Enhancing Treatment Outcomes: Sestrin-2 and Oxidative Stress in Nasal Polyps

Introduction to Nasal Polyposis and Oxidative Stress

Nasal polyposis (NP) is a chronic inflammatory condition affecting the nasal mucosa, characterized by the presence of nasal polyps that can lead to nasal obstruction, loss of smell, and recurrent sinus infections. The multifactorial pathogenesis of NP involves a complex interplay between genetic, environmental, and immunological factors. Chronic inflammation is a key aspect of NP, contributing to the development of polyps and associated symptoms. A growing body of evidence suggests that oxidative stress plays a significant role in the pathogenesis of NP, as it is associated with inflammation and damage to epithelial tissues.

Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these harmful compounds. Elevated levels of ROS can lead to cellular damage, apoptosis, and contribute to the inflammatory processes seen in NP. This oxidative stress may be evaluated through biomarkers such as thiol-disulfide homeostasis, which reflects the redox state of the cell and can indicate the level of oxidative stress present.

The Importance of Sestrin-2 in Inflammation and Immunity

Sestrins are a family of highly conserved proteins that play a critical role in cellular stress responses. Sestrin-2 (SESN2) is particularly important for regulating oxidative stress and inflammation in various tissues, including the immune system. SESN2 functions as an antioxidant by modulating signaling pathways that reduce ROS levels, thereby protecting cells from oxidative damage.

In the context of nasal polyposis, SESN2 may be pivotal in regulating the inflammatory response mediated by immune cells such as macrophages and lymphocytes. Research has shown that SESN2 can inhibit inflammation by activating the Nrf2 pathway, which enhances the expression of antioxidant genes and detoxifying enzymes. Moreover, SESN2 has been implicated in the modulation of inflammatory mediators, suggesting its potential as a therapeutic target in NP management.

Mechanistic Role of SESN2 in Oxidative Stress and Inflammation

SESN2 exerts its effects through several mechanisms:

1. Antioxidant Activity: SESN2 scavenges ROS and modulates antioxidant enzymes, thus protecting against oxidative damage.
2. Regulation of Inflammatory Pathways: It influences various signaling pathways, including the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which plays a crucial role in cell proliferation and survival.
3. Cellular Homeostasis: SESN2 maintains thiol-disulfide homeostasis, which is vital for redox signaling and cellular function.

Thiol-Disulfide Homeostasis as a Marker of Oxidative Stress

Thiol-disulfide homeostasis is a crucial aspect of cellular redox balance and serves as an important biomarker for oxidative stress. The balance between thiols (reduced form) and disulfides (oxidized form) reflects the overall oxidative state of the cell. In healthy individuals, there is a dynamic equilibrium between these two forms, allowing for efficient redox signaling and protection against oxidative stress.

In patients with nasal polyps, studies have shown alterations in thiol-disulfide homeostasis. Elevated levels of disulfides and decreased levels of native thiols have been observed, indicating oxidative stress and an impaired antioxidant defense mechanism. This dysregulation contributes to the inflammatory processes associated with NP and may serve as a potential therapeutic target.

Clinical Implications of Thiol-Disulfide Balance

The assessment of thiol-disulfide levels can provide valuable insights into the oxidative status of NP patients. Key findings may include:

• Increased Disulfides: Higher levels indicate oxidative stress and cellular damage.
• Decreased Native Thiols: Lower levels reflect a compromised antioxidant capacity, which may exacerbate inflammation and tissue damage.
• Correlation with Disease Severity: Altered thiol-disulfide balance could be associated with the severity of NP and its clinical manifestations.

Correlation Between Sestrin-2 Levels and Oxidative Stress Parameters

Recent studies have aimed to elucidate the relationship between SESN2 levels and oxidative stress parameters in nasal polyp tissues. Significant correlations have been observed between SESN2 levels and markers of oxidative stress, such as total oxidant status (TOS) and total antioxidant status (TAS).

Key Findings from Recent Research

1. SESN2 Expression: Studies indicate that SESN2 levels are lower in polyp tissues compared to control tissues, suggesting a potential role in the pathogenesis of NP.
2. Oxidative Stress Markers: Elevated TOS and OSI levels alongside decreased TAS in polyp tissues underscore the role of oxidative stress in NP.
3. ERK1/2 Activation: Increased ERK1/2 levels in NP tissues may indicate a link between SESN2 deficiency and heightened inflammatory responses.

Table 1: Summary of Biomarkers in Nasal Polyp Tissues

NS: Not significant.

Future Directions in Nasal Polyp Research and Treatment

The findings regarding SESN2 and oxidative stress in nasal polyps suggest potential therapeutic strategies aimed at modulating the SESN2 pathway. Targeting oxidative stress and enhancing antioxidant defense mechanisms may provide novel approaches to manage NP effectively.

Potential Therapeutic Strategies

1. SESN2 Activation: Pharmacological agents that enhance SESN2 expression or activity could mitigate oxidative stress and inflammation in NP.
2. Antioxidant Therapies: Compounds that improve thiol-disulfide balance and reduce oxidative damage may have therapeutic implications.
3. Personalized Treatment Approaches: Assessing SESN2 and oxidative stress levels may guide personalized treatment plans for NP patients, optimizing therapeutic outcomes.

FAQ Section

What are nasal polyps?
Nasal polyps are soft, painless growths that develop on the lining of the nasal passages or sinuses due to chronic inflammation.

How does oxidative stress relate to nasal polyps?
Oxidative stress results from an imbalance between reactive oxygen species (ROS) and antioxidant defenses, contributing to inflammation and tissue damage in nasal polyps.

What is sestrin-2?
Sestrin-2 is an antioxidant protein that helps regulate oxidative stress and inflammation, playing a protective role in various tissues.

How can thiol-disulfide homeostasis be measured?
Thiol-disulfide homeostasis can be assessed through biochemical assays that measure the levels of native thiols and disulfides in biological samples.

What are the future directions for treating nasal polyps?
Future treatments may focus on enhancing SESN2 activity, employing antioxidant therapies, and creating personalized treatment plans based on individual oxidative stress levels.

References

1. Erel, O. (2005). A new automated colorimetric method for measuring total oxidant status. Clin Biochem, 38(11), 1103-1111. https://doi.org/10.1016/j.clinbiochem.2005.08.008
2. Erel, O., & Neselioglu, S. (2014). A novel and automated assay for thiol/disulphide homeostasis. Clin Biochem, 47(5), 326-332. https://doi.org/10.1016/j.clinbiochem.2014.09.026
3. Taysi, S., Uslu, C., Yilmaz, A., Aktan, B., & Altas, E. (2006). Lipid peroxidation and some antioxidant enzymes in nasal polyp tissue. Cell Biochem Funct, 24(6), 461-465
4. Gokce, G., Bayramoglu, N. T., & Taysi, S. (2024). Investigation of Nrf2-Keap-1 pathway, sestrin 2 and oxidative stress markers in serum of patients with placenta accreata spectrum. Eur J Obstet Gynecol Reprod Biol, 302, 211-215. https://doi.org/10.1016/j.ejogrb.2024.09.022
5. Bozdemir, K., Sezgin, A., Akkoz, A., Özcan, E., & Korkmaz, M. H. (2013). Evaluation of total oxidative stress parameters in patients with nasal polyps. Eur Arch Otorhinolaryngol, 270, 1861-1865. https://doi.org/10.1007/s00405-012-2307-x
6. Okan, I., & Taysi, S. (2023). Investigation of sestrin-2 levels and thiol-disulfide homeostasis in polyp tissue of patients with nasal polyps. Scientific Reports, 13, 10401. https://doi.org/10.1038/s41598-025-95453-5