Verbenalin as a Promising Therapeutic Agent for Acute Lung Injury and Acute Respiratory Distress Syndrome


Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical conditions that can manifest in response to a wide array of triggers, including bacterial and viral infections, as well as sepsis.

Sepsis, which results from a dysregulated response to infection, not only leads to systemic inflammation and immune dysfunction but also profoundly affects multiple organs, with the lungs being a primary target for injury [1].

ARDS is characterized by increased permeability of the alveolar membranes, disruption of the structural integrity of lung epithelial cells, accumulation of edema and hemorrhage in the alveolar spaces, neutrophil infiltration, and pyroptosis of macrophages [2].

Pyroptosis, a highly inflammatory form of cell death, has been identified as the primary mechanism contributing to tissue damage in ARDS. This damage may stem from the direct action of pathogenic factors or, more frequently, from an overwhelming inflammatory response [3].

The lung, an organ intricately regulated by a complex immune system, is at the forefront of both innate and adaptive immune responses. Immune complexes, formed through the interaction of various immune cells, phagocytosed pathogens, viruses, allergens, antibodies, and antigens, play a pivotal role in the immune response.

Under normal circumstances, small soluble immune complexes are efficiently cleared by the kidneys, while larger, insoluble immune complexes are engulfed and eliminated by macrophages as part of the body’s defense mechanisms. However, in certain cases, immune complexes may deposit at the vascular wall base, activate the complement system, and trigger inflammation and tissue damage [5].

Interestingly, studies have highlighted the role of anti-spike IgG antibodies in causing severe lung injury, disrupting the inflammation-resolving response in cases of ALI induced by viruses such as SARS-CoV [6]. Additionally, sepsis-induced acute lung injury has been associated with the deposition of immune complexes in tissues, further underscoring the complex interplay between immunity and lung health [7].

Novel Insights into Inflammation Resolution

Recent research has unveiled a deeper understanding of the process of inflammation resolution as an active and orchestrated biological phenomenon. This resolution is facilitated by endogenous chemical mediators, including lipoxins, resolvins, and protectins, which actively promote the dampening of inflammation and restoration of tissue homeostasis.

These mediators primarily exert their effects by activating specific G protein-coupled receptors (GPCRs), including ALX/FPR2, GPR18, GPR37, and GPR32 [8].

Among these endogenous mediators, Resolvin D1 (RVD1) and Resolvin D2 (RVD2) have emerged as crucial players in stimulating the resolution of acute inflammation. RVD1 has been shown to significantly attenuate inflammatory responses induced by IgG immune complexes by inhibiting the activity of transcription factors NF-κB and C/EBP in alveolar macrophages [9].

On the other hand, RVD2 suppresses the NLRP3 inflammasome, a key component of the innate immune response, by promoting autophagy in macrophages. This mechanism effectively reduces excessive cytokine production, inhibits neutrophil recruitment, and enhances macrophage phagocytosis in mice afflicted with polymicrobial sepsis [10,11].

RVD2 has also been found to significantly improve survival rates, reduce hypothermia, and decrease bacterial titers in mice, with these effects being dependent on the presence of GPR18 [12]. Notably, GPR18 plays a pivotal role in the process of inflammation resolution, and its expression levels have been linked to the prognosis and severity of sepsis, thus holding potential as a prognostic marker for sepsis outcomes [13].

Traditional Chinese Medicine (TCM) in the Treatment of ALI

Traditional Chinese medicine (TCM) formulations have garnered significant attention for their efficacy in the treatment of acute lung injury [14].

One such formulation is Xuanfeibaidu (XFBD) granules, composed of 13 TCM herbs including raw ephedra, bitter almond, raw gypsum, raw coix seed, Atractylodes lancea, patchouli, Artemisia annua, Polygonum cuspidatum, Verbena, dry grass root, Tingli seed, huaorange red, and raw licorice.

XFBD granules have been recommended for the treatment of COVID-19, and Verbena, one of its components, stands out for its potent protective effects against coronavirus-induced lung injury, particularly in the small airways [15].

The chemical composition of Verbena includes iridoid glycosides, phenylpropanoid glycosides, triterpenes, flavonoids, sterols, volatile oils, and organic acids. Modern pharmacological research has revealed that its various extracts possess a wide range of therapeutic properties, including anti-tumor, anti-inflammatory, analgesic, neuroprotective, immunomodulatory, antioxidative, and anti-early pregnancy effects [16].

Notably, verbenalin, one of the most abundant components of Verbena, has been shown to mitigate acute lung inflammation induced by Pseudomonas aeruginosa through the activation of GPR18 receptors [17].

The Therapeutic Potential of Verbenalin

In a recent study, researchers delved into the pharmacological effects of verbenalin on sepsis and IgG immune complex-induced acute lung injury, both in murine models and in MH-S cells. Their findings provided compelling evidence that verbenalin exerts potent anti-inflammatory effects and effectively inhibits macrophage pyroptosis through the selective activation of the GPR18 receptor.

This discovery holds substantial promise as it offers a potential therapeutic agent and a solid theoretical foundation for the treatment of acute lung injury, a condition that has eluded effective treatments for far too long.

In conclusion, acute lung injury and acute respiratory distress syndrome are complex and debilitating conditions that can arise from a variety of triggers, including infections and sepsis. Recent research has shed light on the crucial role of inflammation resolution in mitigating the damage caused by these conditions, with endogenous mediators like RVD1 and RVD2 emerging as key players.

Additionally, traditional Chinese medicine formulations like XFBD granules, enriched with components such as Verbena, show significant promise in alleviating lung injury. Verbenalin, a component of Verbena, presents a potential breakthrough in the treatment of acute lung injury by selectively targeting the GPR18 receptor to dampen inflammation and prevent macrophage pyroptosis.

As we continue to uncover the intricate mechanisms underlying these conditions, the prospects for more effective treatments and improved outcomes for patients afflicted with ALI and ARDS are indeed promising.

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