number of deaths due to respiratory, cardiac, and carcinogenic disorders associated with higher serum levels of vitamin E.
In this context, the present study aimed to investigate the potential roles of vitamin E as a protective and therapeutic agent against BLM-induced lung fibrosis.
Lung fibrosis is characterized by the excessive accumulation of extracellular matrix components, particularly collagen, leading to the destruction of lung architecture and impairment of gas exchange. The disease can result from various etiologies, including chronic inflammatory conditions, autoimmune diseases, environmental exposures, and infections. Idiopathic Pulmonary Fibrosis (IPF), a form of lung fibrosis with unknown cause, is one of the most common and severe forms, with a median survival of 3-5 years from diagnosis.
The TGF-β1/Smad signaling pathway is a crucial mediator in the pathogenesis of lung fibrosis. TGF-β1 is a potent fibrogenic cytokine that promotes the differentiation of fibroblasts into myofibroblasts, cells responsible for the excessive deposition of extracellular matrix. Activation of TGF-β1 signaling involves the binding of TGF-β1 to its receptors, leading to the phosphorylation of Smad proteins, which then translocate to the nucleus to regulate the expression of fibrotic genes. This pathway is not only pivotal in the development of fibrosis but also in the progression and exacerbation of the disease.
Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defenses, plays a significant role in lung fibrosis. ROS can induce lung injury and inflammation, contributing to the fibrotic process. The oxidative stress further activates fibrogenic signaling pathways, including the TGF-β1/Smad pathway, creating a vicious cycle that perpetuates lung fibrosis.
The COVID-19 pandemic has highlighted the urgent need for effective treatments for lung fibrosis. Post-acute sequelae of SARS-CoV-2 infection, commonly known as “long COVID,” include persistent respiratory symptoms and evidence of lung fibrosis in recovered patients. The pathophysiology of COVID-19-induced lung fibrosis involves direct viral injury to lung cells, dysregulated immune responses, and secondary infections, all contributing to lung damage and scarring. Despite intensive research efforts, there are no specific treatments for COVID-19-induced lung fibrosis, underscoring the need for novel therapeutic approaches.
Current treatments for lung fibrosis are limited and primarily focus on symptom management and slowing disease progression. Antifibrotic drugs, such as pirfenidone and nintedanib, have shown efficacy in slowing the progression of IPF but do not reverse the disease. These drugs target multiple pathways involved in fibrosis, including TGF-β signaling, but their use is associated with significant side effects and limited efficacy. Other therapeutic approaches, including anti-inflammatory and immunomodulatory agents, have been explored, but none have proven effective in reversing lung fibrosis.
The use of BLM to induce lung fibrosis in animal models has been instrumental in understanding the disease and testing potential therapies. BLM induces lung fibrosis through direct cytotoxic effects on lung cells, leading to inflammation, oxidative stress, and activation of fibrogenic pathways. The BLM model replicates many aspects of human lung fibrosis, making it a valuable tool for preclinical studies. However, it also has limitations, including the transient nature of fibrosis and differences in the fibrotic process compared to chronic human lung fibrosis.
Vitamin E, with its antioxidant and anti-inflammatory properties, has been proposed as a potential therapeutic agent for lung fibrosis. Vitamin E can scavenge free radicals, reducing oxidative stress and lipid peroxidation, key contributors to lung fibrosis. It also modulates inflammatory responses by inhibiting the activation of inflammatory pathways and reducing the production of pro-inflammatory cytokines. Additionally, vitamin E has been shown to improve membrane integrity and function, which may protect lung cells from injury and fibrosis.
The role of vitamin E in lung fibrosis has been investigated in various experimental models. Studies have shown that vitamin E supplementation can reduce lung inflammation and fibrosis in animal models of lung injury, including BLM-induced lung fibrosis. These effects are attributed to the antioxidant and anti-inflammatory actions of vitamin E, as well as its ability to modulate fibrogenic signaling pathways, including the TGF-β1/Smad pathway.
The potential therapeutic benefits of vitamin E extend beyond lung fibrosis. Vitamin E has been shown to improve outcomes in various chronic diseases characterized by oxidative stress and inflammation, including cardiovascular diseases, neurodegenerative diseases, and metabolic disorders. Its role in protecting against lipid peroxidation and maintaining cellular membrane integrity is particularly relevant in conditions where oxidative damage is a key pathogenic factor.
The present study aimed to explore the protective and therapeutic effects of vitamin E in a BLM-induced lung fibrosis model. By investigating the impact of vitamin E on lung inflammation, oxidative stress, and fibrogenic signaling pathways, this study sought to elucidate the potential mechanisms by which vitamin E may ameliorate lung fibrosis. The findings of this study could provide valuable insights into the potential use of vitamin E as a therapeutic agent for lung fibrosis and related conditions.
In conclusion, lung fibrosis is a devastating disease with limited treatment options. The COVID-19 pandemic has further underscored the need for effective therapies, as many recovered patients exhibit signs of lung fibrosis. Current treatments focus on symptom management and slowing disease progression but do not reverse the disease. Experimental models, including the BLM-induced lung fibrosis model, have been crucial in understanding the disease and testing potential therapies. Vitamin E, with its antioxidant and anti-inflammatory properties, offers promise as a therapeutic agent for lung fibrosis. Further research is needed to fully understand the mechanisms by which vitamin E exerts its protective effects and to explore its potential in clinical settings.
reference link : https://www.sciencedirect.com/science/article/abs/pii/S1567576924008956
