CN114522221B - Application of secreted protein CTGF in preparation of medicine for treating acute lung injury - Google Patents
Application of secreted protein CTGF in preparation of medicine for treating acute lung injury Download PDFInfo
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- CN114522221B CN114522221B CN202210185007.XA CN202210185007A CN114522221B CN 114522221 B CN114522221 B CN 114522221B CN 202210185007 A CN202210185007 A CN 202210185007A CN 114522221 B CN114522221 B CN 114522221B
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Abstract
The invention relates to an application of secreted protein CTGF in preparing medicines for treating acute lung injury, wherein the Connective Tissue Growth Factor (CTGF) is a downstream signal molecule of a Hippo-YAP signal path, consists of 349 amino acids, is rich in cysteine, can promote the repair of alveolar tissues, has remarkable curative effect, can be directly atomized and absorbed by pulmonary tissues through intravenous administration, improves the drug effect, and can be expressed in most tissue cells of a body without causing rejection reaction of the body, so that the alveoli of the body can be quickly repaired and the pulmonary function of the body can be recovered.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of secreted protein CTGF in preparation of medicines for treating acute lung injury.
Background
Acute lung injury (acute lung injury, ALI) refers to acute hypoxia respiratory insufficiency or respiratory failure caused by diffuse pulmonary interstitial and alveolar edema caused by injury of pulmonary capillary endothelial cells and alveolar epithelial cells in the course of non-cardiac diseases such as severe infection, shock, wound and burn, and Acute Respiratory Distress Syndrome (ARDS) may occur to some extent. Mata analysis performed in the clinical study published internationally in 1967-1994 showed a mortality rate of about 50% (3264 patients). Therefore, how to prevent and effectively treat acute lung injury reduces the incidence of acute respiratory distress syndrome, and is important for mortality rate of critical diseases.
At present, the main treatment methods of acute lung injury are respiratory support treatment and drug treatment, wherein the respiratory support treatment is divided into oxygen therapy, noninvasive mechanical ventilation and invasive mechanical ventilation, and the respiratory support modes can improve hypoxia, reduce respiratory work, relieve respiratory distress, and more effectively improve systemic hypoxia, prevent damage to functions of organs outside the lung, but have no substantial promotion effect on restoration of alveoli. However, new drug treatment methods are continuously developed, some are inhibiting inflammatory factors, reducing inflammatory reactions, some are improving oxygenation and correcting hypoxia, some are promoting absorption of liquid in the lung, such as body fluid management, glucocorticoid treatment, ketoconazole, pentoxifylline, liquid ventilation, nitric Oxide (NO), activated protein C and the like, and are still in clinical research stage, so that NO drug with obvious effect for treating acute lung injury exists at present.
The current treatment of acute lung injury mainly has the following problems:
First, prolonged mechanical ventilation can cause complications such as pneumatic injury to alveoli, sustained high airway pressure, especially high PEEP, can affect the amount of blood returned, respiratory tract infections, laryngeal injury, neonatal lung-bronchial dysplasia, and the like.
Second, although there are many therapeutic approaches, the reliable efficacy has not been determined so far. Pulmonary water clearance and fluid management, alveolar surfactant supplementation therapy, beta receptor agonist application, statin application, glucocorticoid application, anticoagulant application, antioxidant and enzyme inhibitor application, blood purification treatment, nutritional dryness pre-treatment, and the like, and effective treatment methods thereof are still continuously explored.
Therefore, in the treatment of acute lung injury, long-time respiratory support can cause complications, and the complications directly affect the lung repair of an organism, and although a plurality of drug treatment methods exist, no treatment method with obvious curative effect exists at present, so that the problems of reducing mechanical ventilation complications and enhancing the injury repair capability of alveoli are urgent to be solved.
Connective tissue growth factor (Connective tissue growth factor, CTGF), also known as fisp, βig-M2, and IGF-BP8, is a protein consisting of 349 amino acids:
When organism is in serious infection, shock, wound, burn and other non-heart diseases, the damage of pulmonary capillary endothelial cells and pulmonary alveolus epithelial cells causes diffuse pulmonary interstitial, pulmonary alveolus edema and a large amount of inflammatory cells to infiltrate, and Acute Lung Injury (ALI) is caused, and the research of protein chip measurement is carried out after the acute lung injury, the Hippo-YAP pathway of lung tissue is activated when the acute lung injury occurs, and the more serious the lung injury is, the more obvious the pathway is activated, and the rule of the pathway activation is consistent with the repair process of the acute lung injury. CTGF is a downstream effector molecule of the Hipo-yap pathway, so that the protein content of CTGF is consistent with the repair rule of acute lung injury in the lung injury repair process, and CTGF can promote the repair of lung tissues in acute lung injury and is a potential acute lung injury treatment drug.
When organism is in serious infection, shock, wound, burn and other non-heart diseases, the damage of pulmonary capillary endothelial cells and pulmonary alveolus epithelial cells causes diffuse pulmonary interstitial, pulmonary alveolus edema and a large amount of inflammatory cells to infiltrate, and Acute Lung Injury (ALI) is caused, and the research of protein chip measurement is carried out after the acute lung injury, the Hippo-YAP pathway of lung tissue is activated when the acute lung injury occurs, and the more serious the lung injury is, the more obvious the pathway activation is, and the rule of the pathway activation is consistent with the repair process of the acute lung injury. CTGF is a downstream effector molecule of the Hipo-yap pathway, so that the protein content of CTGF is consistent with the repair rule of acute lung injury in the lung injury repair process, and CTGF can promote the repair of lung tissues in acute lung injury and is a potential acute lung injury treatment drug.
Disclosure of Invention
The invention aims at the application of the secreted protein CTGF in preparing medicines for treating acute lung injury, which can effectively treat acute lung injury caused by the stimulation of Lipopolysaccharide (LPS) on lung tissues, inhibit infiltration of inflammatory cells after acute lung injury, promote rapid repair of injured alveoli and restore the lung functions of lung tissues.
The secreted protein CTGF is applied to preparation of medicines for treating acute lung injury.
The acute lung injury includes direct lung injury and indirect lung injury.
The direct lung injury comprises serious lung infection, gastric content inhalation, lung contusion, toxic gas inhalation, drowning, oxygen poisoning and induced lung injury.
The indirect lung injury severe infection comprises severe non-chest trauma, acute severe pancreatitis, massive blood transfusion, extracorporeal circulation and lung injury caused by diffuse intravascular coagulation.
The medicament promotes alveolar tissue repair.
The medicament inhibits infiltration of inflammatory cells.
The drug is administered intravenously.
The administration dosage is 20-50ug/kg per day.
The medicament is administered by nebulization.
The application of the invention, the Connective Tissue Growth Factor (CTGF) is a downstream signal molecule of a Hippo-YAP signal channel, consists of 349 amino acids, is rich in cysteine secretion growth factor, can promote the repair of alveolar tissues, has obvious curative effect, can be directly atomized and absorbed by pulmonary tissues through intravenous administration (CTGF molecular protein is stable, smaller and easy to atomize), improves the drug effect, and has expression in most tissue cells of a body, can not cause rejection reaction of the body, can quickly repair the pulmonary bubbles of the body and recover the pulmonary functions of the body.
In the process of non-heart-source diseases such as severe infection, shock, wound, burn and the like, diffuse pulmonary interstitial and alveolar edema are caused by injury of pulmonary capillary endothelial cells and alveolar epithelial cells, acute hypoxia respiratory insufficiency or respiratory failure is characterized by reduced lung volume, reduced lung compliance and serious ventilation/blood flow proportion imbalance, the acute lung injury is clinically represented by progressive hypoxia and respiratory distress, pulmonary imaging is represented by heterogeneous exudative lesions, causes of the acute lung injury are numerous, such as severe lung infection, pulmonary contusion, toxic gas inhalation, severe non-chest wound, acute severe pancreatitis and the like, the acute lung injury is classified into direct lung injury and indirect lung injury according to different inducing factors, the applicant adopts a classical LPS induced acute lung injury model of mice to carry out drug verification of CTGF treatment of the acute lung injury, the result shows that the dose of control secretion protein CTGF is 20-50 ug/kg/day, the lung tissue injury repair of mice after the acute lung injury can be promoted, and the lung injury can be enhanced by adopting a lung stimulator of 10 g/mL lung organ and the acute lung injury can be effectively enhanced by using the CTGF organ.
Drawings
FIG. 1 protein chip determines changes in HIPPO-YAP pathway following acute lung injury;
FIG. 2HIPPO-YAP pathway schematic;
FIG. 3CTGF security verification;
FIG. 4 in vivo validation of CTGF treatment effects;
figure 5 organoids verify CTGF therapeutic effects in vitro.
Detailed Description
Reagent (I)
1. Reagent: CTGF (brand: R & D, cat# 9237-CT-050);
t1 alpha/Podoplanin (Sigma, cat# 1995);
EpCAM (Abcam, cat# ab 187276);
dispase (brand: corning Biocoat, cat# 354235).
2. Sample source: wild type C57 mouse lung stem progenitor cells AEC2s cultured lung organoids, wild type C57 mice.
Second embodiment
Example 1
CTGF safety was verified by tail vein injection into mice using CTGF concentration gradients.
Male C57 mice of 6-8 weeks old are selected, LPS is injected into the trachea to prepare an acute lung injury model, CTGF is injected into tail veins according to the doses of 20ug/kg, 100ug/kg and 200ug/kg according to the weight of the mice, the administration interval time is 24 hours, and the administration is continuous for 7 days, lung tissues are taken out on the 21 st day after the administration is finished, and 4% paraformaldehyde fixation, paraffin embedding, slicing and Masson staining are carried out.
Masson staining results: it can be observed that the 20ug/kg dose group had no blue coloration of the lung tissue, showing no fibrosis of the lung tissue, the 100ug/kg dose group had a blue coloration of the lung tissue locally, showing a slight fibrosis of the lung tissue, the 200ug/kg dose group had a large amount of blue coloration of the lung tissue, showing fibrosis of the lung tissue, see fig. 3. Thus, when CTGF is used for treating acute lung injury at a concentration of 100ug/kg or 200ug/kg, fibrosis of lung tissue is caused, and when CTGF is used for treating acute lung injury at a concentration of 20ug/kg, fibrosis of lung tissue is not caused, so that CTGF is used for treating acute lung injury at a concentration of 20ug/kg, and safety is provided.
Example 2
Male C57 mice of 6-8 weeks old are selected, LPS is injected into the trachea to prepare an acute lung injury model, and the acute lung injury model is divided into an ALI group and a CTGF treatment group (ALI-CTGF), wherein the ALI-CTGF group is subjected to CTGF administration by tail intravenous injection according to the weight of the mice at a dosage of 20ug/kg, the administration interval time is 24 hours, and the administration is carried out for 7 days continuously, lung tissues are taken out on 3 rd, 5 th and 7 th days of the administration respectively, and 4% paraformaldehyde fixation, paraffin embedding, slicing and pathology detection HE staining are carried out.
HE staining results: acute Lung Injury (ALI) group was observed on day 3, with severe alveolar destruction in lung tissue, massive inflammatory cell infiltration, massive protein tissue exudation, and small red blood cell leakage; on day 3 of the ALI-CTGF group, a small amount of inflammatory cell infiltration in the alveoli, thickening of the alveolar septum, but no alveolar destruction, no protein tissue exudation, no erythrocyte leakage were observed; on day 5 of ALI group, right obvious alveolus in lung tissue is damaged, a large amount of inflammatory cells infiltrate, protein tissue exudes, and red blood cells do not leak; on day 5 of the ALI-CTGF group, no inflammatory cell infiltration of alveoli, complete alveoli structure, no protein tissue exudation and no erythrocyte leakage were observed; on day 7 of the ALI group, local alveoli in lung tissues are damaged, alveoli compartments are thickened, inflammatory cells are clear and moist, local small amount of protein tissues exude, and red blood cells are not leaked; on day 7 of the ALI-CTGF group, no inflammatory cells were observed in the alveoli, the lung alveoli had intact structure, no protein tissue exudation, no leakage of erythrocytes, and experimental results suggested that administration of CTGF after the occurrence of acute lung injury promoted repair of lung injury (inhibited inflammation cells from becoming clear), see fig. 4.
Example 3
Selecting 6-8 week old male C57 mice, injecting anaesthetic animal into 2% pentobarbital at 60mg/kg dosage, sterilizing with 75% alcohol, taking out lung tissue, ophthalmic shearing the lung tissue, adding 10U/MLDISPASE digestive enzyme, digesting 45min in 37 ℃ water bath, filtering with 200 meshes, collecting cells, adding 2ul T1 alpha into 1:500, incubating at 4 ℃ for 30min, washing three times, adding donkey anti-mouse magnetic bead secondary antibody, incubating at 4 ℃ for 15min, passing magnetic bead sorting plate through column, adding T1 alpha-cells into 1:400, adding 2ul EpCAM, incubating at 4 ℃ for 30min, washing, adding donkey anti-rabbit magnetic bead secondary antibody, incubating at 4 ℃ for 15min, sorting T1 alpha-EpCAM+ cells, culturing according to 1.5x10 5/cm 2 mixed culture with Matrigel, culturing for 24h, culturing for one group as NS group, culturing with MTEC medium, culturing for another group as CTGF group, adding 10ng/ml CTGF medium into MTEC, culturing for two groups, and observing the growth law of the two groups by microscopic observation.
CTGF stimulated lung organoid assay results: in vitro culture of lung organoids, CTGF stimulated lung organoid group grew at a significantly faster rate than NS group lung organoids, and organoid sphere diameter 1-2 times greater than NS group, experimental conclusion: CTGF promotes proliferation and differentiation of pulmonary devices, see figure 5.
Sequence listing
<110> Chinese people liberation army characteristic medical center
<120> Application of secreted protein CTGF in preparation of medicine for treating acute lung injury
<141> 2022-02-25
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 349
<212> PRT
<213> Artificial sequence (ARTIFICIAL SEQUENCE)
<400> 1
Met Thr Ala Ala Ser Met Gly Pro Val Arg Val Ala Phe Val Val Leu
1 5 10 15
Leu Ala Leu Cys Ser Arg Pro Ala Val Gly Gln Asn Cys Ser Gly Pro
20 25 30
Cys Arg Cys Pro Asp Glu Pro Ala Pro Arg Cys Pro Ala Gly Val Ser
35 40 45
Leu Val Leu Asp Gly Cys Gly Cys Cys Arg Val Cys Ala Lys Gln Leu
50 55 60
Gly Glu Leu Cys Thr Glu Arg Asp Pro Cys Asp Pro His Lys Gly Leu
65 70 75 80
Phe Cys His Phe Gly Ser Pro Ala Asn Arg Lys Ile Gly Val Cys Thr
85 90 95
Ala Lys Asp Gly Ala Pro Cys Ile Phe Gly Gly Thr Val Tyr Arg Ser
100 105 110
Gly Glu Ser Phe Gln Ser Ser Cys Lys Tyr Gln Cys Thr Cys Leu Asp
115 120 125
Gly Ala Val Gly Cys Met Pro Leu Cys Ser Met Asp Val Arg Leu Pro
130 135 140
Ser Pro Asp Cys Pro Phe Pro Arg Arg Val Lys Leu Pro Gly Lys Cys
145 150 155 160
Cys Glu Glu Trp Val Cys Asp Glu Pro Lys Asp Gln Thr Val Val Gly
165 170 175
Pro Ala Leu Ala Ala Tyr Arg Leu Glu Asp Thr Phe Gly Pro Asp Pro
180 185 190
Thr Met Ile Arg Ala Asn Cys Leu Val Gln Thr Thr Glu Trp Ser Ala
195 200 205
Cys Ser Lys Thr Cys Gly Met Gly Ile Ser Thr Arg Val Thr Asn Asp
210 215 220
Asn Ala Ser Cys Arg Leu Glu Lys Gln Ser Arg Leu Cys Met Val Arg
225 230 235 240
Pro Cys Glu Ala Asp Leu Glu Glu Asn Ile Lys Lys Gly Lys Lys Cys
245 250 255
Ile Arg Thr Pro Lys Ile Ser Lys Pro Ile Lys Phe Glu Leu Ser Gly
260 265 270
Cys Thr Ser Met Lys Thr Tyr Arg Ala Lys Phe Cys Gly Val Cys Thr
275 280 285
Asp Gly Arg Cys Cys Thr Pro His Arg Thr Thr Thr Leu Pro Val Glu
290 295 300
Phe Lys Cys Pro Asp Gly Glu Val Met Lys Lys Asn Met Met Phe Ile
305 310 315 320
Lys Thr Cys Ala Cys His Tyr Asn Cys Pro Gly Asp Asn Asp Ile Phe
325 330 335
Glu Ser Leu Tyr Tyr Arg Lys Met Tyr Gly Asp Met Ala
340 345
Claims (3)
1. Use of the secreted protein CTGF for the preparation of a medicament for the treatment of acute lung injury caused by pulmonary tissue after stimulation with lipopolysaccharide, the medicament being administered at a dose of 20ug/kg per day.
2. The use according to claim 1, characterized in that: the drug is administered intravenously.
3. The use according to claim 1, characterized in that: the medicament is administered by nebulization.
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4411499A (en) * | 1998-06-05 | 1999-12-20 | Human Genome Sciences, Inc. | Connective tissue growth factor-4 |
| WO2012061811A2 (en) * | 2010-11-05 | 2012-05-10 | Fibrogen, Inc. | Treatment method for lung remodeling diseases |
| AU2012242768B2 (en) * | 2011-04-12 | 2017-10-12 | Moerae Matrix, Inc. | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
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Non-Patent Citations (4)
| Title |
|---|
| miR-26a-5p alleviates lipopolysaccharide‑induced acute lung injury by targeting the connective tissue growth factor;Hongyan Li等;Molecular Medicine Reports;第23卷(第1期);文献号：5 * |
| The Hippo-YAP pathway regulates the proliferation of alveolar epithelial progenitors after acute lung injury;Chen Hu等;Cell Biology International;第43卷(第10期);第1174-1183页 * |
| YAP activity protects against endotoxemic acute lung injury by activating multiple mechanisms;Ling‑Yan Liu等;International Journal of Molecular Medicine;第46卷(第6期);第2235-2250页 * |
| Yes激酶相关蛋白活化对急性肺损伤修复的影响及其机制;黄天鹏等;中国临床药理学与治疗学;第25卷(第3期);摘要，第2.1、2.4节，图1、图3 * |
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