Application of codonopsis pilosula glycoside I in preparation of medicine for preventing and / or treating acute lung injury

Abstract

The invention discloses a novel application of codonopsis pilosula glycoside I in preparation of a medicine for preventing and / or treating acute lung injury, and belongs to the technical field of biological medicines. By constructing an LPS-induced sepsis secondary attack acute lung injury animal model, it is proved in vivo that codonopsis pilosula glycoside I can significantly relieve pulmonary edema and improve pathological injury of lung tissue through oral administration, the action mechanism of codonopsis pilosula glycoside I lies in multi-target regulation and control of inflammation immune balance, local down-regulation of expression of proinflammatory factors IL-1beta, TNF-alpha, IL-6, IL-18, NLRP3 and MPO of lung tissue, and in-vivo improvement of pulmonary edema and pathological injury of lung tissue. The anti-inflammatory factor IL-10 is up-regulated, and the levels of CRP, IL-6 and TNF-alpha in serum can be reduced and the level of IL-10 can be improved on the system level, so that the inflammatory cascade reaction is blocked.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a drug for the treatment of acute lung injury, particularly the application of codonopsis pilosula, an effective component of the natural drug Codonopsis pilosula, in the preparation of drugs for the prevention and / or treatment of acute lung injury. Background Technology

[0002] Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are critical clinical conditions triggered by various factors such as infection, trauma, and sepsis. Its core pathological features include diffuse damage to the alveolar epithelium and pulmonary capillary endothelium, leading to non-cardiogenic pulmonary edema, hyaline membrane formation, and refractory hypoxemia. As the most common and severe complication of sepsis, ALI has a persistently high clinical morbidity and mortality rate, and surviving patients often suffer from long-term sequelae such as pulmonary dysfunction and cognitive impairment, placing a heavy burden on the healthcare system. Sepsis-related ALI caused by Gram-negative bacterial infection accounts for more than 50% of cases, with lipopolysaccharide (LPS), a core component of the bacterial cell wall, being the primary causative agent. This molecule diffuses into the lungs via the bloodstream, initiating a systemic inflammatory response and serving as a major trigger for clinical ALI and the basis for classic animal models.

[0003] LPS-induced ALI pathological processes exhibit multi-target and cascade amplification characteristics, involving the interaction of multiple pathological processes such as inflammation regulation, oxidative stress, and apoptosis.

[0004] Uncontrolled inflammatory response: LPS activates the TLR4 signaling pathway, triggering the activation of transcription factors such as NF-κB, inducing the massive release of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, while simultaneously inhibiting the expression of anti-inflammatory factors such as IL-10. This leads to an imbalance between pro-inflammatory and anti-inflammatory factors, resulting in a "cytokine storm" and triggering systemic inflammatory response syndrome (SIRS). Furthermore, LPS can directly activate the NLRP3 inflammasome, promoting the maturation and release of pro-inflammatory factors such as IL-1β and IL-18, creating a "secondary blow" in the inflammatory cascade and exacerbating lung tissue damage. Recent studies have shown that LPS can also induce the expression of novel inflammatory mediators such as Lix, further recruiting neutrophils to infiltrate lung tissue and exacerbating inflammatory damage.

[0005] Neutrophil infiltration and oxidative stress: Intrapulmonary neutrophil infiltration is the core pathological feature of ALI. Myeloperoxidase (MPO), as a key marker of neutrophil activation, amplifies oxidative stress by catalyzing the generation of reactive oxygen species (ROS) and releasing proteases, thereby damaging the integrity of alveolar epithelial and vascular endothelial cells, further exacerbating the increase in pulmonary microvascular permeability, and ultimately leading to lung damage such as pulmonary edema and alveolar barrier disruption.

[0006] Current clinical treatment strategies for LPS-induced ALI still have significant limitations. Conventional treatment mainly relies on supportive therapies such as mechanical ventilation and fluid management, lacking specific drugs. In terms of drug therapy, traditional anti-inflammatory drugs such as glucocorticoids can suppress the inflammatory response in the short term non-specifically, but long-term or high-dose use can easily lead to serious side effects such as immunosuppression, secondary infections, glucose metabolism disorders, and osteoporosis. Targeted biologics, such as monoclonal antibodies against specific inflammatory factors like TNF-α, IL-1, and IL-6, can precisely block inflammatory pathways, but they have problems such as high production costs, the need for intravenous administration, poor patient compliance, and the potential to interfere with the body's normal immune surveillance function. Moreover, they are difficult to address the pathological characteristics of multi-target synergistic effects.

[0007] Meanwhile, most of these drugs rely on intravenous or intramuscular injection, which is inconvenient for early intervention, pre-hospital emergency care, and treatment of patients with chronic inflammatory lung disease requiring long-term management, thus limiting their clinical application. In contrast, oral administration is convenient to use and suitable for early intervention and long-term maintenance therapy, making it a hot research topic for ALI treatment drugs.

[0008] Traditional Chinese medicine (TCM) has accumulated rich theoretical and practical experience in the prevention and treatment of respiratory diseases such as pneumonia and lung injury. The multi-component, multi-target effects of TCM are highly compatible with the complex pathological mechanisms of ALI (Alternative Lung Infection). Therefore, screening and discovering active ingredients with clear therapeutic effects from this important natural medicine treasure trove provides a valuable source for developing novel ALI treatments. However, systematic research on the treatment of LPS-induced ALI using active ingredients of TCM is still relatively scarce. Most studies remain at the basic experimental stage, lacking systematic mechanistic elucidation and drug development.

[0009] Tangshenoside I is a naturally occurring compound found in the Campanulaceae family (…). Campanulaceae Codonopsis pilosula ( ) Codonopsis ) and the genus Leopard ( Campanumoea Codonopsis pilosula is an active ingredient found in very low concentrations in plants and has been shown to possess pharmacological activities such as anti-inflammatory, antioxidant, and immunomodulatory effects. CN 110438079A reports its use in in vitro enhancement of NK cell killing activity; CN 118203591A demonstrates that Codonopsis pilosula glycoside I can significantly inhibit the transcriptional activity of NF-κB, reduce the transcriptional activity of activator protein-1 (AMP), which reduces collagen synthesis and promotes collagen degradation, and increase the transcriptional activity of antioxidant reactive elements. Its application in the preparation of drugs or skincare products for preventing and treating photoaging of the skin can significantly alleviate the symptoms of photoaging.

[0010] Although the multiple pharmacological activities of codonopin I have been reported in the literature, there are currently no reports on its therapeutic effects on ALI. Summary of the Invention

[0011] The purpose of this invention is to provide a new pharmaceutical use for codonopin I, specifically its use in the preparation of drugs for the prevention and / or treatment of acute lung injury.

[0012] This invention has revealed that codonopsis pilosula 1 has clear clinical application value in the prevention and / or treatment of septic acute lung injury. Experiments have confirmed that codonopsis pilosula 1 has significant protective and repairing effects on lipopolysaccharide (LPS)-induced acute lung tissue injury, and its mechanism involves the effective regulation of various lung injury-related cytokines. Furthermore, codonopsis pilosula 1 can be administered orally, offering advantages such as convenient administration, suitability for early intervention, and long-term maintenance therapy, providing important evidence for its drug development.

[0013] The sources of tangshenoside I described in this invention include, but are not limited to, those from the genus Codonopsis (Codonopsis). Codonopsis ) and the genus Leopard ( Campanumoea It is obtained by extraction, separation, and purification from the roots, stems, fruits, or leaves of plants, or by preparation through chemical or biological synthesis methods.

[0014] The molecular formula of Codonopsis pilosula Ⅰ is C 29 H 42 O 18 It has a molecular weight of 678.64, CAS number 117278-74-7, and its specific structural formula is shown below:

[0015] The purity of Codonopsis pilosula glycoside I is ≥90%, preferably ≥95%, and meets pharmaceutical or food grade standards.

[0016] Therefore, the present invention primarily provides the use of codonopin I in the preparation of medicaments for the prevention and / or treatment of acute lung injury.

[0017] Furthermore, the acute lung injury described in this invention specifically refers to acute pathological lung injury, including but not limited to pulmonary edema, lung tissue inflammation, and / or damage to the integrity of the alveolar walls.

[0018] Furthermore, the acute lung injury described in this invention is sepsis-related lung injury induced by bacterial lipopolysaccharide.

[0019] This invention demonstrates, in vivo, the definite preventive and therapeutic effects of oral administration of codonopsis pilosula I on acute lung injury by constructing an animal model of septic lung injury that simulates the pathological process of secondary clinical trauma, and reveals the multi-target anti-inflammatory and lung barrier protective effects of codonopsis pilosula I.

[0020] Based on the above-mentioned effects, the present invention also provides a medicament for the prevention and / or treatment of acute lung injury, wherein the medicament contains a therapeutically effective amount of codonopsis glycoside I as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

[0021] Furthermore, the drug of the present invention preferably uses codonopin I as the sole active ingredient.

[0022] Furthermore, the drug of the present invention is preferably formulated into an oral dosage form, including but not limited to tablets, pills, capsules, granules, powders, oral liquids or syrups.

[0023] This invention does not limit the pharmaceutically acceptable carriers or excipients, which can be any carriers or excipients well known to those skilled in the art, such as solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants, anti-flocculation agents, filter aids, and release inhibitors, etc., any one or more of these.

[0024] The drug described in this invention for the prevention and / or treatment of acute lung injury can also reduce the rate of weight loss caused by acute lung injury, improve pathological damage to lung tissue, and regulate the levels of inflammatory factors in serum and lung tissue.

[0025] This invention, through animal experiments, confirms that codonopin I, as a drug for the prevention and / or treatment of acute lung injury, has a clear protective effect in the prevention and treatment of sepsis-related acute lung injury, specifically demonstrating the following outstanding beneficial effects:

[0026] It has a significant anti-lung injury effect, can effectively alleviate the rapid weight loss caused by acute lung injury in model animals, significantly improve lung tissue pathological damage, and regulate the immune balance of inflammatory factors;

[0027] Through multi-target synergistic therapy, it comprehensively intervenes in the complex pathological process of acute lung injury. At the systemic level, it can significantly downregulate the levels of pro-inflammatory mediators such as CRP, TNF-α, and IL-6 in peripheral blood, and upregulate the level of anti-inflammatory factor IL-10. Locally in lung tissue, it can significantly reduce the levels of pro-inflammatory factors IL-1β, TNF-α, IL-6, IL-18, MPO, and NLRP3, and simultaneously increase the level of IL-10, thus restoring the immune balance of the lungs and blocking the amplification effect of the inflammatory cascade.

[0028] Codonopsis pilosula glycoside I is derived from medicinal and edible plants, has high safety, no significant side effects, and can exert significant therapeutic effects through oral administration. It is convenient to use and suitable for long-term or early intervention. Attached Figure Description

[0029] Figure 1 The results show the effects of codonopin I on body weight and lung edema (dry / wet ratio) in mice with LPS-induced acute lung injury.

[0030] Figure 2 These are comparison images of H&E-stained sections of lung tissue from different experimental groups of mice, showing the pathological morphology.

[0031] Figure 3 The results are immunohistochemical staining of pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and IL-18 in the lung tissue of mice in different experimental groups.

[0032] Figure 4 The results are immunohistochemical staining of myeloperoxidase, NLRP3 inflammasome and anti-inflammatory factor IL-10 expression in the lung tissue of mice in different experimental groups.

[0033] Figure 5 The results are obtained by ELISA detection of C-reactive protein and inflammatory factors IL-6, TNF-α and IL-10 concentrations in the peripheral blood of mice in different experimental groups.

[0034] Data in the figure t The test was used to analyze differences between groups, * indicates p <0.05, ** indicates p <0.01, *** indicates p <0.001, *** indicates p <0.0001. Implementation

[0035] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings and specific examples. It should be noted that the embodiments are merely illustrative and are intended to provide a thorough understanding of the technical solutions of the present invention and to provide guidance for those skilled in the art to implement and apply the present invention. It should be understood that these descriptions do not constitute any limitation on the scope of protection of the present invention.

[0036] Unless otherwise expressly stated, the production processes, experiments, tests or analysis methods involved in the embodiments of the present invention are all considered to be conventional methods known to those skilled in the art, and only need to be implemented in accordance with conventional conditions or relevant product instructions. The steps and names involved are also generally clear and unambiguous in the art.

[0037] The instruments, equipment, raw materials, reagents, or samples used in the embodiments are not subject to any special restrictions on their source. They are all conventional products that can be purchased through regular commercial channels or prepared by known methods, and their source does not have a substantial impact on the implementation results of the present invention.

[0038] Unless otherwise expressly defined, the scientific and technical terms used in this invention have the meanings commonly understood by one of ordinary skill in the art. In case of any conflict, the definitions in this specification shall prevail.

[0039] The terms “comprising,” “including,” “having,” etc., used in this invention should be understood as open-ended, meaning “including but not limited to.” The term “and / or” includes any and all combinations of one or more of the associated listed items. Quantitative terms such as “a,” “one,” etc., do not exclude multiples; “multiple” or “a variety” refers to quantities greater than or equal to two.

[0040] The terms "preferred", "better", and "exemplary" used in this invention are only used to describe specific solutions or effects and are not intended to limit the necessary scope of the solution or the scope of protection.

[0041] This invention relates to the description of numerical parameters (such as quantity, concentration, temperature, time, etc.), and it should be understood that reasonable deviations naturally exist due to measuring instruments, operational errors, statistical fluctuations, etc. The range of such deviations should be within limits acceptable to those skilled in the art based on common sense.

[0042] The specific experimental protocols involved in the following embodiments of the present invention have all been reviewed and approved by the Ethics Committee of Sichuan Normal University, Animal Experiment Ethics Approval No. 2025LS037, and all operations have strictly followed relevant animal ethics and welfare guidelines.

[0043] The experimental animals were 12-week-old male C57BL / 6 mice weighing 22-26g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd., with experimental animal license number SCXK (Sichuan) 2022-0039.

[0044] Housing environment and conditions: The experimental animal room of Sichuan Normal University was used, with a room temperature of 20-22℃, humidity of 40-60%, and alternating light and dark lighting for 12 hours. Mice had free access to water and food. The mouse feed and bedding were commercial SPF grade, and the drinking water was sterile water. Before the experiment, the mice were acclimatized in the experimental animal room for 2 weeks, with a stocking density of 2 mice per cage.

[0045] Codonopin I was provided by Chengdu Bencao Tianyun Biotechnology Co., Ltd. Its chemical structure was determined by NMR and mass spectrometry, and its purity was >95% as determined by HPLC.

[0046] Lipopolysaccharide (LPS) is derived from Escherichia coli (E. coli) Escherichia coliO111:B4, purchased from Sigma-Aldrich.

[0047] The ELISA kits required for animal experiments were purchased from Hangzhou Lianke Biotechnology Co., Ltd., and the antibodies for histopathological detection were provided by Servicebio Biotechnology Co., Ltd. Example

[0048] Example 1

[0049] Healthy male C57BL / 6J mice were randomly divided into four experimental groups: normal control group (NC), LPS model group (LPS), low-dose codonopsis glycoside I treatment group (DSL), and high-dose codonopsis glycoside I treatment group (DSH).

[0050] A LPS-induced acute lung injury model was established using the "two-hit" method. Except for the normal control group, mice in all other groups received an intraperitoneal injection of sterile saline solution (2 mg / kg) of LPS on day 1. Twenty-four hours later, a second intraperitoneal injection of 5 mg / kg of LPS was administered. All mice were euthanized six hours after the second injection.

[0051] Two groups of mice were given codonopsis glycoside I orally by gavage 3 hours after the first LPS injection. The low-dose group was given 5 mg / kg and the high-dose group was given 10 mg / kg. The dosage was adjusted according to the conversion factor method. Codonopsis glycoside I was dissolved in sterile physiological saline to a concentration of 40 mg / mL and administered.

[0052] Both the normal control group and the LPS model group were administered sterile saline solution via empty loading, while the normal control group was treated in parallel by intraperitoneal injection of sterile saline solution.

[0053] Six hours after the second LPS injection, mice in each group were weighed, and blood was collected from their eyeballs to collect serum. The collected serum was then immediately stored at -80°C.

[0054] Mice were euthanized, and their intact lung tissue was immediately dissected and harvested. The left lung was used to calculate the dry / wet weight ratio of the lung tissue to assess pulmonary edema, while the right lung was fixed with paraformaldehyde.

[0055] Example 2

[0056] An acute lung injury (ALI) model was established in mice by intraperitoneal injection of lipopolysaccharide (LPS). The intervention effects of codonopsis pilosula glycoside I on acute weight loss and pulmonary edema (measured by the dry / wet ratio of lung tissue) in mice were analyzed.

[0057] Figure 1In the study, compared with the NC group, mice in the LPS group showed significant acute weight loss within 30 hours after intraperitoneal injection of LPS, exhibiting typical acute pathological conditions, which may be closely related to the systemic inflammatory response, reduced food intake, and metabolic disorders induced by LPS. However, compared with the LPS group, the weight loss of mice in the DSL and DSH groups was significantly alleviated after intervention with codonopsis glycoside I, especially in the DSH group, indicating that intervention with codonopsis glycoside I produced a systemic protective effect.

[0058] Pulmonary edema is one of the core pathological features of LPS-induced ALI. The dry / wet ratio of lung tissue is a classic indicator for assessing pulmonary edema; the lower the ratio, the more severe the pulmonary edema.

[0059] Left lung tissue was taken from each group of mice, dried with absorbent paper, and the wet weight (W) was immediately measured using an analytical balance. The tissue was then dried in a 60°C oven until the weight remained constant, and the dried weight (D) was accurately measured. The wet-to-dry weight ratio (D / W) was then calculated to reflect the degree of pulmonary edema.

[0060] Depend on Figure 1 The statistical results of the lung wet / dry weight ratio showed that the dry / wet ratio of lung tissue in the LPS group was significantly lower than that in the NC group, indicating a significant increase in lung tissue water content and severe pulmonary edema. However, after intervention with codonopsis glycoside I, the dry / wet ratio of lung tissue in the DSL and DSH groups significantly recovered, with statistically significant differences compared to the LPS group. This indicates that codonopsis glycoside I can effectively reduce LPS-induced lung fluid exudation, alleviate pulmonary edema, and maintain pulmonary vascular barrier function.

[0061] Therefore, codonopin I has a certain protective effect against LPS-induced ALI in mice, can alleviate acute weight loss in model mice, and reduce lung edema damage in lung tissue, exhibiting a dose-dependent effect.

[0062] Example 3

[0063] Lung tissues from mice in each experimental group were stained with hematoxylin and eosin (H&E) to observe the pathological morphology of the mouse lung tissues and to evaluate the intervention effect of codonopsis glycoside I on lung tissue damage caused by acute lung injury.

[0064] Figure 2 In the NC group, the lung tissue structure was intact, the alveolar cavities were clear and regular, the alveolar walls were thin and uniform, there was no congestion or edema in the pulmonary interstitium, no obvious inflammatory cell infiltration was observed, and the airway epithelial cells were neatly arranged without shedding or damage. The LPS group, on the other hand, showed typical pathological features of acute lung injury, with severe alveolar structural disorder and collapse, and partial fusion of alveolar cavities; a large number of inflammatory cells (mainly neutrophils) infiltrated the pulmonary interstitium and alveolar cavities; the alveolar walls were significantly thickened, accompanied by congestion, edema and a small amount of hemorrhage; airway epithelial cells were shed, the mucosa was damaged, and local exudate accumulation was visible.

[0065] Compared with the LPS group, the DSL and DSH groups showed significant improvement in lung tissue pathological damage after intervention with Codonopsis pilosula I, with reduced alveolar structural disorder, decreased alveolar cavity collapse and fusion, significantly reduced number of inflammatory cells infiltrating the pulmonary interstitium and alveolar cavities, relief of alveolar wall thickening, congestion, edema and hemorrhage symptoms, reduced airway epithelial cell damage and shedding, and a significant reduction in the overall degree of lung tissue pathological damage. The high-dose group showed even better improvement.

[0066] Pathological results confirmed that codonopin I can significantly improve the pathological damage of LPS-induced ALI lung tissue in mice, reduce tissue edema, and protect the structural integrity of lung epithelium / vascular endothelium.

[0067] Example 4

[0068] The expression, localization, and levels of pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-18 in the lung tissue of mice in each experimental group were detected by immunohistochemical staining (IHC), and the optical density of the positively stained areas was semi-quantitatively analyzed by an image analysis system.

[0069] Figure 3 The results showed that IL-1β, TNF-α, IL-6, and IL-18 were weakly expressed in the lung tissue of the NC group. Positive staining (brownish-yellow granules) was mainly scattered in a small number of interstitial lung cells and airway epithelial cells. The number of positive cells was low, the staining intensity was light, and the mean optical density (MOD) was significantly lower than in other groups, suggesting that pro-inflammatory factors in the lungs maintained low-level expression under physiological conditions. In the LPS group, all four pro-inflammatory factors were strongly expressed. Positive staining was widely distributed in alveolar epithelial cells, interstitial lung cells, and infiltrating inflammatory cells (such as neutrophils and macrophages). The number of positive cells was significantly increased, the staining intensity was deep, and the MOD value was significantly higher than in the normal control group. Furthermore, factor expression was mainly concentrated in severely damaged lung tissue areas, suggesting that LPS-induced ALI activates pulmonary inflammatory pathways, leading to the release of large amounts of pro-inflammatory factors and their involvement in lung tissue damage. Compared with the LPS group, the expression of IL-1β, TNF-α, IL-6 and IL-18 in the DSL / DSH group after intervention with Codonopsis pilosula I was significantly downregulated, the number of positive cells was significantly reduced, the staining intensity was weakened, and the MOD value was significantly reduced. The expression distribution range of the four factors was narrowed, mainly limited to a small number of residual inflammatory cells and the lung interstitial area, and the downregulation effect was more significant in the high-dose group.

[0070] In summary, IHC staining results confirmed that Codonopsis pilosula 1 can significantly downregulate the abnormally high expression of IL-1β, TNF-α, IL-6, and IL-18 in the lung tissue of LPS-induced ALI mice, reduce the accumulation of pro-inflammatory factors in the lungs, thereby alleviating excessive inflammatory response in the lungs and exerting a lung-protective effect.

[0071] Furthermore, the expression levels and localization of myeloperoxidase (MPO), NLRP3 inflammasome, and anti-inflammatory cytokine IL-10 in the lung tissue of mice in each experimental group were detected by immunohistochemical staining, and the optical density of the positively stained areas was semi-quantitatively analyzed by an image analysis system.

[0072] Depend on Figure 4 The test results showed that MPO in the NC group was weakly positive, with positive staining (brownish-yellow granules) scattered in a small number of lung interstitial cells. The number of positive cells was small, the staining intensity was light, and the mean optical density (MOD) value was extremely low, indicating that the activation level of neutrophils was low under physiological conditions. NLRP3 was weakly positive, mainly located in the cytoplasm of lung epithelial cells and a small number of macrophages. The staining intensity was weak, and the positive cells were sparse, maintaining the basic inflammatory homeostasis. IL-10 was moderately positive, distributed in lung interstitial cells and airway epithelial cells, providing a basis for anti-inflammatory regulation under physiological conditions, and the MOD value was within the normal range.

[0073] In comparison, the LPS group showed significantly increased MPO expression, exhibiting strong positive staining and widespread distribution in the lung interstitium, alveolar cavities, infiltrating neutrophils, and lung epithelial cells. The number of positive cells increased dramatically, and the staining was deep. The MOD value was significantly higher than that of the NC group, indicating that neutrophils infiltrated and activated extensively, participating in lung tissue damage. NLRP3 expression was significantly upregulated, exhibiting strong positive staining and mainly located in the cytoplasm of macrophages, lung epithelial cells, and infiltrating inflammatory cells. Positive cells were widely distributed, with high staining intensity, and the MOD value was significantly increased, suggesting that LPS activated the NLRP3 inflammasome pathway and promoted the release of pro-inflammatory factors. Although IL-10 expression showed slight compensatory production, the MOD value was still significantly lower than that of the NC group, indicating insufficient anti-inflammatory effect and inability to inhibit excessive inflammatory response.

[0074] Furthermore, in the DSL / DSH group after intervention with codonopin I, MPO expression was significantly downregulated, positive staining intensity was significantly weakened, and the number of positive cells was significantly reduced compared to the model group, mainly limited to a small amount of lung interstitial area, and the MOD value was significantly reduced, proving that codonopin I can inhibit LPS-induced neutrophil infiltration and activation; NLRP3 expression was significantly reduced, positive staining intensity was weakened, the distribution range of positive cells was reduced, cytoplasmic staining was lighter, and the MOD value was significantly lower than that of the model group, indicating that codonopin I can inhibit the activation of NLRP3 inflammasomes; IL-10 expression was significantly upregulated, showing strong positive staining, with an increase in the number of positive cells and deeper staining intensity, widely distributed in lung interstitium, airway epithelial cells and infiltrating inflammatory cells, and the MOD value was significantly higher than that of the LPS group, and the upregulation effect was better in the high-dose group, indicating that codonopin I can enhance the anti-inflammatory response of the lungs.

[0075] In summary, IHC staining results confirmed that codonopsis pilosula I downregulates MPO (inhibits neutrophil infiltration and activation) and inhibits NLRP3 inflammasome activation in a dose-dependent manner, while upregulating the expression of the anti-inflammatory factor IL-10, balancing the pro-inflammatory / anti-inflammatory response in the lungs, alleviating LPS-induced acute lung injury, regulating inflammatory cell infiltration, inhibiting inflammasome pathway activation, and enhancing anti-inflammatory compensation.

[0076] Example 5

[0077] Serum was collected from mice in each experimental group, and the concentrations of systemic inflammatory markers CRP, IL-6, TNF-α, and IL-10 were detected using enzyme-linked immunosorbent assay (ELISA). The results are as follows: Figure 5 As shown.

[0078] In the NC group, CRP maintained a low baseline concentration. As an acute-phase reactive protein, its expression level was extremely low under physiological conditions, indicating no significant systemic inflammatory response. The concentrations of IL-6 and TNF-α were at the lower limit of the normal reference range, maintaining basic inflammatory homeostasis without abnormal elevation. IL-10 was expressed at physiological levels, forming a balance with pro-inflammatory factors and regulating the stability of the systemic inflammatory response.

[0079] The concentration of CRP in the LPS group was significantly higher than that in the NC group, indicating that LPS induces the activation of the systemic acute inflammatory response and increases the synthesis of acute phase proteins in the liver. The concentrations of IL-6 and TNF-α increased sharply, several times higher than those in the NC group. As early core pro-inflammatory factors, they were released in large quantities into the peripheral blood, mediating the systemic inflammatory cascade. The expression of IL-10 was significantly insufficient, and the anti-inflammatory-pro-inflammatory balance was severely imbalanced, failing to inhibit the excessive inflammatory response.

[0080] After intervention with codonopsis glycoside I, the CRP concentration in the DSL / DSH group was significantly reduced, significantly lower than that in the LPS group, with a more significant reduction in the high-dose group, indicating that codonopsis glycoside I can inhibit the activation of systemic acute inflammatory response. The concentrations of IL-6 and TNF-α were significantly reduced, showing a dose-dependent decrease compared to the LPS group, with a more significant reduction in the high-dose group, indicating that codonopsis glycoside I can effectively inhibit the release of core pro-inflammatory factors in peripheral blood and block the amplification of the inflammatory cascade. The concentration of IL-10 was significantly increased, substantially higher than that in the LPS group, and the IL-10 concentration in the high-dose group was higher than that in the NC group, suggesting that codonopsis glycoside I can enhance the systemic anti-inflammatory response and restore the balance between pro-inflammatory and anti-inflammatory factors.

[0081] In summary, codonopin I can reduce systemic inflammatory response associated with LPS-induced acute lung injury by downregulating the abnormally high expression of pro-inflammatory mediators such as peripheral blood CRP, IL-6, and TNF-α, while upregulating the level of the anti-inflammatory factor IL-10, thereby reconstructing the systemic inflammatory balance.

[0082] Example 6

[0083] Weigh 1000g of Codonopsis pilosula I and dissolve it in approximately 80L of sterile purified water. Under light-protected and stirring conditions, add 10g of ascorbic acid, 10g of citric acid, 200g of sucralose, and an appropriate amount of edible flavoring in sequence, stirring until completely dissolved. Make up the volume to 100L with sterile purified water, filter through a 0.22μm microporous membrane for sterilization, and aseptically dispense into 10mL brown oral liquid bottles (each bottle containing approximately 100mg of Codonopsis pilosula I). ​​Seal the bottles to prepare Codonopsis pilosula I oral solution.

[0084] Example 7

[0085] Weigh out 50g of Codonopsis pilosula I, 150g of microcrystalline cellulose, 50g of lactose, and 15g of croscarmellose sodium, mix them evenly, add an appropriate amount of 10% povidone K30 ethanol solution as a binder to prepare a soft mass, granulate it through a 20-mesh sieve, dry it into granules at 50-60℃, add 3g of magnesium stearate and mix evenly, compress it into tablets containing 50mg of Codonopsis pilosula I per tablet, and coat it with a gastric-soluble film-coating premix to make Codonopsis pilosula I film-coated tablets.

[0086] Example 8

[0087] Weigh out 50g of codonopsis glycoside I, 145g of microcrystalline cellulose, and 30g of low-substituted hydroxypropyl cellulose, pass them through a 100-mesh sieve, mix them evenly in a three-dimensional mixer, and fill them into No. 0 hard capsule shells. Each capsule contains 50mg of codonopsis glycoside I, thus making codonopsis glycoside I hard capsules.

[0088] The present invention provides, through preferred embodiments, the application of codonopinide I in the prevention and / or treatment of acute lung injury. It should be noted that the above embodiments do not exhaustively describe all details, nor do they limit the present invention to the above-described embodiments. Those skilled in the art can make appropriate improvements based on the above content. All similar substitutions and modifications are obvious to those skilled in the art. Modifications or appropriate changes and combinations made to the methods and applications of the present invention without departing from the content, spirit, and scope of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of a lognansofside I in the preparation of a medicament for preventing and / or treating acute lung injury.

2. Use according to claim 1, characterized in that The acute lung injury is acute lung pathological injury.

3. Use according to claim 2, characterized in that The acute lung pathological injury is lung edema, lung tissue inflammation and / or alveolar wall integrity impairment.

4. Use according to claim 1 or 2, characterised in that The acute lung injury is sepsis-related lung injury induced by bacterial lipopolysaccharide.

5. A medicament for preventing and / or treating acute lung injury, comprising a therapeutically effective amount of a lognansofside I as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients.

6. The medicament for preventing and / or treating acute lung injury according to claim 5, wherein the medicament comprises the lognansofside I as the only active ingredient of the medicament.

7. The medicament for preventing and / or treating acute lung injury according to claim 5 or 6, characterized by The medicament is prepared into an oral administration dosage form.

8. The medicament according to claim 7, wherein the oral administration dosage form is any one of a tablet, a pill, a capsule, a granule, a powder, an oral solution or a syrup.

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