Endothelial cells (ECs) are fundamental components of the cardiovascular system, lining the inner walls of all blood vessels. Their significance extends beyond forming a mere barrier; they are pivotal in maintaining hemostasis, regulating vascular tone and endothelial permeability, and playing a crucial role in suppressing leukocyte activation.
Resting ECs, characterized by their non-interactive state with leukocytes, owe this quiescence to the sequestration of leukocyte-interactive proteins such as P-selectin and chemokines within specialized secretory vesicles known as Weibel–Palade bodies. Moreover, these cells maintain a low transcription level of adhesion molecules like E-selectin, VCAM-1, and ICAM-1, essential for their dormant state.
The transition from this resting state to one of dysfunction, or EC dysfunction, marks a significant shift with dire implications for vascular health. EC dysfunction is instrumental in the onset and progression of a plethora of diseases. These range from acute lung infections, exemplified by COVID-19, to chronic conditions such as coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders like depression. The common thread among these varied pathologies is the pivotal role of inflammation in EC dysfunction, with ICAM-1 serving as a hallmark marker for EC activation and infiltration.
Given the wide-ranging side effects and resistance issues associated with traditional anti-inflammatory therapies—including ketoconazole, activated protein C, and glucocorticoids—the quest for safer, more effective treatments is paramount. This need is particularly acute in the context of acute lung injury (ALI), where the pulmonary endothelium’s integrity is critical. The endothelium serves as a battleground, a primary target for circulating cells and mediators of injury. The interaction between leukocytes and ECs is a critical juncture in the development and progression of ALI, facilitating leukocytes’ adhesion and migration across ECs through a synergy of adhesion molecules.
The traditional Chinese medicinal Allii macrostemonis bulbs (AMBs) emerge as a beacon of hope against this backdrop. Renowned for their medicinal and dietary benefits since ancient times, AMBs and their derivatives demonstrate a wide array of biological activities. These include anti-platelet aggregation, lipid-lowering, antitumor, antibacterial, and antidepressant effects, alongside significant antioxidant potential and analgesic activity. Previous investigations have highlighted the potential of AMBs in safeguarding endothelial function, primarily through their antioxidant properties and regulation of nitric oxide production. However, the exploration into AMBs’ regulation of endothelial function, particularly through their main active component—saponins from AMBs (SAMB)—remains in its infancy.
This study ventures into this underexplored territory, examining SAMB’s ability to protect ECs by inhibiting inflammation, both in vitro and in vivo. Utilizing human umbilical vein endothelial cells (HUVECs), the study investigates the effects of SAMB against inflammation induced by exogenous (lipopolysaccharide, LPS) and endogenous (tumor necrosis factor-α, TNF-α) inflammatory mediators. Furthermore, the therapeutic potential of SAMB is evaluated in vivo through a model of septic ALI induced in C57BL/6 mice by intraperitoneal LPS administration. This research endeavors to open new avenues for the clinical management of ALI, proposing SAMB as a novel preventive and therapeutic strategy.
Unveiling the Anti-Inflammatory Effects of SAMB on Endothelial Cells: Insights into Mechanisms and Therapeutic Potential
This comprehensive study delves into the anti-inflammatory properties of saponins from Allii Macrostemonis Bulbs (SAMB) and their effect on endothelial cells (ECs), both in vitro and in vivo. The research meticulously explores the pathway through which SAMB exerts its effects, targeting the intricate interplay of cellular mechanisms that govern inflammation and endothelial dysfunction. By employing exogenous pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) and endogenous inflammatory mediators such as tumor necrosis factor-α (TNF-α), the study successfully induced inflammation in human umbilical vein endothelial cells (HUVECs).
The investigation revealed that SAMB significantly reduced monocyte adhesion to HUVECs in both models by downregulating the expression of vascular cell adhesion molecule-1 (VCAM-1). This finding is particularly notable as it underscores SAMB’s ability to mitigate one of the key steps in the inflammatory response. Further mechanistic exploration uncovered that SAMB inhibited the degradation of IκBα, leading to the suppression of NF-κB p65 phosphorylation. This, in turn, dampened the NF-κB-dependent expression of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, as well as VCAM-1. This discovery points to SAMB’s potential in addressing endothelial inflammation, a critical factor in the pathogenesis of acute lung injury (ALI) and other inflammatory conditions.
To assess the therapeutic potential of SAMB in vivo, a murine model of septic ALI was established through intraperitoneal administration of LPS. SAMB administration demonstrated a significant reduction in lung injury, evidenced by decreased levels of inflammatory factors in both lung tissues and sera, and a reduction in VCAM-1 expression in lung tissue. These results not only confirm SAMB’s anti-inflammatory effects but also highlight its potential to protect the endothelium in a clinically relevant setting.
An interesting observation emerged regarding the differential impact of SAMB on TNF-α levels. While SAMB did not significantly alter TNF-α mRNA levels in lung tissues, it notably affected serum levels. This discrepancy suggests that the peak transcription of TNF-α may have already occurred prior to observation, yet the protein level remained elevated, indicating a possible delayed effect of SAMB on systemic inflammation.
The study further delves into the role of VCAM-1, a key regulator of leukocyte adhesion and transendothelial migration, and its potential as a therapeutic target. The demonstrated inhibitory effect of SAMB on VCAM-1 expression, both in vitro and in vivo, underscores its promise as an innovative therapeutic agent for addressing endothelial-inflammation-related disorders. The potential impact of SAMB on soluble VCAM-1 (sVCAM-1) levels, however, remains an area for future research.
At the heart of SAMB’s mechanism of action is its impact on the NF-κB signaling pathway, a central regulator of inflammatory and adhesion factor expression in ECs. The study illustrates SAMB’s ability to stabilize IκBα, effectively inhibiting NF-κB p65 activation induced by LPS in HUVECs. This effect did not extend to significant alterations in the expression and phosphorylation of IKK, suggesting a specific disruption in the ubiquitination or degradation of IκBα that warrants further investigation.
The study also addresses the determination of SAMB dosage, drawing on traditional uses and adjusting for potency and efficacy. Initial dosages based on clinical recommendations proved excessive, prompting a recalibration of the dose-response relationship to identify an optimal range that balances effectiveness with potential toxicity.
In conclusion, this study provides compelling evidence of SAMB’s ability to mitigate endothelial inflammation and ALI through the inhibition of the NF-κB/VCAM-1 pathway. These findings pave the way for future research to further delineate SAMB’s mechanism of action, identify its active components, and evaluate its clinical applicability in treating diseases associated with endothelial inflammation. The depth and breadth of this investigation offer valuable insights into SAMB’s therapeutic potential, positioning it as a promising candidate for addressing the unmet need for safe and effective treatments for endothelial-inflammation-related diseases.
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