Application of luteolin tetramethyl ether in preparation of medicine for treating acute lung injury

Abstract

The invention belongs to the technical field of chemical medicines, and particularly relates to application of luteolin tetramethyl ether in preparation of a medicine for treating acute lung injury. According to the application disclosed by the invention, the fact that the luteolin tetramethyl ether has a very remarkable effect on preventing and treating the acute lung injury is found for the first time, and an experimental result shows that compared with a blank group, the inflammation of a modeling group is remarkably expressed, tissue swelling is caused, and the condition is very obviously reversed after the luteolin tetramethyl ether is given; the application shows that the luteolin tetramethyl ether can be used for preparing the medicine for treating the acute lung injury or used as a leading medicine for treating the acute lung injury, an important theoretical basis is provided for exploring a new idea for efficiently preventing and treating the acute lung injury with low toxicity, and the luteolin tetramethyl ether has important clinical guiding significance for treating the acute lung injury. A new treatment approach is provided for clinical treatment of acute lung injury, and a basis is provided for new use of old medicines and innovative therapy.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to the application of luteolin tetramethyl ether in the preparation of drugs for treating acute lung injury. Background Technology

[0002] Acute lung injury (ALI) is an immune-inflammatory disease of the lungs characterized by increased alveolar capillary permeability, induced by multiple factors. It is a clinical problem caused by acute, excessive pneumonia, with a mortality rate as high as 25% to 45% due to various complications. Despite significant progress in modern intensive care medicine, ALI still results in high morbidity and mortality, highlighting the urgent need to find effective drugs and methods for treating it.

[0003] Luteolin tetramethyl ether (5,7,3',4'-Tetramethoxyflavone, TMF) possesses various biological activities, including antifungal, antimalarial, antimycobacterial, and anti-inflammatory activities. It can inhibit the expression of EP2, EP4, β-catenin, and COX-2 genes in chondrocytes, suppress the expression of proteins in the EP / cAMP / PKA and β-catenin signaling pathways, and protect chondrocytes from apoptosis by regulating IRE1α, reversing the expression patterns of endoplasmic reticulum stress genes induced by IRE1α deficiency. However, to date, no studies have reported on the application of luteolin tetramethyl ether in the treatment of acute lung injury. Summary of the Invention

[0004] The purpose of this invention is to provide the application of luteolin tetramethyl ether in the preparation of drugs for treating acute lung injury, providing a new candidate compound and mechanism of action for the clinical treatment of acute lung injury, and has important clinical application prospects.

[0005] According to a first aspect of the invention, the use of luteolin tetramethyl ether in the preparation of a medicament or lead compound for treating acute lung injury is provided, wherein the molecular formula of luteolin tetramethyl ether is C 19 H 18 O6, with CAS number 855-97-0, has the structure shown in formula (I).

[0006]

[0007] Formula (I) In response to the current lack of drugs and methods for treating acute lung injury, this invention is the first to discover that luteolin tetramethyl ether has a very significant effect in the prevention and treatment of acute lung injury. Experimental results show that, compared with the control group, the model group showed significant expression of inflammation and tissue swelling. After administration of luteolin tetramethyl ether, the condition was significantly reversed. This indicates that luteolin tetramethyl ether can be used to prepare drugs for the treatment of acute lung injury, or as a lead-agent drug for the treatment of acute lung injury. This provides an important theoretical basis for exploring new ideas for the prevention and treatment of acute lung injury with low toxicity and high efficiency, has important clinical guiding significance for the treatment of acute lung injury, and provides a new treatment approach for the clinical treatment of acute lung injury. This invention provides a foundation for the repurposing of old drugs and innovative therapies.

[0008] In some embodiments, the drug also includes pharmaceutically acceptable salts, such as hydrochloride, phosphate, sulfate, sodium salt, potassium salt, etc.

[0009] In some embodiments, the drug also includes pharmaceutically acceptable excipients, such as fillers, binders, disintegrants, coating materials, antioxidants, flavoring agents, etc. Commonly used excipients include lactose, microcrystalline cellulose, starch, ethanol, magnesium stearate, talc, sucrose, food coloring, etc.

[0010] In some embodiments, the drug has at least one of the following functions: (1) Reduces inflammatory cell infiltration and tissue edema in lung tissue; (2) Improve lung function and restore the elastic properties of lung tissue and respiratory function; (3) It reduces the expression level of lung inflammatory factors (such as TNF-α, IL-6, IL-1β) and has an anti-inflammatory effect. Attached Figure Description

[0011] Figure 1 The images show the HE staining results of lung tissues from mice in different experimental groups. A represents the blank control group (CON), B represents the model group (ALI), C represents the low-dose luteolin tetramethyl ether group (TMF-L), D represents the high-dose luteolin tetramethyl ether group (TMF-H), and E represents the positive control group (DEX).

[0012] Figure 2 The graph shows the lung function test results of mice in different experimental groups. In the graph, A represents the 50% tidal volume expiratory flow rate (EF50), B represents the end-expiratory apnea (EEP) value, and C represents the enhanced apnea (Penh) value. * indicates... P <0.05, ** represents P <0.01, *** represents P <0.001, **** represents P <0.0001.

[0013] Figure 3The graph shows the results of bronchoalveolar lavage fluid analysis in mice from different experimental groups. A represents total cell count, and B represents total protein content. * in the graph indicates... P <0.05, ** represents P <0.01, *** represents P <0.001, **** represents P <0.0001.

[0014] Figure 4 The figures show the qRT-PCR results of lung inflammatory factor expression in mice from different experimental groups. A represents IL-1β expression, B represents TNF-α expression, and C represents IL-6 expression. * indicates... P <0.05, ** represents P <0.01, *** represents P <0.001. Detailed Implementation

[0015] The present invention will be further described in detail below with reference to specific embodiments. It is worth noting that the following embodiments are only for better explaining the content of the present invention and do not limit the scope of protection of the present invention. Process steps not disclosed in the embodiments are prior art. Unless otherwise specified, all raw materials are commercially available.

[0016] The following experiment will investigate the effect of luteolin tetramethyl ether on the induction of acute lung injury, in order to illustrate the application of luteolin tetramethyl ether as a drug for the treatment of acute lung injury.

[0017] Model preparation: Mice were intraperitoneally anesthetized until corneal reflex was reduced and limb muscles were relaxed. The anesthetized mice were placed supine on the operating table, and the sides of the head were gently pinched with the thumb and forefinger to keep the nostrils facing upwards and the head slightly tilted back. LPS solution (5 mg / mL) was administered via intratracheal spray to mice in all groups except the sham-operated group to establish the ALI model.

[0018] Forty male 7-week-old C57BL / 6 mice were randomly divided into 5 groups: (1) Blank control group (CON): 8 animals. PBS was administered via tracheal infusion during modeling, and physiological saline was administered via nebulization during treatment. (2) Model group (ALI): 8 animals. LPS was administered via tracheal drip during modeling and saline was administered via nebulization during treatment. (3) Low-dose luteolin tetramethyl ether (TMF-L) group: 8 animals were given LPS via tracheal infusion during modeling and low-dose TMF via nebulization for 20 minutes (5 μM / mL / day) during treatment for 2 consecutive days. (4) High-dose luteolin tetramethyl ether (TMF-H) group: 8 animals were given LPS via tracheal drip during modeling and high-dose TMF via nebulization for 20 minutes (10 μM / mL / day) during treatment for 2 consecutive days. (5) Dexamethasone group (DEX): 8 animals were given LPS via tracheal infusion during modeling and DEX via intraperitoneal injection (5 mg / kg / day) during treatment for 2 days.

[0019] Two days after intervention, the mice in each group were sacrificed, and their lung tissues were fixed with paraformaldehyde, embedded in paraffin blocks, and stained with hematoxylin and eosin (HE).

[0020] The results are as follows Figure 1 As shown, compared with the CON group, the ALI group showed extensive inflammatory cell infiltration and tissue swelling in the lung tissue. Figure 1 B), the lung tissue inflammatory cell infiltration and tissue edema of mice in the TMF-L group and TMF-H group were significantly reduced ( Figure 1 C, Figure 1 D).

[0021] The lung function of mice in each group was tested using a mouse lung function testing instrument, and the results are as follows: Figure 2 As shown, compared with the CON group, the ALI group had significantly higher EF50, EEP, and Penh levels. P <0.05), after administration, EF50, EEP, and Penh were significantly reduced ( P <0.05). This indicates that lung function was improved in mice given luteolin tetramethyl ether, reflecting the recovery of lung tissue elasticity and respiratory function.

[0022] 1500 μL of bronchoalveolar lavage fluid from each of the above groups of mice was collected for total cell counting and total protein content detection. The results are as follows: Figure 3 As shown, compared with the CON group, the ALI group had increased total cells and total protein, while the drug-treated groups had decreased.

[0023] The mRNA expression levels of inflammatory markers such as IL-6, IL-1β, and TNF-α in the lung tissue of sacrificed mice in the above experimental groups were determined using real-time quantitative PCR. The specific procedures were as follows: RNA was extracted from an appropriate amount of lung tissue, and cDNA was synthesized and stored at 4 ℃. Real-time PCR was then performed, with a pre-denaturation cycle of 95 ℃ for 30 s, followed by a reaction at the same temperature for 5 s, and then at 60 ℃ for 30 s, for a total of 39 cycles. β-actin was used as an internal control, and measurements were performed in triplicate. ﹣ΔΔCt Calculate the relative expression level of the target gene.

[0024] The results are as follows Figure 4As shown, the expression levels of lung inflammation-related factors (TNF-α, IL-6, IL-1β) in the ALI group mice were significantly higher than those in the CON group, indicating that the LPS-induced model successfully triggered a lung inflammatory response; the inflammatory factors in the TMF-L group and the TMF-H group were significantly lower than those in the model group, indicating that luteolin tetramethyl ether has a significant anti-inflammatory effect.

[0025] The above experimental results indicate that luteolin tetramethyl ether has a significant effect on the prevention and treatment of acute lung injury. It can effectively improve lung tissue pathological damage and respiratory function, and reduce the expression levels of inflammatory factors such as IL-6, IL-1β and TNF-α in acute lung injury. It can be used to prepare drugs for the treatment of acute lung injury.

[0026] The above descriptions are merely some specific embodiments of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the inventive concept of the present invention, and all such modifications and improvements fall within the scope of protection of the present invention.

Claims

1. Application of luteolin tetramethyl ether in the preparation of drugs or lead compounds for the treatment of acute lung injury.

2. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable salts.

3. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable excipients.

4. The application according to any one of claims 1-3, characterized in that, The drug has at least one of the following functions: (1) Reduces inflammatory cell infiltration and tissue edema in lung tissue; (2) Improve lung function and restore the elastic properties of lung tissue and respiratory function; (3) It reduces the expression level of inflammatory factors in the lungs and has an anti-inflammatory effect.

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