CN113274389A - Application of flufenidone in preparation of medicine for treating acute lung injury - Google Patents
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- CN113274389A CN113274389A CN202110777599.XA CN202110777599A CN113274389A CN 113274389 A CN113274389 A CN 113274389A CN 202110777599 A CN202110777599 A CN 202110777599A CN 113274389 A CN113274389 A CN 113274389A
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Abstract
The invention discloses an application of flufenidone in preparation of a medicine for treating acute lung injury, wherein the acute lung injury is caused by lipopolysaccharide and/or hydrochloric acid, and the administration dosage of the flufenidone to a human body is 64.1 mg/kg/day. The flufenidone can reduce the death rate of lipopolysaccharide-induced acute lung injury mice, relieve the infiltration degree of inflammatory cells in the lung, and reduce the level of inflammatory factors and protein concentration in alveolar lavage fluid; meanwhile, the flufenidone can also reduce the levels of inflammatory factors, chemokines and total protein concentration in the alveolar lavage fluid of mice with acute lung injury induced by hydrochloric acid. In general, the medicine prepared from the flufenidone (namely 1- (3-fluorophenyl) -5-methyl-2 (1H) pyridone) has a relieving effect on acute lung injury, and can be used as a novel candidate therapeutic medicine for the acute lung injury.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of 1- (3-fluorophenyl) -5-methyl-2 (1H) pyridone (called 'flufenidone' for short) in preparation of a medicine for treating acute lung injury.
Background
Acute Lung Injury (ALI) is a life-threatening disease with high mortality and morbidity, and if not timely treated, can develop Acute Respiratory Distress Syndrome (ARDS) within hours to days, clinically manifested as severe hypoxemia and dyspnea. Acute lung injury is caused by a variety of causes, including trauma, inhalation of toxic/corrosive gases, pneumonia caused by infection with various pathogens, and severe sepsis [1 ]. In addition, aspiration of acidic gastric contents is also a common complication in clinical anesthesia and perioperative period, and the acidic liquid entering the lung causes corrosive damage to epithelial cells, which can also cause acute lung injury. When acute lung injury caused by lung infection or sepsis, etc. progresses to the ARDS stage, the therapeutic effect of antibacterial drugs, etc. gradually becomes poor, and the death rate at this stage is considerably high. The incidence of ALI and ARDS in the united states is reported to be 79/10 million per year and 59/10 million per year, respectively, with a mortality rate of about 35% to 40%. However, the currently clinically recommended treatment measures for reducing the ALI/ARDS mortality rate are only mechanical ventilation support treatment, and there are no drugs with positive curative effects in terms of drug therapy, such as hormone shock therapy and the like, and some studies show that the use of hormones can not improve the death outcome of patients and has the risk of causing superinfection; other immunity-improving drugs only have an auxiliary effect on the whole body. Currently, there is no effective drug that can significantly reduce the mortality of ALI/ARDS. Therefore, the development of effective drugs for treating ALI/ARDS is at hand. Acute lung injury models commonly used in pharmaceutical research are Lipopolysaccharide (LPS) and hydrochloric acid-induced animal models, LPS is a major virulence factor of the cell wall of gram-negative bacteria, is an important lung injury-inducing factor, and has been widely used to simulate acute lung injury to evaluate effective anti-inflammatory drug candidates. LPS intratracheal instillation is a classic acute lung injury construction method, and the characteristics of the acute lung injury of mice constructed by the method are similar to those of human acute lung injury. The intratracheal instillation of hydrochloric acid (HCl) is also a common animal model which is generally adopted at home and abroad at present to simulate the inhalation of haze acidic substances or other corrosive gases and the inhalation of acidic gastric contents to cause acute lung injury.
Flufenidone [1- (3-fluorophenyl) -5-methyl-2 (1H) ] is a novel pyridone small molecular compound, can be used for treating liver, lung and other multi-organ fibrosis in preclinical research, and is approved by the national drug administration to carry out anti-hepatic fibrosis phase 2 drug clinical test. Pulmonary fibrosis and acute lung injury are two completely different diseases, the pulmonary fibrosis is that the excessive deposition of fibroblasts and extracellular matrix such as collagen causes the structural destruction of the lung in various persistent injuries (such as immunity, aging and the like) for years to decades, while the pathogenesis of the acute lung injury is mainly that under strong stimulus or physical stimulus, a large number of alveolar epithelial cells are damaged in a short time to cause the apoptosis, necrosis and formation of the pulmonary hyaline membrane of the diffuse alveolar epithelial cells; meanwhile, macrophages and neutrophils are induced to the lung, releasing a large amount of proinflammatory factors and inflammatory factors, and a local strong inflammatory response leads to severe pulmonary ventilation dysfunction. At present, no research on the curative effect of flufenidone on acute lung injury exists. Therefore, the invention aims to further define the treatment effect of the flufenidone on acute lung injury by examining the influence of the flufenidone on mice with acute lung injury induced by LPS and HCl.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects and shortcomings in the background technology, provide a new application of flufenidone in preparing a medicine for treating acute lung injury, and provide a new candidate medicine for treating acute lung injury. The whole animal experiment proves that the flufenidone has obvious effect of treating acute lung injury induced by lipopolysaccharide and hydrochloric acid.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
an application of flufenidone in preparing a medicament for treating acute lung injury, wherein the acute lung injury is caused by lipopolysaccharide and/or hydrochloric acid.
For the above application, preferably, the administration dosage of the flufenidone to a human body is 64.1 mg/kg/day.
Compared with the prior art, the invention has the beneficial effects that:
the flufenidone can reduce the death rate of lipopolysaccharide-induced acute lung injury mice, relieve the infiltration degree of inflammatory cells in the lung, and reduce the level of inflammatory factors and protein concentration in alveolar lavage fluid; meanwhile, the flufenidone can also reduce the levels of inflammatory factors, chemokines and total protein concentration in the alveolar lavage fluid of mice with acute lung injury induced by hydrochloric acid.
The results show that the medicine prepared from the flufenidone (namely 1- (3-fluorophenyl) -5-methyl-2 (1H) pyridone) has a relieving effect on acute lung injury, and can be used as a novel candidate therapeutic medicine for acute lung injury. The flufenidone is a new indication for the medicine to treat acute lung injury.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a graph of the survival of mice with LPS-induced acute lung injury reduced by flufenidone;
FIG. 2 is a graph of the reduction of LPS-induced lung inflammation by Flufenidone, HE staining in mice with acute lung injury;
FIG. 3 is a graph of total protein concentration in alveolar lavage fluid from LPS-reduced mice with flufenidone;
FIG. 4 is a graph showing that flufenidone reduces the level of IL-1 β expression in alveolar lavage fluid from LPS-induced acute lung injury mice;
FIG. 5 is a graph of flufenidone reducing MCP-1 mRNA transcript levels in lung tissue of lipopolysaccharide-induced acute lung injury mice;
FIG. 6 is a graph showing that flufenidone reduces the level of TNF- α expression in alveolar lavage fluid from LPS-induced acute lung injury mice;
FIG. 7 is a graph of total protein concentration in alveolar lavage fluid from mice with hydrochloric acid-induced acute lung injury reduced by flufenidone;
FIG. 8 is a graph showing that flufenidone reduces IL-1 β expression levels in alveolar lavage fluid from acute lung injury mice induced by hydrochloric acid;
FIG. 9 is a graph showing that flufenidone reduces IL-6 expression levels in alveolar lavage fluid from mice with acute lung injury induced by hydrochloric acid.
Detailed Description
In order to facilitate understanding of the invention, the invention will be described more fully and in detail with reference to the accompanying drawings and preferred embodiments, but the scope of the invention is not limited to the specific embodiments below.
Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
Example 1:
an application of flufenidone in preparing the medicine for treating acute lung injury is disclosed.
To demonstrate the efficacy of flufenidone in the preparation of a medicament for the treatment of acute lung injury, the present example provides the following experiments, the experimental procedures of which are as follows:
1. materials and reagents
Flufenidone (lot No. 20150516, Haitan province Haikou pharmaceutical factory); lps (sigma); concentrated hydrochloric acid; IL-1. beta., TNF-. alpha., IL-6ELISA kit (Thermo Fisher); MCP-1 primer (Biotech).
2. Laboratory animal
Male C57BL/6J mice, clean grade, were purchased from Changsha lechleri Limited liability company.
3. Experimental methods
3.1 preparing lipopolysaccharide-induced acute lung injury mouse model, observing the curative effect of the flufenidone on treating acute lung injury
32 clean grade C57BL/6J mice (8 weeks old, male, 20-22g in weight) were randomized into 3 groups: control group, lipopolysaccharide model group, lipopolysaccharide + flufenidone treatment group, 8 each group. After adaptive feeding for 1 week, the lipopolysaccharide model group and the lipopolysaccharide and flufenidone group are injected with lipopolysaccharide solution (4mg/kg, the preparation concentration of the suspension is 4mg/ml in advance) through an intratracheal drip, a control group is injected with physiological saline with the same volume through an intratracheal drip, wherein, the mice of the lipopolysaccharide and flufenidone treatment group are subjected to intragastric gavage treatment by the flufenidone solution dissolved in 0.5 percent CMCNa at 3 days before the model building (500mg/kg/day, once a day and 3 days of continuous administration), the mice of the control group and the lipopolysaccharide model group are subjected to intragastric gavage by CMCNa with the same volume, and all the mice are killed at 48 hours after the model building.
48 clean grade C57BL/6J mice (8 weeks old, male, 20-22g in weight) were also numbered and randomized into 2 groups: and the lipopolysaccharide model group and the lipopolysaccharide plus flufenidone treatment group are 24 mice in each group, the treatment method of each group of mice is the same as that of the mice, the survival condition of the mice is observed and recorded every 6 hours after the model is made, and the observation is stopped until the mice are not dead for 72 hours continuously.
3.2 preparing mouse model of acute lung injury induced by hydrochloric acid, observing the curative effect of flufenidone on acute lung injury
32 clean grade C57BL/6J mice (8 weeks old, male, 20-22g in weight) were randomized into 3 groups: control group, hydrochloric acid model group, hydrochloric acid + flufenidone treatment group, 8 of each group. After adaptive feeding for 1 week, intratracheally instilling a hydrochloric acid solution (1.5ml/kg, the prepared concentration of the hydrochloric acid solution is 0.1N in advance, the pH value is adjusted to 1) in a hydrochloric acid model group and a hydrochloric acid and flufenidone group, intratracheally instilling an isometric physiological saline in a control group, wherein, the intratracheally instilling treatment is carried out on the mice in the hydrochloric acid and flufenidone treatment group by starting to instill a flufenidone solution dissolved in 0.5 percent CMCNa in 3 days before the molding (500mg/kg/day, continuous administration is carried out for 3 days), the intratracheally instilling treatment is carried out on the mice in the control group and the hydrochloric acid model group by the CMCNa with the same volume, and all the mice are killed at 48 hours after the molding.
The chest of the mouse is opened, the lung is taken out, the left lung is taken out and fixed in 10 percent paraformaldehyde for pathological examination after the right ventricle is fully irrigated, and the right lung is placed in a liquid nitrogen tank after the right lung is divided into leaves. The degree of lung inflammatory cell infiltration was observed by paraffin section line HE staining. Inflammatory factors in alveolar lavage fluid and lung tissues are detected by an ELISA method or a qt-PCR method, apoptosis marker expression level in lung tissues is detected by Western-blot, and total protein concentration in the alveolar lavage fluid is detected by a BCA method.
The pulmonary inflammation degree is analyzed by referring to a scoring method adopted by SusanV, and the like according to the pulmonary alveolitis scoring standard, wherein the scoring standard is as follows: grade 0 (integral 0) is alveolitis free; grade I (score 1) is mild alveolitis, namely, mononuclear cell infiltration is seen to thicken alveolus intervals, but lesions are limited, the area accounts for less than 20% of the whole lung, and the alveolus structure is basically normal; grade II (score 2) is moderate alveolitis, i.e. the affected area accounts for about 20-50% of the whole lung; grade iii (score 3) is severe alveolitis, i.e. the affected area accounts for more than 50% of the whole lung, and there are occasionally monocytes in the alveolar cavities and lung consolidation due to hemorrhage; grade IV (score 4) is severe alveolitis, i.e. the affected area is over 75% of the whole lung, with mononuclear cells in the alveolar cavities and lung consolidation due to bleeding.
And randomly selecting 10 fields of 100 times of each section for scoring, and taking the average value as the score value of the sample.
4. Statistical method
All the measurement data are as follows
The comparisons between groups are shown to be analyzed by one-way variance (ANOVA) and the mouse death curves by log-rank. P<0.05 the difference was considered statistically significant.
5. Results of the experiment
5.1 Lipopolysaccharide acute Lung injury mortality in mice
The mice in the lipopolysaccharide model group began to die at 6 hours after the model creation, the lipopolysaccharide + flufenidone treatment group began to die at 48 hours, and the death curves showed that the mortality rate of the mice in the lipopolysaccharide + flufenidone treatment group was significantly lower than that in the lipopolysaccharide model group (survival count of AKF-PD treatment group: 10/24; survival count of LPS model group: 3/24, p ═ 0.02), as shown in FIG. 1.
5.2HE staining results
The alveolar structure of the blank control group of mice is basically normal when observed under a light mirror, the alveolar wall is intact, no obvious lesion exists, and no inflammatory cells are distributed; the pulmonary alveolar structure of a mouse with the lipopolysaccharide model group is obviously damaged and disordered, a large number of mixed inflammatory cells (including macrophages and neutrophils) are subjected to diffuse infiltration, part of lung tissues are seriously changed, and erythrocytes in the pulmonary alveolar cavity and a small amount of collagen deposition in interstitium can be seen; the degree of alveolar structural disorder and inflammatory cell infiltration of the lipopolysaccharide and flufenidone treatment group are obviously reduced compared with the model group, the pulmonary alveolar structural disorder and the inflammatory cell infiltration are basically not changed and bleed (see figure 2), and the pneumonia score is obviously reduced (see table 1).
TABLE 1 mouse alveolar inflammation scores for each group
Compared with normal group, P <0.05, compared with model group, P <0.01
5.3 lipopolysaccharide acute Lung injury mouse alveolar lavage fluid and Total protein concentration, inflammatory factor/chemokine level in Lung tissue
Compared with the blank control group, the total protein concentration, the IL-1 beta and TNF-alpha levels and the MCP-1 mRNA level in the lung tissue of the alveolar lavage fluid of mice in the lipopolysaccharide model group are obviously increased (p <0.05), and the total protein concentration, the IL-1 beta and TNF-alpha levels and the MCP-1 mRNA level in the alveolar lavage fluid of the mice in the flufenidone treatment group and the lung tissue are obviously reduced (p <0.05) compared with the mice in the lipopolysaccharide model group, as shown in the figure 3, the figure 4, the figure 5 and the figure 6.
5.4 Total protein concentration and inflammatory factor levels in acute Lung injury mouse alveolar lavage fluid induced by hydrochloric acid
Compared with the blank control group, the total protein concentration, IL-1 beta and IL-6 levels in the alveolar lavage fluid of the mice in the hydrochloric acid model group are obviously increased (p <0.05), and the total protein concentration, IL-1 beta and IL-6 levels in the alveolar lavage fluid of the mice in the flufenidone treatment group are obviously reduced (p <0.05) compared with the mice in the hydrochloric acid model group, as shown in figure 7, figure 8 and figure 9.
6. Conclusion of the experiment
The flufenidone can effectively treat lipopolysaccharide and hydrochloric acid induced acute lung injury mice, and the drug dose conversion is carried out according to the weight of the mice being 20g and the weight of the human body being 60 kg: the administration dose of the mouse is 500mg/kg/day, and the administration dose corresponding to the human body is as follows: 64.1mg/kg/day, i.e., 3200 mg/day. The conversion equation was mouse dose (mg/kg/day) to 7.8 human dose (mg/kg/day). Accordingly, the present invention provides that the dosage of flufenidone administered is 64.1 mg/kg.
Claims (2)
1. The application of the flufenidone in preparing the medicine for treating acute lung injury is characterized in that the acute lung injury is acute lung injury caused by lipopolysaccharide and/or hydrochloric acid.
2. The use of claim 1, wherein said flufenidone is administered to a human at a dose of 64.1 mg/kg/day.
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