CN116919937A - Application of novel anti-inflammatory mediator MaR1 in preparation of medicines for preventing and/or treating pulmonary arterial hypertension - Google Patents
Application of novel anti-inflammatory mediator MaR1 in preparation of medicines for preventing and/or treating pulmonary arterial hypertension Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The application discloses application of a novel anti-inflammatory mediator MaR1 in preparation of a medicament for preventing and/or treating pulmonary arterial hypertension. The experimental results of the application show that: in vivo experiments, maR1 can obviously reduce right ventricular blood pressure, right ventricular hypertrophy index, inhibit pulmonary artery vascular remodeling and reduce vascular injury in a rat and mouse pulmonary artery high pressure model. In order to explore the treatment effect of MaR on pulmonary arterial hypertension, maR of the last week of animal model modeling is given to obtain the same result, maR1 can obviously reduce right ventricular blood pressure and right ventricular hypertrophy index, inhibit pulmonary arterial vascular remodeling, reduce the injury degree of pulmonary blood vessels and have a certain treatment effect on pulmonary arterial hypertension.
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to application of a novel anti-inflammatory medium MaR1 in preparation of a medicine for preventing and/or treating pulmonary arterial hypertension.
Background
Inflammatory response is one of the important defensive responses of the body, and is used for responding to injury stimulus such as external induction factors, pathogen infection and the like so as to maintain the homeostasis of the internal environment. Excessive inflammation, long-term chronic inflammation, and slow resolution of inflammatory responses will lead to the development of a variety of diseases. Recent studies indicate that the resolution response of inflammation is an active process mediated by a series of pro-inflammatory resolution lipid mediators (specialized proresolving lipid mediator, SPM). Novel anti-inflammatory mediator MaR (maresin-1) is a novel anti-inflammatory mediator with remarkable anti-inflammatory effect synthesized by M2 macrophages from endogenous docosahexaenoic acid (docosahexenoic acid, DHA) through lipoxygenase oxidation and other approaches during the period of inflammation resolution. MaR1 has remarkable protective effects in various inflammatory diseases, including liver ischemia reperfusion injury, LPS-induced acute lung injury, abdominal aortic aneurysm and the like, and the effect of MaR1 in pulmonary arterial hypertension is not clear.
Pulmonary arterial hypertension (Pulmonary arterial hypertension, PAH) is a progressive cardiovascular disease characterized by pulmonary vascular remodeling and right ventricular hypertrophy and dysfunction as major pathologies. Sustained constriction of pulmonary vessels, vascular remodeling, inflammatory cell infiltration, etc., results in narrowing and occlusion of the lumen of pulmonary vessels, progressive increases in pulmonary vascular resistance and pulmonary arterial pressure, and ultimately results in right heart failure and even death. The pulmonary artery high pressure is defined as that the average pulmonary artery pressure measured by the right ventricular catheter in the sea level resting state is more than or equal to 25mmHg, the pulmonary arteriole wedge pressure is less than or equal to 15mmHg, and the pulmonary vascular resistance is more than 3Wood units. Pulmonary hypertension has attracted considerable clinical attention, and clinical therapies are still mainly focused on improving vasodilation function, including prostacyclin and its analogues, endothelin receptor antagonists, phosphodiesterase inhibitors of the NO pathway, guanylate cyclase agonists, calcium channel blockers, and the like. Although the medicines can improve disease symptoms and delay disease development to a certain extent, the treatment efficiency is low, and the occurrence of pulmonary arterial hypertension cannot be fundamentally inhibited. Pulmonary artery revascularization is a major pathological feature of pulmonary arterial hypertension, and currently there is a lack of therapeutic drugs targeting pulmonary artery revascularization.
Disclosure of Invention
The application aims to provide a novel medical application of MaR 1.
The novel medical application of MaR1 provided by the application is the application of MaR1 in preparing a medicine for preventing and/or treating pulmonary arterial hypertension.
Specifically, the application is one of the following 1) -5):
1) MaR1 the application in preparing medicines for inhibiting occurrence and development of pulmonary arterial hypertension;
2) The application of MaR1 in preparing a medicament for inhibiting pulmonary artery vascular remodeling;
3) MaR the use of MaR for the manufacture of a medicament for reducing right ventricular blood pressure;
4) Use of MaR1 for the manufacture of a medicament for reducing right ventricular hypertrophy index;
5) MaR1 in the preparation of a medicament for reducing pulmonary artery vascular injury.
The experimental results of the application show that: in vivo experiments, maR1 can obviously reduce right ventricular blood pressure and right ventricular hypertrophy index, inhibit pulmonary artery vascular remodeling and reduce pulmonary artery vascular injury in a rat and mouse pulmonary artery high pressure model. In order to explore the treatment effect of MaR on pulmonary arterial hypertension, maR of the last week of animal model modeling is given to obtain the same result, maR1 can obviously reduce right ventricular blood pressure and right ventricular hypertrophy index, inhibit pulmonary arterial vascular remodeling, reduce the damage degree of pulmonary arterial blood vessels and have a certain treatment effect on pulmonary arterial hypertension.
Drawings
Figure 1 shows MaR reduces right ventricular blood pressure and right ventricular hypertrophy in rats. Mct induced pulmonary arterial hypertension animal model pattern; after MCT modeling, the right ventricular blood pressure is obviously increased compared with a control group, and the MCT modeling is simultaneously given MaR1 treatment, compared with the MCT modeling, the right ventricular blood pressure is obviously reduced; after MCT modeling, the right ventricular hypertrophy index was significantly increased compared to the control group, while the MCT modeling was given MaR treatment with significantly reduced compared to the MCT modeling. * P < 0.001vs CTRL, # # P < 0.001, # # P < 0.005vs MCT Vehicle.
Figure 2 shows MaR inhibits rat pulmonary artery vascular remodeling. A. The paraffin sections of the pulmonary artery were HE stained to represent the map. Compared with a control group, the MCT module is obviously increased in thickness of the blood vessel medium membrane, and compared with a MaR treatment group and a modeling group, the MCT module is obviously inhibited in thickness increase of the blood vessel medium membrane; B. the ratio of the area of the tunica media in the blood vessel to the total cross-sectional area of the blood vessel was counted. The MCT model was significantly increased in intima-media thickening in pulmonary arteries compared to the control, and the model was given MaR treatment group at the same time significantly inhibited the intima-media thickening compared to the model. * P < 0.001vs CTRL, # # P < 0.001vs MCT Vehicle.
Figure 3 shows MaR that reduces right ventricular blood pressure and right ventricular hypertrophy in mice. A. Hypoxia in combination with SU5416 induced pulmonary arterial hypertension animal model pattern. B. Compared with a control, the low-oxygen combined SU5416 model building module has the advantages that the right ventricular blood pressure is obviously increased, and compared with a model building module, the model building simultaneous administration MaR1 treatment group has the advantage that the right ventricular blood pressure is obviously reduced; C. the right ventricular hypertrophy index of the hypoxia combined SU5416 model group is obviously increased compared with the control, and the right ventricular hypertrophy index of the model-making simultaneous administration MaR1 treatment group is obviously reduced compared with the model-making group. * P < 0.001vs CTRL, # P < 0.005, # P < 0.001vs HySU Vehicle.
Figure 4 shows MaR reduces pulmonary artery vascular remodeling in mice. A. The paraffin sections of the pulmonary artery were HE stained to represent the map. The thickness of the blood vessel medium membrane in the hypoxia combined SU5416 modeling module is obviously increased, and compared with the modeling module, the modeling module is given with MaR1 treatment group at the same time, the increase of the thickness of the blood vessel medium membrane is obviously inhibited; B. the ratio of the area of the tunica media in the blood vessel to the total cross-sectional area of the blood vessel was counted. The thickening degree of the middle membrane of the pulmonary artery is obviously increased compared with a control model, and the thickening degree of the middle membrane is obviously inhibited by the model and the MaR1 treatment group compared with the model. * P < 0.001vs CTRL, # # P < 0.001vs HySU Vehicle.
Fig. 5 shows that administration of MaR1 after molding can reduce right ventricular blood pressure and relieve right ventricular hypertrophy in rats. A therapeutic action model construction diagram of MaR1 in MCT induced pulmonary hypertension; after the MCT is molded, the right ventricular blood pressure is obviously increased compared with a control group, and after the molding, the right ventricular blood pressure is obviously reduced compared with the MCT molding group by the MaR1 treatment group; after the MCT is molded, the right ventricular hypertrophy index is obviously increased compared with a control group, and after the molding, the right ventricular hypertrophy index is obviously reduced compared with the MCT molding group by the MaR treatment group. * P < 0.005vs CTRL, # P < 0.05vs MCT Vehicle.
Figure 6 shows that post-molding administration MaR1 reduced pulmonary artery vascular remodeling. A. The paraffin sections of the pulmonary artery were HE stained to represent the map. Compared with a control group, the MCT module is obviously increased in thickness of the blood vessel medium film; compared with the modeling group, the MaR1 treatment group after modeling remarkably inhibits the increase of the thickness of the blood vessel medium membrane; B. the ratio of the area of the tunica media in the blood vessel to the total cross-sectional area of the blood vessel was counted. MCT building blocks significantly increased the intima-media thickening in pulmonary arteries compared to controls, and administration of MaR1 treatment after modeling significantly inhibited the intima thickening compared to the building blocks. * P < 0.001vs CTRL, # # P < 0.001vs MCT Vehicle.
Detailed Description
The following detailed description of the application is provided in connection with the accompanying drawings that are presented to illustrate the application and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the application in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1 investigation of the protective Effect of MaR1 on pulmonary hypertension Using rat pulmonary hypertension model
The experimental object: healthy male SPF-grade SD rats of 8-10 weeks old, weighing 200-250g, purchased from Liaoning Changsheng Biotechnology Co., ltd, and bred in SPF-grade animal houses at university of Dalian medical science. The raising environment is maintained at the room temperature of 20-25 ℃ and the relative humidity of 50-60%, the lighting is carried out for 12h/d, and the people can drink and eat food freely. Conventional rat feed is provided by Jiangsu Meidisen biomedical Co. The treatment of animals during the experiment meets the ethical standards of animals.
Pulmonary artery high pressure model establishment: monocrotoline (MCT, available from MCE company under the trade designation HY-N0750) is a common model of pulmonary hypertension in rats. SD rats are injected with 60mg/kg of monocrotaline once, rats in a control group are injected with the same volume of physiological saline ethanol solution once, and molding is completed after 21 days.
Right ventricular blood pressure (right ventricle systolic pressure, RVSP) measurement: 3 weeks after MCT injection, rats were anesthetized intraperitoneally with 10% chloral hydrate (0.4 ml/100 g) and right ventricular blood pressure was measured via a right ventricular cannula using PT-103N baroreceptors and BL-420N signal acquisition and processing systems (Chengdu Telec).
Determination of right ventricular hypertrophy index (right ventricular hypertrophy index, RVHI): after the blood pressure measurement is finished, the rat is sacrificed, the heart is taken out, the root of a blood vessel and the left and right atria are cut off, the wall of the right ventricle is carefully dissociated, after the filter paper absorbs water, the right ventricle, the left ventricle and the ventricular septum are weighed, and the right ventricular hypertrophy index is calculated according to a formula: rvhi=rv/(lv+s).
Pulmonary tissue and pulmonary artery pathology detection: rat right lower lung lobes were fixed with 4% paraformaldehyde for 24h, embedded in paraffin, and serial sections were performed with a slice thickness of 5 μm. Lung tissue sections were used for HE staining, immunohistochemistry and immunofluorescence.
MaR1 the composition can reduce right ventricular blood pressure and right ventricular hypertrophy of rats
The MCT-induced pulmonary artery model of rats, maR (maresin 1, from Cayman Chemical, cat No. 10878) treatment group was intraperitoneally injected with MaR1 ng/dose per day, and control group was injected with the same volume of physiological saline, as shown in fig. 1, the MCT-made module had significantly increased right ventricular blood pressure and right ventricular hypertrophy index of rats compared with the control group, and the model was made while MaR1 treatment group had significantly decreased right ventricular blood pressure of rats compared with the model making module, reduced right ventricular hypertrophy, and had a protective effect on pulmonary arterial hypertension.
MaR1 inhibiting pulmonary artery vascular remodeling in rats
As shown in fig. 2, the HE staining results of the lung tissue sections showed that the MCT fabrication module had significantly increased thickness of the middle pulmonary artery compared to the control group, and that the membrane thickness of the middle pulmonary artery was significantly reduced and pulmonary artery vessel remodeling was inhibited by the simultaneous modeling of the middle pulmonary artery and MaR1 treatment groups compared to the modeling module.
EXAMPLE 2 investigation of the protective Effect of MaR1 on pulmonary hypertension Using the mouse pulmonary hypertension model
The experimental object: 8-10 week old healthy male SPF grade C57BL/6 mice purchased from Liaoning Changsheng Biotechnology Co., ltd and bred in SPF grade animal houses at university of Dalian medical university. The raising environment is maintained at the room temperature of 20-25 ℃ and the relative humidity of 50-60%, the lighting is carried out for 12h/d, and the people can drink and eat food freely. Conventional mouse feed is provided by Jiangsu Meidisen biological medicine Co. The treatment of animals during the experiment meets the ethical standards of animals.
Pulmonary artery high pressure model establishment: mice were induced with hypoxia in combination with SU5416 (from MCE company, cat No. HY-10374) to have pulmonary hypertension model with a hypoxia chamber oxygen content of 10% for the model, and SU5416 was subcutaneously injected at 20mg/kg body weight 3 times at the beginning of the experiment (day 0) and 7 days, 14 days after modeling. The control group was normally fed with normoxic (21%) and injected subcutaneously with the same volume of DMSO solvent at the beginning of the experiment and 7 and 14 days after modeling, after 21 days, the modeling was completed.
MaR1 the composition can reduce right ventricular blood pressure and right ventricular hypertrophy of mice
Hypoxia combined with SU5416 induced pulmonary artery model of mice MaR1 treatment groups were intraperitoneally injected MaR1 ng/day with the same volume of saline as control groups. As shown in fig. 3, after the molding of the hypoxia combined SU5416, the right ventricular blood pressure and the right ventricular hypertrophy index of the mice are obviously increased, and the molding is carried out, and the administration of MaR1 simultaneously obviously reduces the right ventricular blood pressure of the mice, reduces the right ventricular hypertrophy and has a protective effect on pulmonary arterial hypertension.
MaR1 alleviating pulmonary arterial hypertension vessel remodeling in mice
The results of HE staining of lung tissue sections are shown in fig. 4, and modeling with MaR1 treatment significantly inhibited pulmonary artery vascular remodeling compared to modeling.
EXAMPLE 3 investigation of the therapeutic Effect of MaR1 on pulmonary arterial hypertension Using rat pulmonary arterial hypertension model
The experimental object: healthy male SPF-grade SD rats of 8-10 weeks old, weighing 200-250g, purchased from Liaoning Changsheng Biotechnology Co., ltd, and bred in SPF-grade animal houses at university of Dalian medical science. The raising environment is maintained at the room temperature of 20-25 ℃ and the relative humidity of 50-60%, the lighting is carried out for 12h/d, and the people can drink and eat food freely. Conventional rat feed is provided by Jiangsu Meidisen biomedical Co. The treatment of animals during the experiment meets the ethical standards of animals.
MaR1 dosing regimen: the molding is completed after 21 days by injecting 60mg/kg MCT once through subcutaneous injection, and after 14 days, maR1 treatment group injecting MaR 1.1 ng/kg abdominal cavity once through subcutaneous injection for 21 days, and molding is completed after 21 days.
After molding, maR1 is given to reduce the right ventricular blood pressure of the rat, relieve the right ventricular hypertrophy and inhibit pulmonary artery vascular remodeling, and MaR1 has a therapeutic effect on pulmonary arterial hypertension.
After MCT-induced modeling of the pulmonary artery model of the rat, maR1 administration group was continuously injected with MaR1 ng/unit for 7 days as shown in fig. 5, the MCT-made group significantly increased the right ventricular blood pressure and right ventricular hypertrophy index of the rat, and the MaR 1-treated group significantly decreased the right ventricular blood pressure and right ventricular hypertrophy of the rat compared to the MCT-made group. The results of HE staining of lung tissue sections are shown in fig. 6, and administration of MaR after molding significantly inhibited pulmonary artery vascular remodeling compared to MCT molding. In conclusion, maR1 treatment group rats had significantly reduced right ventricular blood pressure, right ventricular hypertrophy and reduced pulmonary artery vascular remodeling, and MaR had therapeutic effects on pulmonary arterial hypertension.
The present application is described in detail above. It will be apparent to those skilled in the art that the present application can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the application and without undue experimentation. While the application has been described with respect to specific embodiments, it will be appreciated that the application may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the application following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the application pertains.
Claims (6)
- Use of mar1 in the manufacture of a medicament for the prevention and/or treatment of pulmonary hypertension.
- 2. The use according to claim 1, characterized in that: the application is MaR1 in preparing medicines for inhibiting occurrence and development of pulmonary arterial hypertension.
- 3. The use according to claim 1, characterized in that: the application is MaR1 in preparing a medicine for inhibiting pulmonary artery vascular remodeling.
- 4. The use according to claim 1, characterized in that: the application is MaR1 in the preparation of medicaments for reducing right ventricular blood pressure.
- 5. The use according to claim 1, characterized in that: the application is MaR1 in the preparation of a medicament for reducing the right ventricular hypertrophy index.
- 6. The use according to claim 1, characterized in that: the application is MaR1 in the preparation of medicaments for relieving pulmonary artery vascular injury.
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| CN202210364270.5A CN116919937A (en) | 2022-04-08 | 2022-04-08 | Application of novel anti-inflammatory mediator MaR1 in preparation of medicines for preventing and/or treating pulmonary arterial hypertension |
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