Application of irisin in preparation of medicine for treating hemorrhagic shock

Abstract

The invention provides application of tectoridin in preparation of a medicine for treating hemorrhagic shock, belongs to the technical field of biological medicines, and finds that tectoridin can reduce the death rate of hemorrhagic shock and improve organ functions. According to the record of the embodiment of the invention, after iris is intravenously injected into a rat with blood loss induced hemorrhagic shock, the death rate is obviously reduced, the average arterial pressure is increased, the lactic acid production is reduced, and organ injury markers are reduced. It is shown that irisin can significantly improve haemodynamic disorders and organ function impairment caused by hemorrhagic shock, and is an effective target for treating hemorrhagic shock.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to the application of irisin in preparing a medicine for treating hemorrhagic shock. Background Art

[0002] Hemorrhagic shock is a life-threatening circulatory failure state caused by a decrease in blood volume, which leads to cardiac pump failure and decreased vasoconstriction, resulting in an imbalance between cellular oxygen supply and demand.

[0003] In hemorrhagic shock, the body's oxygen delivery and energy storage cannot meet the needs of cells, resulting in a disorder of the normal homeostatic environment, causing tissue cell and organ dysfunction, which is closely related to the patient's prognosis. For patients with traumatic hemorrhagic shock, basic treatment measures include controlling bleeding, maintaining airway patency, fluid resuscitation, analgesia and other symptomatic treatments, and continuous monitoring of various indicators is required. The overall goal of treating shock is to improve microcirculation and oxygen utilization through individualized measures and restore the stability of the internal environment. The treatment goals at different stages will be different, so the corresponding indicators need to be monitored. However, there are still some controversies in terms of fluid resuscitation, prevention and treatment of TIC, selection of imaging examinations, and timing and method of surgery. A large number of animal experiments and clinical studies have shown that shock resuscitation helps improve the prognosis of hemorrhagic shock, but because a large amount of blood rich in oxygen and nutrients flows into the ischemic area, it may aggravate tissue damage caused by ischemia, leading to complications such as impaired organ function, hypothermia and traumatic coagulopathy.

[0004] Clinical studies have shown that hemorrhagic shock causes a sharp decrease in blood flow, which may lead to dysfunction of multiple organs such as the myocardium, cerebral cortex, kidneys and liver, increasing the risk of disability and death. Therefore, focusing on how to protect and improve the organ function of patients with hemorrhagic shock is crucial to simplify clinical treatment and improve patient prognosis. Summary of the invention

[0005] In view of this, the purpose of the present invention is to provide the use of irisin in the preparation of a drug for treating hemorrhagic shock. Irisin can reduce the mortality rate of hemorrhagic shock and improve organ function, providing a new approach for the treatment of hemorrhagic shock.

[0006] The present invention provides application of irisin in preparing medicine for treating hemorrhagic shock.

[0007] Preferably, the drug is an injectable preparation.

[0008] The invention provides an injection preparation for treating hemorrhagic shock, comprising 400-600 μg / ml irisin.

[0009] Preferably, the injection preparation uses physiological saline as a carrier.

[0010] Preferably, the dosage of irisin is 200-300 μg / kg.

[0011] The present invention provides the use of irisin in preparing a medicine for improving organ damage caused by hemorrhagic shock.

[0012] Preferably, the organ damage includes heart damage, kidney damage, lung damage and / or intestinal damage.

[0013] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides the use of irisin in the preparation of a drug for treating hemorrhagic shock. The present invention has found that irisin can reduce the mortality rate of hemorrhagic shock and improve organ function. According to the records in the embodiments of the present invention, in rats with hemorrhagic shock induced by blood loss, after intravenous injection of irisin, the mortality rate was significantly reduced, the mean arterial pressure increased, the lactate production was reduced, and the organ damage markers were reduced. It shows that irisin can significantly improve the hemodynamic disorders and organ function damage caused by hemorrhagic shock, and is an effective target for the treatment of hemorrhagic shock. The present invention not only provides a new choice and idea for the current treatment of hemorrhagic shock, but also broadens the selection field of drugs for the treatment of hemorrhagic shock, and also contributes to the development of this technical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the effect of intravenous injection of irisin on the postoperative hemorrhagic shock rats, where A is the survival rate 72 hours after surgery, B is the blood pressure 6 hours after surgery, and C is the lactate monitoring chart 1 hour, 3 hours and 6 hours after surgery.

[0015] Figure 2 This is the effect of intravenous injection of irisin on the heart of rats with hemorrhagic shock after surgery, where A is the left ventricular intrapressure detection graph 6 hours after surgery, B is the left ventricular maximum rising rate detection graph 6 hours after surgery, and C is the left ventricular maximum falling rate detection graph 6 hours after surgery.

[0016] Figure 3 The figure shows the effect of intravenous injection of irisin on the markers of postoperative myocardial injury in rats with hemorrhagic shock, where A is the change of serum troponin I content, B is the change of creatine kinase isoenzyme content, and C is the change of lactate dehydrogenase content.

[0017] Figure 4 The figure shows the effect of intravenous injection of irisin on the markers of postoperative renal injury in rats with hemorrhagic shock, where A is the change in creatinine content and B is the change in urea nitrogen content.

[0018] Figure 5The figure shows the effect of intravenous injection of irisin on postoperative organ damage in rats with hemorrhagic shock, where A is a HE staining comparison of the heart, kidney, colon and lung, B is a cardiac pathology scoring table, C is a kidney pathology scoring table, D is a colon pathology scoring table, and E is a lung pathology scoring table. DETAILED DESCRIPTION

[0019] The present invention provides the use of irisin in preparing a medicine for treating hemorrhagic shock. In the present invention, the medicine is an injection preparation.

[0020] The present invention also provides an injection preparation for treating hemorrhagic shock, comprising 400-600 μg / ml irisin. In the present invention, the injection preparation preferably uses physiological saline as a carrier, and the concentration of irisin is preferably 450-550 μg / ml, and more preferably 480-520 μg / ml.

[0021] In the present invention, the dosage of irisin is preferably 200-300 μg / kg, more preferably 220-280 μg / kg, and even more preferably 250 μg / kg.

[0022] The present invention also provides the use of irisin in preparing a medicine for improving organ damage caused by hemorrhagic shock.

[0023] In the present invention, the organ damage includes heart damage, kidney damage, lung damage and / or intestinal damage. In the present invention, irisin injection can significantly increase mean arterial pressure, left ventricular intraventricular pressure, left ventricular maximum rate of ascent and left ventricular maximum rate of descent; after irisin injection, troponin I, creatine kinase isoenzyme, urea nitrogen and creatinine expression are all reduced, indicating that irisin reduces organ damage in hemorrhagic shock, alleviates pathological changes shown by HE staining and reduces organ damage scores.

[0024] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0025] Example 1

[0026] Preparation of hemorrhagic shock model

[0027] Experimental groups:

[0028] (1) Normal mouse group (Sham group): a normal control group, which was always given a normal diet as a control for the irisin group;

[0029] (2) Hemorrhagic shock group (HS): 40% of the blood of rats was drawn to induce hemorrhagic shock, which served as the control of the irisin group;

[0030] (3) Vehicle group (HS+Veh): 40% of the blood of the rats was drawn to induce hemorrhagic shock, and 0.5 ml of normal saline was given 30 min later, which served as the control of the irisin group;

[0031] (4) Irisin group (HS+Irisin): 40% of the blood of the rats was drawn to induce hemorrhagic shock, and 0.5 ml of normal saline + 250 μg / kg irisin was given 30 minutes later.

[0032] Experimental methods:

[0033] 1. Experimental materials: SPF rats (purchased from Beijing Keyu Animal Breeding Center), sodium pentobarbital, low molecular weight heparin, 4-0 silk thread, ophthalmic scissors, ophthalmic forceps, retractors, etc.;

[0034] 2. Modeling method:

[0035] (1): SPF rats weighing 230-270 g were selected and kept at room temperature of 25±2°C and humidity of 50±10% and were deprived of food and water for 24 hours before surgery;

[0036] (2): Rats were weighed and selected with the same body weight and divided into four groups: sham operation group, hemorrhagic shock group, vehicle group, and irisin group. The rats were first anesthetized with 3% sodium pentobarbital (50 mg / kg) intraperitoneally. After the rats were anesthetized for 5 minutes, they were placed on a fixed table. The tail of the animal was gently pinched to confirm whether the animal was in an anesthetized state, and anesthetic was injected to ensure continuous anesthesia.

[0037] (3) Fix the rat's limbs with medical tape so that it lies supine on the operating table, remove the hair on the rat's neck, and disinfect with iodine;

[0038] (4) Prepare six 4-cm 4-0 sutures in advance, cut the skin 2 cm long in the middle of the neck, bluntly separate the subcutaneous muscles, separate the anterior tracheal muscles, and separate them downward along the left and right sternocleidomastoid tendons. After seeing the left and right carotid sheaths, retract the hooks to expose the common carotid artery. Bluntly separate the subcutaneous muscles to the left thoracic inlet, and a slightly pulsating jugular vein can be seen.

[0039] (5) Separate the right common carotid artery and left jugular vein, ligate the proximal end (ligate with frog heart clamp) and distal end (dead knot) of the common carotid artery and jugular vein, use ophthalmic scissors to make a small cut in the external carotid artery, insert the catheter, and when the catheter is successfully inserted into the carotid artery, ligate the thread hanging on the proximal end of the blood vessel (slipknot), open the frog heart clamp and continue to insert the catheter for 2-3 cm, then ligate the thread at the proximal end (dead knot); use the same method to insert the catheter 3-4 cm into the right common carotid artery and jugular vein;

[0040] (6) The catheterization time should be maintained within 30 minutes. After the catheterization is completed, 500 U / kg of systemic heparinization is performed through the right jugular vein, and after 10 minutes of observation and stabilization, 40% of the total blood volume (total blood volume = body weight × 0.06 (ml / g) + 0.77 ml) is extracted. 20% of the blood volume is extracted within the first 7 minutes, and then 20% of the blood volume is extracted within the next 13 minutes.

[0041] (7) Rats were placed in cages and the delayed medical response time lasted for 30 minutes without resuscitation to simulate a state of shock.

[0042] Survival test

[0043] After the hemorrhagic shock model was successfully established, the survival of the rats was observed at different time points, including 0 hours, 1 hour, 2 hours, 3 hours, 4 hours, 12 hours, 24 hours, 36 hours and 72 hours.

[0044] Systemic hemodynamics and cardiac function testing

[0045] Based on the above modeling method, a catheter was inserted into the left carotid artery to monitor the mean arterial pressure for 6 hours after hemorrhagic shock. At the same time, a catheter was inserted into the right carotid artery to monitor the blood pressure, maximum rate of rise and maximum rate of fall of the left ventricle for 6 hours.

[0046] Lactic acid content, heart and kidney function, and organ HE staining

[0047] After the simulated shock state, the myocardial injury markers of the rats, including serum troponin I, creatine kinase isoenzyme, urea nitrogen and creatinine, were observed at 1 hour, 3 hours and 6 hours. In addition, the lactic acid content of the rat serum was measured at 3 hours, and the heart, kidney, colon and lung tissues of the rats were selected for HE staining, and the tissue damage was evaluated by pathological scoring.

[0048] Experimental Results

[0049] The experimental results are as follows Figures 1 to 5 shown.

[0050] 1. Effect of irisin on mortality in rats with hemorrhagic shock

[0051] In rats with hemorrhagic shock, the mortality rates of the vehicle group and irisin group were higher than those of the control group. After irisin injection, the 72-hour mortality rate of rats with hemorrhagic shock was significantly reduced ( Figure 1 Specifically, the mortality rate of rats in the irisin group was significantly lower than that in the vehicle group and the hemorrhagic shock group, and the statistical results showed a significant difference.

[0052] The data are expressed as mean ± standard error, the sample size was 10 in each group, and p < 0.05 was considered statistically significant.

[0053] The mean arterial pressure, left ventricular pressure, maximum left ventricular rate of ascent, and maximum left ventricular rate of descent of rats with hemorrhagic shock, including the vehicle group and irisin group, were lower than those of the control group, indicating that the hemodynamics and cardiac function of rats with hemorrhagic shock were impaired;

[0054] After irisin injection, the mean arterial pressure, left ventricular pressure, maximum left ventricular rate of ascent and maximum left ventricular rate of descent of rats with hemorrhagic shock increased, indicating that irisin improved the hemodynamics and cardiac function of rats. Figure 2 The effect of irisin injection on mean arterial pressure, left ventricular pressure, maximum rate of rise of the left ventricle and maximum rate of fall of the left ventricle. The mean arterial pressure, left ventricular pressure, maximum rate of rise of the left ventricle and maximum rate of fall of the left ventricle in the irisin group were significantly higher than those in the shock group.

[0055] 2. Effects of irisin on cardiac and renal markers in rats with hemorrhagic shock

[0056] In the rats with hemorrhagic shock, including the shock group, vehicle group, and irisin group, the serum troponin I, creatine kinase isoenzyme, urea nitrogen, and creatinine were higher than those in the control group 3 hours later, indicating organ damage in rats with hemorrhagic shock;

[0057] After irisin injection, the expression of troponin I, creatine kinase isoenzymes, urea nitrogen and creatinine in rats with hemorrhagic shock decreased, indicating that irisin reduced organ damage in rats with hemorrhagic shock. Figure 3 and Figure 4 The effect of irisin infusion on serum troponin I, creatine kinase isoenzymes, urea nitrogen and creatinine in rats with hemorrhagic shock. The troponin I, creatine kinase isoenzymes, urea nitrogen and creatinine in the irisin group were significantly lower than those in the shock group.

[0058] Effects of irisin on the structure and pathological scores of heart, kidney, intestine and lung in rats with hemorrhagic shock

[0059] HE staining of rats with hemorrhagic shock, including those in the shock group, vehicle group, and irisin group, showed disordered arrangement of myocardial fibers, abnormal distribution of myocardial interstitium, and red blood cell leakage. Lung tissue showed thickening of alveolar septa, shrinkage of alveolar cavities, red blood cell extravasation, and accumulation of macrophages and neutrophils. Kidney tissue was severely damaged, as shown by enlarged glomerular volume, vacuoles, and swelling and deformation of some renal tubules. In addition, hemorrhagic shock caused obvious necrosis, edema, and disordered arrangement at the tips of the intestinal villi of rats, and some villus epithelial cells fell off into clumps. In order to quantify the degree of pathological damage to these organs, a scoring system was used to divide the damage into four levels: 0 points for no damage, 1 point for mild damage, 2 points for moderate damage, and 3 points for severe damage. The results showed that the pathological evaluation scores of the heart, kidneys, lungs, and intestines increased significantly. This result clearly indicated that hemorrhagic shock caused serious damage to the heart, kidneys, lungs, and intestinal structures of rats.

[0060] After irisin injection, the pathological changes in the heart, kidney, lung and intestine of rats with hemorrhagic shock were alleviated, and the pathological evaluation scores also decreased accordingly. This suggests that irisin can reduce the structural damage to the heart, kidney, lung and intestine caused by hemorrhagic shock. Figure 5 As shown in the results, after irisin injection, the disordered arrangement of myocardial fibers, abnormal distribution of myocardial interstitium and red blood cell leakage were improved; the thickening of alveolar septa, shrinkage of alveolar cavities, red blood cell extravasation and accumulation of macrophages and neutrophils in lung tissue were also alleviated; the increase in glomerular volume and vacuolation, swelling and deformation of renal tubules in kidney tissue were alleviated; the necrosis, edema and disordered arrangement of intestinal villus tips were alleviated, the shedding of villus epithelium was reduced, and the pathological evaluation score was significantly decreased.

[0061] In summary, hemodynamic disorders and organ dysfunction are the main manifestations of hemorrhagic shock. In rats with hemorrhagic shock induced by blood loss, after the injection of irisin, a significant increase in mean arterial pressure, left ventricular intracardiac pressure, maximum left ventricular rise rate and maximum left ventricular fall rate was observed. In addition, irisin also significantly reduced the production of troponin I, creatine kinase isoenzymes, urea nitrogen and creatinine in serum, alleviated the pathological changes shown by HE staining, and reduced the organ injury score. This shows that irisin can significantly improve hemodynamics and organ dysfunction as well as organ structure and function during hemorrhagic shock. Therefore, irisin may become an effective target for the treatment of hemorrhagic shock. Based on this, irisin has the potential to be developed as a new drug or drug target, providing new ways and means for the treatment of hemorrhagic shock and improving its prognosis.

[0062] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Application of irisin in the preparation of drugs for treating hemorrhagic shock.

2. The use according to claim 1, characterized in that: The medicine is an injection preparation.

3. An injection preparation for treating hemorrhagic shock, characterized in that: Including 400-600 μg / ml irisin.

4. The injection preparation according to claim 3, characterized in that: The injection preparation uses physiological saline as a carrier.

5. The injection preparation according to claim 3, characterized in that: The dosage of irisin is 200-300 μg / kg.

6. Use of irisin in the preparation of drugs for improving organ damage caused by hemorrhagic shock.

7. The use according to claim 6, characterized in that: The organ damage includes heart damage, kidney damage, lung damage and / or intestinal damage.

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