Application of traditional Chinese medicine composition in preparation of medicine for preventing and / or treating cardiopulmonary injury caused by sepsis

Abstract

The invention discloses application of a traditional Chinese medicine composition in preparation of a medicine for preventing and / or treating cardiopulmonary injury caused by sepsis. The traditional Chinese medicine composition comprises astragalus membranaceus, cassia twigs, Chinese herbaceous peony, Chinese dates and fresh ginger. The traditional Chinese medicine composition can remarkably improve the heart function, relieve myocardial and lung tissue damage and reduce the levels of serum CK-MB, LDH, IL-1beta and TNF-alpha, is applied to preparation of the medicine for preventing and / or treating heart and lung damage caused by sepsis, effectively inhibits heart and lung damage caused by sepsis, and has a good application prospect.

Description

Technical Field

[0001] The present invention relates to the use of a traditional Chinese medicine composition in preparing a medicine for preventing and / or treating cardiopulmonary injury caused by sepsis. Background Art

[0002] Sepsis is an organ dysfunction caused by the host's uncontrolled response to infection. It is a common cause of death in critically ill patients in clinical ICUs, and is typically characterized by multiple organ failure. The organ systems in the human body are interdependent, and the heart, as the top priority in the cardiovascular system, plays an extraordinary role. Heart damage will lead to a decrease in the body's blood supply, tissue hypoxia, mitochondrial dysfunction, and metabolic dysfunction. As a common damaged target organ in sepsis, the heart has become an important risk factor for death from sepsis. The lung is the most vulnerable organ, and impaired pulmonary microcirculation is the most terrible complication of septic lung injury. In the case of sepsis, acute lung injury or acute respiratory distress syndrome can lead to high mortality and multiple organ failure. At present, there is no treatment for septic cardiomyopathy based on evidence-based medicine. The existing treatment of septic cardiomyopathy in clinical practice is mainly to stabilize organ function, such as the use of EMCO therapy, control infection, fluid resuscitation, and symptomatic treatment. In terms of medication, anti-infective drugs, vasoactive drugs, beta-blockers, and anti-inflammatory drugs are mostly used for basic treatment. It is worth noting that there are some reports on the use of traditional Chinese medicine to treat sepsis, such as Xuebijing Injection (suitable for heat toxicity and blood stasis syndrome), Shenfu Injection (suitable for heart yang deficiency and sudden loss of yang qi), Shengmai Injection (suitable for deficiency of both qi and yin, weak pulse and impending loss of yang qi), Shenmai Injection (suitable for deficiency of both qi and yin syndrome); Huangqi Injection (suitable for deficiency of heart qi and blood stasis syndrome), etc.

[0003] The current clinical treatments for sepsis-induced cardiopulmonary injury are expensive, and the drugs used may have some side effects. For example, norepinephrine, a first-line drug for treatment among vasoactive drugs, can reduce cardiac preload in sepsis-induced cardiomyopathy and prevent pulmonary edema in its early use, but excessive afterload will reduce CO and lead to abnormal cardiac function. In addition, due to the characteristics of sepsis, its treatment is complicated, there is no specific treatment method, and the prognosis of sepsis patients cannot be improved; it is urgent to develop drugs suitable for the prognosis treatment of sepsis patients. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a Chinese medicine composition for use in the preparation of a drug for preventing and / or treating cardiopulmonary injury caused by sepsis.

[0005] Technical solution: The present invention discloses the use of a traditional Chinese medicine composition in the preparation of a drug for preventing and / or treating cardiopulmonary injury caused by sepsis. The traditional Chinese medicine composition comprises astragalus, cinnamon twig, peony root, jujube and ginger.

[0006] Among them, in the traditional Chinese medicine composition, the mass ratio of astragalus, cinnamon twig, peony, jujube and ginger is 2:0.4-2.5:0.4-2.5:0.4-2.5:0.4-2.5; preferably 2:1:1:1:1.

[0007] Among them, the cardiopulmonary injury caused by sepsis is myocardial injury, cardiac function damage, myocardial fiber disorder and rupture caused by sepsis; inflammatory cell infiltration of alveolar walls, obvious thickening of alveolar septa, alveolar wall edema and / or bleeding.

[0008] Wherein, the cardiopulmonary injury caused by sepsis is heart function damage or lung tissue damage caused by sepsis.

[0009] Wherein, the cardiac function damage is cardiac diastolic and / or systolic dysfunction.

[0010] The Chinese medicine composition reduces the disordered arrangement and rupture of myocardial fibers caused by sepsis.

[0011] The Chinese medicine composition reduces the inflammatory cell infiltration of the alveolar wall, the significant thickening of the alveolar septum, the edema of the alveolar wall and / or the bleeding caused by sepsis.

[0012] The Chinese medicine composition reduces the elevated levels of CK-MB, LDH, IL-1β and TNF-α in serum caused by sepsis.

[0013] The preparation method of the Chinese medicine composition comprises the following steps: taking raw Chinese medicinal materials such as astragalus, cinnamon twig, peony, jujube and ginger, adding 10 to 15 times the volume of water, soaking for 1 to 2 hours, decocting for 2 to 4 hours, pouring out the decoction, adding 10 to 15 times the volume of water, decocting for 1 to 2 hours, combining the two extracts, filtering, and concentrating under reduced pressure to obtain the composition; preferably, taking raw Chinese medicinal materials such as astragalus, cinnamon twig, peony, jujube and ginger, adding 10 times the volume of water, soaking for 1 hour, decocting for 2 hours, pouring out the decoction, adding 10 times the volume of water, decocting for 1 hour, combining the two extracts, filtering, and concentrating under reduced pressure to obtain the composition.

[0014] The Chinese medicine composition is administered by intragastric administration, with a dosage of 2.5 to 10 g / kg, preferably 5 g / kg, and is used in the form of an oral preparation as a drug for treating cardiopulmonary injury caused by sepsis.

[0015] Principle of invention: Huangqi Guizhi Wuwu Decoction comes from the "Golden Chamber" written by Zhang Zhongjing in the Eastern Han Dynasty. The original text records that "blood stasis is weak in both yin and yang, Cunkou Guanshang is weak, Chizhong is tight, and the external symptoms are numbness of the body, such as wind stasis, Huangqi Guizhi Wuwu Decoction is the main treatment". This prescription has the effects of regulating the Rongwei, invigorating qi and warming the meridians, dispelling wind and dispersing evil, invigorating qi and promoting yang, nourishing blood and removing numbness, and is the first prescription for treating blood stasis. In recent years, Huangqi Guizhi Wuwu Decoction is commonly used in clinical treatment of diseases such as diabetic peripheral neuropathy, primary osteoporosis, and facial nerve paralysis. It is widely used and has significant efficacy. This prescription is composed of five medicinal materials: astragalus, cinnamon twig, peony, ginger, and jujube. Among them, astragalus is the monarch, which is sweet and warm to invigorate qi and replenish the Wei Qi on the surface. Cinnamon twig disperses wind and cold and warms the meridians to relieve numbness. It is compatible with astragalus to invigorate qi and warm yang, and harmonize blood and promote menstruation. Cinnamon twig gets astragalus to invigorate qi and invigorate Wei Yang; astragalus gets cinnamon twig, which consolidates the surface without leaving evil. Peony nourishes blood and harmonizes the Ying and relieves blood stasis. When used with cinnamon twig, it regulates Ying and Wei and harmonizes the exterior and interior. The two medicines are ministers. Ginger is pungent and warm, dispersing wind evil to help cinnamon twig; jujube is sweet and warm, nourishing blood and replenishing qi to support the work of astragalus and peony; when used with ginger, it can harmonize Ying and Wei and regulate various medicines as an adjuvant. The above five flavors of medicinal materials have the effect of "solidifying the exterior without retaining evil, dispersing evil without hurting the righteous, and taking into account both evil and righteousness". The astragalus and cinnamon twig in the prescription have a certain cardioprotective effect. Sepsis is a life-threatening organ dysfunction caused by the body's dysregulated response to infection. It can affect multiple organs, leading to organ damage or failure. Among them, the heart and lungs are the most vulnerable target organs. If sepsis cardiopulmonary injury is not treated in time, the mortality rate can reach more than 50%. Sepsis-induced myocardial injury is characterized by left ventricular dilatation, decreased left ventricular ejection fraction, elevated levels of myocardial injury markers (CK-MB) and inflammatory factors (TNF-α, IL-1β, etc.). Infiltration of inflammatory cells in the alveolar wall, significant thickening of the alveolar septum, pulmonary interstitial edema, and alveolar wall edema are the main characteristics of sepsis-induced lung injury. Based on the protective potential of Huangqi Guizhi Wuwu Decoction against heart and lung injury, it is expected to be used to treat sepsis-induced cardiopulmonary injury.

[0016] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the Chinese medicine composition of the present invention is used in the preparation of drugs for preventing and / or treating cardiopulmonary injury caused by sepsis, significantly enhancing cardiac function, and can increase the abnormally reduced left ventricular ejection fraction (EF) and shortening fraction (FS) caused by LPS by 38.2% and 53.1%, respectively; significantly improve the disordered arrangement and breakage of myocardial fibers caused by sepsis, and reduce the infiltration of inflammatory cells in the alveolar wall, obvious thickening of the alveolar septum, pulmonary interstitial edema and alveolar wall edema; significantly reduce the levels of myocardial injury markers and inflammatory factors in serum, and reduce the abnormally elevated serum CK-MB, IL-1β, and TNF-α levels caused by LPS by 42.8%, 41.8%, and 46.9%, respectively, effectively inhibiting the cardiopulmonary injury caused by sepsis, and having good medicinal prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is a picture of the cardiac ultrasound results of mice;

[0018] Figure 2 The left ventricular ejection fraction and shortening fraction of mice. In the figure, ** represents p<0.01, *** represents p<0.001, and **** represents p<0.0001.

[0019] Figure 3 HE staining results of heart tissues of mice in each group;

[0020] Figure 4 HE staining results of lung tissues of mice in each group;

[0021] Figure 5 The results of serum CK-MB and LDH levels in mice are shown in Figure 1. A is serum CK-MB, B is LDH, and * represents p<0.05, *** represents p<0.001, and **** represents p<0.0001.

[0022] Figure 6 The results of serum IL-1β and TNF-α levels in mice are shown in Figure 1. A is serum IL-1β, B is TNF-α, and *** represents p<0.001, **** represents p<0.0001. DETAILED DESCRIPTION

[0023] The technical scheme of the present invention is further described below in conjunction with the examples. The test materials used in the examples can all be purchased through conventional channels.

[0024] Experimental Materials:

[0025] Experimental animals: Healthy C57BL / 6J mice (male, weighing 22-24 g), clean grade, provided by the Comparative Medicine Center of Yangzhou University.

[0026] Experimental drugs: Astragalus, cinnamon twig, peony root and jujube were purchased from Shangyuantang Pharmacy (Nanjing, Jiangsu).

[0027] Experimental reagents: physiological saline: purchased from Anhui Shuanghe Pharmaceutical; lipopolysaccharide (LPS): Sigma, USA; PBS, paraformaldehyde: Jiangsu Keygen Biotechnology Co., Ltd.; LDH kit: Nanjing Jiancheng Bioengineering Institute; mouse CK-MB, IL-1β, TNF-α detection kits were purchased from Aifang Biotechnology Co., Ltd.

[0028] Experimental instruments: Ultra-high resolution small animal ultrasound imaging system Vevo 3100LT: FUJIFILM Visual Sonics; SpectraMax M2e microplate reader: Moleclar Devices, USA.

[0029] Example 1

[0030] The Chinese medicine composition of the present invention (abbreviated as HGWD): 20g of Astragalus, 10g of Cinnamon Twig, 10g of Peony Root, 10g of Jujube, and 10g of Ginger;

[0031] The preparation method is as follows: take 20g of raw Chinese medicinal materials of astragalus, 10g of cinnamon twig, 10g of peony, 10g of jujube, and 10g of ginger, add 10 times the volume of deionized water, soak for 1 hour, extract twice with boiling water method, each time for 1 hour, combine the two extracts, filter, and concentrate under reduced pressure to obtain a crude drug concentration of 2.0g / mL.

[0032] Example 2

[0033] Establishment of mouse sepsis model and grouping

[0034] 58 healthy C57BL / 6J mice (male, weighing 24-26g), clean grade, free access to food and water, 12 hours of light per day, and adaptive feeding for 7 days before the experiment was officially carried out. The mice were randomly divided into a control group (Control) of 10, a model group (LPS) of 12, a low-dose group of the Chinese medicine composition of the present invention (HGWD-L, 2.5g crude drug / kg) of 12, a medium-dose group of the Chinese medicine composition of the present invention (HGWD-M, 5g crude drug / kg), and a high-dose group of the Chinese medicine composition of the present invention (HGWD-H, 10g crude drug / kg) of 12. The control group and the model group were gavaged with physiological saline (0.15mL / 10g) for 7 days every day; the low, medium and high dose groups of the Chinese medicine composition of the present invention were gavaged for 7 days according to the set doses. One hour after the last day of administration, the control group was intraperitoneally injected with PBS, and each mouse in the remaining groups was intraperitoneally injected with LPS (10mg / kg) for 12 hours.

[0035] Determination of cardiac function indexes

[0036] After 12 hours of treatment, the mice in the above groups were treated with an appropriate amount of depilatory cream evenly applied to the heart of the mice to remove the hair of the mice so that the skin of the heart was completely exposed. After the mice were anesthetized with 1% isoflurane, they were fixed on the operating board with their chests facing up, and an appropriate amount of coupling agent for detection was applied to the heart. The probe was placed on the chest of the mice, and the ultra-high-resolution small animal ultrasound imaging system Vevo 3100LT was used to select two-dimensional M-mode ultrasound for echocardiography. Three cardiac cycles were measured continuously, and the data were processed with VevoLAB 3.2.6 software to obtain the left ventricular ejection fraction (EF) and fractional shortening (FS).

[0037] Serum CK-MB, LDH, IL-1β, and TNF-α levels

[0038] After 12 hours of treatment, the eyeballs of the mice in the above groups were removed for blood collection, and the serum was collected by centrifugation after standing. The levels of mouse serum creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), interleukin 1β (IL-1β) and tumor necrosis factor (TNF-α) were determined according to the instructions of the kit.

[0039] HE staining

[0040] After blood collection, the mouse heart was dissected and fixed with 4% formalin for 24 hours, dehydrated, tissue transparent, paraffin embedded, sectioned, dewaxed, hematoxylin-eosin (HE) stained, dehydrated and mounted, and the morphology of myocardial cells was observed under an optical microscope.

[0041] Statistical analysis

[0042] One-way analysis of variance (ANOVA) and Tukey's test were used to test the statistical differences of the samples using IBM SPSS Statistics 26.0, and p < 0.05 was considered statistically significant.

[0043] Example 3

[0044] Effect of the Chinese medicine composition of the present invention on cardiac function in septic mice:

[0045] Figure 1 and 2 The figures are respectively the cardiac ultrasound, left ventricular ejection fraction (EF) and fractional shortening (FS) results of the mice in the present invention. Figure 1 As shown in the data, compared with the control group (Control), the EF and FS of the model group (LPS) were significantly decreased (p<0.01); compared with the LPS group, the EF and FS of the low-dose group (HGWD-L) and the medium-dose group (HGWD-M) were significantly increased (p<0.05, p<0.01), indicating that the Chinese medicine composition of the present invention can significantly improve the cardiac dysfunction of mice caused by sepsis.

[0046] Example 4

[0047] Effects on pathological changes of myocardial tissue in septic mice:

[0048] Figure 3 The HE staining results of the heart tissues of the mice in each group of the present invention are shown. It can be seen from the figure that the myocardial texture of the mice in the Control group is clear and the myocardial cells are arranged regularly, while the myocardial fibers in the LPS group are obviously arranged in disorder and partially broken. After being treated with the Chinese medicine composition of the present invention, the cell texture tends to be clear and the myocardial cells are arranged gradually in a regular manner.

[0049] Example 5

[0050] Effect of the Chinese medicine composition of the present invention on pathological changes of lung tissue in septic mice

[0051] Figure 4 The HE staining results of lung tissue disease of each group of mice in the present invention are shown. It can be seen from the figure that the alveolar wall structure of the mice in the Control group is intact, while in the LPS group, obvious focal alveolar structural disorder, narrowing of the alveolar cavity, expansion of the surrounding alveolar cavity, mild emphysema, and a large number of acute and chronic inflammatory cell infiltrations in the interstitium and alveolar cavity are observed. After treatment with the Chinese medicine composition of the present invention, the alveolar structure tends to be intact and the inflammatory cells are significantly reduced.

[0052] Example 6

[0053] Effect of the Chinese medicine composition of the present invention on serum LDH and CK-MB levels in mice with septic cardiomyopathy

[0054] Serum CK-MB and LDH levels are reliable indicators of myocardial injury. Figure 5 The result graph of serum CK-MB and LDH levels of the mice of the present invention shows that compared with those of the Control group, the serum CK-MB and LDH levels of the mice in the LPS group were significantly increased (p<0.0001); and compared with the LPS group, the CK-MB and LDH levels of the mice in the HGWD-L and HGWD-M groups were significantly decreased (p values ​​were all less than 0.05), indicating that the Chinese medicine composition of the present invention can reduce myocardial damage in septic mice.

[0055] Example 7

[0056] Effect of the Chinese medicine composition of the present invention on the levels of IL-1β and TNF-α in mice with septic cardiomyopathy

[0057] IL-1β and TNF-α are typical pro-inflammatory cytokines. Figure 6 The results of serum IL-1β and TNF-α levels in mice of the present invention are shown in FIG. Figure 6 It can be seen that compared with the Control group, the serum IL-1β and TNF-α levels of mice in the LPS group were significantly increased (p<0.0001); compared with the LPS group, the IL-1β and TNF-α levels of mice in the HGWD-L and HGWD-M groups were significantly decreased (p<0.01), indicating that the Chinese medicine composition of the present invention can significantly reduce the levels of serum inflammatory factors in septic mice and reduce the inflammatory response.

[0058] Therefore, the Chinese medicine composition of the present invention can significantly improve cardiac function, reduce myocardial and lung tissue damage, and reduce serum CK-MB, LDH, IL-1β and TNF-α levels. It is used in the preparation of drugs for preventing and / or treating cardiopulmonary damage caused by sepsis, effectively inhibits heart and lung damage caused by sepsis, and has good application prospects.

Claims

1. Use of a Chinese medicine composition in the preparation of a drug for preventing and / or treating cardiopulmonary injury caused by sepsis, characterized in that: The traditional Chinese medicine composition comprises astragalus, cinnamon twig, peony root, jujube and ginger.

2. The use according to claim 1, characterized in that: In the traditional Chinese medicine composition, the mass ratio of astragalus, cinnamon twig, peony root, jujube and ginger is 2:0.4-2.5:0.4-2.5:0.4-2.5:0.4-2.

5.

3. The use according to claim 1, characterized in that: The sepsis-induced cardiopulmonary injury refers to cardiac function damage or lung tissue damage caused by sepsis.

4. The use according to claim 3, characterized in that: The cardiac function damage is cardiac diastolic and / or systolic dysfunction.

5. The use according to claim 1, characterized in that: The traditional Chinese medicine composition reduces the disordered arrangement and rupture of myocardial fibers caused by sepsis.

6. The use according to claim 1, characterized in that: The traditional Chinese medicine composition reduces the inflammatory cell infiltration of the alveolar wall, the obvious thickening of the alveolar septum, the edema of the alveolar wall and / or the bleeding caused by sepsis.

7. The use according to claim 1, characterized in that: The traditional Chinese medicine composition reduces the elevated serum CK-MB, LDH, IL-1β and TNF-α levels caused by sepsis.

8. The use according to claim 1, characterized in that: The preparation method of the Chinese medicine composition comprises the following steps: taking raw Chinese medicinal materials such as astragalus, cinnamon twig, peony, jujube and ginger, adding 10 to 15 times the volume of water, soaking for 1 to 2 hours, decocting for 2 to 4 hours, pouring out the decoction, adding 10 to 15 times the volume of water again, decocting for 1 to 2 hours, combining the two extracts, filtering, and concentrating under reduced pressure to obtain the composition.

9. The use according to claim 1, characterized in that: The Chinese medicine composition is administered by intragastric administration, with a dosage of 2.5 to 10 g / kg, and is used in the form of an oral preparation as a drug for combating cardiopulmonary injury caused by sepsis.

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