KR20110037784A

KR20110037784A - Pharmaceutical composition for the treatment of acute lung injury and acute respiratory distress syndrome, containing 5-(6-quinoxalinylmethylene)-2,4-thiazolidione as an active ingredient

Info

Publication number: KR20110037784A
Application number: KR1020090095352A
Authority: KR
Inventors: 이용철
Original assignee: 전북대학교산학협력단; 전북대학교병원
Priority date: 2009-10-07
Filing date: 2009-10-07
Publication date: 2011-04-13

Abstract

The present invention provides a pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome containing 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (Cas No: 648450-29-7) do.

Compound 5- (6-quinoxalinylmethylene) -2,4-thiazolidinedione of the present invention is an inflammatory cell such as lymphocytes, neutrophils, or eosinophils that cause inflammation of airway mucosal tissues. Cytokines which prevent the inflow into bronchoalveolar alveoli, alleviate airway hypersensitivity, inhibit the expression of vascular endothelial growth factor (VEGF) in lung tissue, reduce vascular permeability of bronchoalveolar alveoli, and inflame lung tissue By suppressing the expression of cytokines and cell adhesion molecules, it can be effectively used for the treatment of acute lung injury and acute respiratory distress syndrome.

Description

Pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome containing 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione as an active ingredient respiratory distress syndrome, containing 5- (6-quinoxalinylmethylene) -2,4-thiazolidione as an active ingredient}

The present invention relates to a pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome, and more particularly, to acute containing 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione as an active ingredient. The present invention relates to a pharmaceutical composition for treating lung damage and acute respiratory distress syndrome.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are one of the most clinically important diseases due to high morbidity and mortality in both adults and children.

Acute lung injury and acute respiratory distress syndrome have the same pathophysiological mechanism, but are classified according to the severity of the disease and do not have high left atrial pressure according to the diagnostic criteria of the American-European consensus conference. Pulmonary edema with increased shadow on both lungs under left atrial pressure (18 mmHg or less), with PaO ₂ / FiO ₂ values below 300 defined as acute lung injury and below 200 defined as acute respiratory distress syndrome. (Bernard GR, et al .; The American-European Consensus Conference on ARDS .; Definitions, mechanisms, relevant outcomes, and clinical trial coordination .; Am J Respir Crit Care Med 1994; 149: 818-24.).

Acute lung injury or acute respiratory distress syndrome ultimately leads to severe inflammatory reactions in the lungs (pulmonary ARDS) or pulmonary vessels (extra-pulmonary ARDS), resulting in various pathophysiological phenomena (Gunther). A, Walmrath D, Grimminger F, Seeger W .; Pathophysiology of acute lung injury; Semin Respir Crit Care Med 2001; 22: 247-58). The pathological findings of acute lung injury are mainly due to the inflammatory response, which fills the alveoli with inflammatory cells and proteins instead of air, creates a vitreous membrane, and infiltrates the pulmonary interstitium.

Several cytokines play a role in this process, especially in the case of blood clotting (Suter PM, Suter S, Girardin E, Roux-Lombard P, Grau GE, Dayer JM; High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis .; Am Rev Respir Dis 1992; 145: 1016-22).

As described above, acute lung injury is a pathological condition that can be caused by various causes. The acute lung injury is known to be accompanied by inflammatory cell infiltration, airway hypersensitivity, vascular permeability, and plasma exudation around the bronchus.

In relation to the treatment of acute lung injury, important proteins and inhibitors that act on various signaling systems have been studied.

On the other hand, PI3K is a representative lipid signaling kinase in vivo, and was initially known to be associated with receptors for various tumor-inducing proteins and growth factors, but recently, it is a key element in various signal transmissions related to cell proliferation, survival, or differentiation. It has been found that various functions of PI3K are activated through several receptors.

PI3K is further divided into Class I, II, and III, of which Class I is the most studied group.

PI3Kγ is a subtype of class I PI3K, more specifically class IB. Recently, as PI3Kγ is known to be involved in the pathophysiology of autoimmune diseases, research is being conducted on the role of PI3Kγ in various inflammatory diseases, and in particular, the study of PI3Kγ protein expression through genetic manipulation in the field of treatment of autoimmune diseases It is actively underway.

5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS605240), known as an inhibitor of PI3Kγ protein, has been shown to inhibit the action of PI3Kγ protein in rheumatoid arthritis animal models and vasculitis models. Therapeutic effects have been reported in rheumatoid arthritis and vasculitis.

However, rheumatoid arthritis, vasculitis disease, and acute lung injury disease differ in related media, inflammation mediators such as cytokines, and fundamental pathogenesis, making it difficult to apply the therapeutic agents developed in the inflammatory disease to acute lung injury disease. there was.

In particular, acute lung injury disease plays an important role in the development of constituent cells, such as bronchial and bronchial smooth muscle cells that make up the lungs, and other pathological symptoms of acute lung injury disease, even if merely inhibiting the inflammatory response For example, pathologies such as airway hypersensitivity tend to be untreated.

Therefore, there is a need to develop new therapeutic agents that can effectively treat various pathologies of acute lung injury disease.

In order to solve the above problems of the prior art, an object of the present invention is to provide a pharmaceutical composition having an excellent effect in suppressing acute lung injury and acute respiratory distress syndrome.

In addition, another object of the present invention is to effectively treat damaged lungs by using the pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome.

According to one embodiment of the present invention, the present invention provides acute lung injury containing 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (Cas No: 648450-29-7) Provided are pharmaceutical compositions for the treatment and acute respiratory distress syndrome.

[Formula 1]

In the present invention, the acute lung injury and acute respiratory distress syndrome have the same pathophysiological mechanism, the lung edema findings of increased shadow on both lungs on chest X-ray examination in the state of high left atrial pressure (less than 18 mmHg left atrial pressure) When the PaO ₂ / FiO ₂ value is less than 300, it is defined as acute lung injury, and if it is less than 200, it is defined as acute respiratory distress syndrome.

In the pharmaceutical composition of the present invention, the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione inhibits the influx of inflammatory cells into macrophages, lymphocytes, neutrophils, and eosinophils into lung tissue. Acute lung injury and acute respiratory distress syndrome can be treated.

In the pharmaceutical composition of the present invention, the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione inhibits the expression of vascular endothelial growth factor (VEGF) and causes acute lung injury and acute respiratory distress syndrome. Can cure.

In the pharmaceutical composition of the present invention, the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione can treat acute lung injury and acute respiratory distress syndrome by reducing vascular permeability of the bronchoalveolar alveoli.

In the pharmaceutical composition of the present invention, the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione is interleukin-1b (IL-1b), interleukin-8 (IL-8), and tumor necrosis By suppressing the expression of factor-alpha (TNF-a), acute lung injury and acute respiratory distress syndrome can be treated.

In the pharmaceutical composition of the present invention, the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione inhibits the expression of vascular cell adhesion molecule 1 (VCAM-1) to acute lung Injury and acute respiratory distress syndrome can be treated.

Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils, and the like. It is not limited.

In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

According to another aspect of the present invention, the present invention comprises the steps of administering a pharmaceutical composition containing the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione as an active ingredient to mammals other than humans Provided is a method for treating acute lung injury and acute respiratory distress syndrome disease in a mammal, except human.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, or humans in various ways, orally or parenterally, and in the case of parenteral administration, intraperitoneal injection, intravenous injection. , Subcutaneous, intramuscular, transdermal, or airway, or intraperitoneal.

Preferred dosages of the pharmaceutical compositions of the present invention vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, condition of food, time of administration, route of administration, rate of excretion and response to reaction, It may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at 0.001 to 500 mg / kg, preferably at 0.01 to 100 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.

The pharmaceutical compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container.

In this case, the formulation may be in the form of powder, granules, tablets, capsules, suspensions, emulsions, syrups, oral formulations of aerosols, external preparations, suppositories, or injections, and may further include dispersants or stabilizers.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for illustrating the present invention, and thus the scope of the present invention is not construed as being limited by these embodiments.

Hereinafter, 8-week-old female C57BL / 6 mice used in Examples were purchased from Orientbio Inc. (Seongnam, South Korea), and 5- (6-quinoxalinylmethylene) -2,4-thiazolidinedione ( AS 605240) used a product of Enzo Life Science, USA.

In addition, in the following experimental step, 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) was the first lipopolysaccharide (LPS, lipopolysaccharide) at doses of 10 mg and 30 mg, respectively, per mouse weight. ) Intraperitoneally administered two times before and two hours after inhalation.

Example One. AS Administered Changes in Inflammatory Cells During

Inflammation measured in bronchoalveolar lavage fluid when 5- (6-quinoxalinylmethylene) -2,4-thiazolidinedione (AS 605240) is administered in an acute lung injury mouse model induced by lipopolysaccharide (LPS) Changes in the cells were observed.

Changes in inflammatory cells were measured for fractional changes in total inflammatory cells and macrophage, lymphocytes, neutrophils, and eosinophils.

In order to observe changes in inflammatory cells, mice were treated with dimethyl sulfoxide (DMSO, dimethyl sulfoxide) as a drug vehicle at 10 mg / kg and 30 mg / kg doses of 5- (6-quinosali, respectively). Nimethylene) -2,4-thiazolidinedione (AS 605240) was administered, and bronchoalveolar alveoli obtained from each group were washed 12 hours after inhalation of lipopolysaccharide to quantify the inflammatory cells present in the alveolar lavage fluid, 1 is shown.

After inhaling saline, mice treated with dimethyl sulfoxide (DMSO) were used as the control (SAL + VEH), and lipopolysaccharide (LPS) was inhaled as the negative control (LPS + VEH). Mice treated with sulfoxide (DMSO, dimethyl sulfoxide) were used.

Referring to FIG. 1, inflammatory cells are increased more than four times in the negative control group (LPS + VEH) induced acute lung injury compared to the control group (SAL + VEH) without acute lung injury due to inhalation of lipopolysaccharide (LPS). Serious inflammatory reactions were found to occur. In negative controls, macrophage, lymphocytes, neutrophils, and eosinophils levels were all increased.

The increase in inflammatory cells induced by the lipopolysaccharide (LPS) significantly decreased in the group treated with 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240), 10 In the group treated with the mg / kg dose (LPS + AS 10 mg / kg), the total number of inflammatory cells measured was reduced, and macrophages, lymphocytes, neutrophils, and eosinophils, respectively, were measured. All the measured values for the items also decreased significantly.

Inflammatory cell levels measured as described above were further decreased with increasing dose of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240), and treated with 30 mg / kg dose. In the group (LPS + AS 30mg / kg), the reduction was less than 50% compared to the negative control.

Thus, 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) is a macrophage, lymphocyte, neutrophils, or inflammation that causes inflammation in airway mucosal tissues. It was found that acute lung injury and acute respiratory distress syndrome could be effectively treated by preventing inflammatory cells such as eosinophils from entering the bronchoalveolar alveoli.

Example 2. AS Airway hypersensitivity changes when administered 605240

Effect of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) on airway hypersensitivity following injury in lung tissue in acute lung injury mouse model induced by lipopolysaccharide (LPS) Was observed.

Airway hypersensitivity was assessed by measuring the changes in airway respiratory function after aerosol administration of methacholine through the airways.

For airway hypersensitivity measurement, C57BL / 6 mice were anesthetized with a pentobarbital, and the trachea was dissected.

Connect the animal respirator to the incisional organ and the mechanical nebulizer (single volume: 10 ml / kg, respiratory rate: 150 times / min, end-tidal pressure: 2 cm H ₂ O) while direct nebulizer through the ventilator. Methacholine was administered as the dose was gradually increased from 5.0 mg / ml to 50 mg / ml, and airway resistance (Rrs) was continuously measured.

Airway hypersensitivity was measured by evaluating the maximum value of airway resistance (Rrs) measured at each methacholine concentration as a percentage of the baseline of airway resistance (Rrs) measured in a control group administered saline instead of lipopolysaccharide (LPS). The results are shown in FIG. Inflammation of the airways causes narrowing of the airways, which increases airway resistance. As airway resistance increases, airway hyperresponsiveness increases. Airway hypersensitivity increases during acute lung injury.

Referring to FIG. 2, the negative control group (LPS + VEH) induced by acute lung injury by lipopolysaccharide (LPS) shifts the dose response curve to airway resistance to the left as compared to the saline-administered group (SAL + VEH). When the concentration of methacholine was higher than 10mg / ml, airway resistance (Rrs) increased significantly, and when the concentration of methacholine was higher than 25mg / ml, airway resistance (Rrs) increased more than 200%. This was observed.

However, in the group administered the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) of the present invention, the left displacement of the dose response curve observed in the negative control was alleviated. The airway resistance (Rrs) measurement also decreased.

Through the above results, 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) inhibits airway hypersensitivity, which is a major symptom of acute lung injury, and thus acute lung injury and acute respiratory distress syndrome. It can be seen that the effective treatment.

Example 3. AS At 605240 doses VEGF Changes in concentration and vascular permeability

Vascular Endothelial Growth Factor (VEGF) by Administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) in an Acute Lung Injury Mouse Model Induced by Lipopolysaccharide (LPS) And changes in vascular permeability.

To observe the changes in vascular endothelial growth factor (VEGF) and vascular permeability, mice were dosed at 10 mg / kg and 30 mg / kg of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione, respectively. (AS 605240), and bronchial alveolar lavage fluid from each group was isolated 12 hours after lipopolysaccharide inhalation. Separation of alveolar lavage fluid was performed by inserting a tube into the mouse airway, injecting 0.9% NaCl solution, and then sucking it with a syringe.

Vascular endothelial growth factor in the isolated alveolar lavage fluid was quantified by Western blot method using an anti-vascular endothelial growth factor antibody (Anti-VEGF antibody, Santa Cruz Biotechnology, Santa Cruz, CA). 3 is shown.

Vascular permeability was quantitatively analyzed using Evans blue dye (EBD), which was diluted to 5 mg / ml with 0.9% NaCl solution, and then diluted with 20 mg / kg of mouse vein at a dose of 20 mg / kg. After injection, mice were sacrificed 30 minutes later.

In order to evaluate how the vascular endothelial growth factor (VEGF) concentration change is related to the increase in vascular permeability, which is an important factor of pathophysiology, the vascular endothelial growth factor (VEGF) concentration and Evans blue die were measured. Vascular permeability was assessed using the Pearson's correlation test (SPSS v 16.0).

The results were expressed as the mean and standard error of the measured values obtained from 7 mice in each group.

Referring to FIG. 3, the negative control group (LPS + VEH, lane 2) induced acute lung injury compared to the saline treatment group (SAL + VEH, lane 1) without lung injury due to inhalation of lipopolysaccharide (LPS). The expression level of vascular endothelial growth factor (VEGF) was increased in alveolar lavage fluid but decreased with administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240). there was.

The phenomena of VEGF expression reduction were quantified using a densitometer, and are shown in FIG. 4. Referring to the graph of FIG. 4, 5- (6-quinanolinylmethylene) In the group treated with -2,4-thiazolidinedione (AS 605240), the expression of vascular endothelial growth factor was significantly decreased compared to the negative control induced with acute lung injury (LPS + VEH). In particular, in the group administered at a dose of 30 mg / kg (LPS + AS 30mg / kg), the expression of vascular endothelial growth factor (VEGF) decreased by about 50% compared to the negative control group, and almost reduced to the expression level of the saline treatment group. Could.

In addition, when analyzing the results of measuring the vascular permeability using the Evans blue die of Figure 5, Evans in the alveolar lavage of the negative control group (LPS + VEH) induced acute lung injury compared to the saline treatment group (SAL + VEH) The amount of blue die detected increased. Thus, it was found that vascular permeability in bronchial alveoli was increased in acute lung injury mice.

Increased vascular permeability in these lung-damaged mice was reduced by administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240), which was 5- (6-quinosalinylmethylene)- The decrease was more pronounced in the high dose group of 2,4-thiazolidinedione (AS 605240) (LPS + AS 30 mg / kg).

Referring to FIG. 6, the expression of the vascular endothelial growth factor (VEGF) and the increase in vascular permeability have increased plasma exudation as the expression of the vascular endothelial growth factor (VEGF) increases, resulting in a correlation coefficient of 0.735. The relationship was directly proportional.

Based on the above results, 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) of the present invention exerts an excessive immune response in acute lung injury through PI3K / Akt signaling system. By suppressing the expression of vascular endothelial growth factor (VEGF) and reducing the vascular permeability of the bronchoalveolar alveolar vascular endothelial growth factor (VEGF), it was found that it can be useful for the treatment of acute lung injury and acute respiratory distress syndrome.

Example 4. AS Cytokines when administered 605240 ( cytokine ) And changes in the expression of adhesion molecules

Interleukin-1b (IL-1b), Interleukin-8 (IL-8), and Tumor Necrosis Factors, Cytokines Important to the Pathophysiology of Acute Lung Injury Mouse Model Induced by Lipopolysaccharide (LPS) Changes in the expression of alpha (TNF-a) and vascular cell adhesion molecule 1 (VCAM-1) were observed.

In order to observe the expression changes of cytokines and cell adhesion molecules, 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (10 mg / kg and 30 mg / kg, respectively) was observed in mice. AS 605240) and bronchial alveoli obtained from each group were extracted 12 hours after lipopolysaccharide inhalation.

Quantification of interleukin-1b (IL-1b), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a), and VCAM-1 in the extracted bronchial alveoli by Western blot method 7 to 10 are shown.

The interleukin-1b was used as an anti-interleukin-1b antibody (anti-IL-1b antibody, ENDOGEN, Woburn, MA), and the interleukin-8 was an anti-interleukin-8 antibody (R & D). systems, USA), and the tumor necrosis factor-alpha was used as an anti-tumor necrosis factor-alpha antibody (Anti-TNF-alpha antibody, ENDOGEN, Woburn, MA), and the VCAM-1 was anti-VCAM- Western blot was performed using 1 antibody (anti-VCAM-1 antibody, Santa Cruz Biotechnology, Santa Cruz, CA).

After inhaling saline, mice treated with dimethyl sulfoxide (DMSO, dimethyl sulfoxide) were used as a control (SAL + VEH), and lipopolysaccharide (LPS) was inhaled as a negative control (LPS + VEH). Mice treated with dimethyl sulfoxide (DMSO, dimethyl sulfoxide) were used.

7 to 10, acute lung injury-induced negative control (LPS + VEH, lane 2) compared to the control group (SAL + VEH, lane 1) without acute lung injury due to inhalation of lipopolysaccharide (LPS) ) Increased expression of interleukin-1b (IL-1b), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a), and VCAM-1.

The increased expression of cytokines induced by the lipopolysaccharide (LPS) was significantly reduced in the group treated with 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240), In the group treated with the 10 mg / kg dose (LPS + AS 10 mg / kg, lane 3), interleukin-1b (FIG. 7), interleukin-8 (FIG. 8), tumor necrosis factor-alpha (FIG. 9), and VCAM-1 The expression level of FIG. 10 was significantly reduced.

In addition, as the dose of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) was increased, the expression of cytokines and cytoadhesion molecules gradually decreased, and thus 30 mg / kg dose. In the group treated with (LPS + AS 30 mg / kg), the expression of cytokines and VCAM-1 induced by lipopolysaccharide (LPS) was significantly suppressed, and reduced to the expression level of the control group treated with saline. It could be known.

Therefore, through the above results, 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) is inflamed to lung tissue through excessive immune response in acute lung injury and acute respiratory distress syndrome. It was found to inhibit the expression of cytokines and cell adhesion molecules.

As described above, the pharmaceutical composition containing 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) of the present invention causes excessive immune response and inflammation of airway mucosal tissues. Prevents inflammatory cells, such as macrophages, lymphocytes, neutrophils, or eosinophils, from entering the alveolar alveoli, inhibits airway hypersensitivity, and vascular endothelial growth factor (VEGF) It can be effectively used in the treatment of acute lung injury and acute respiratory distress syndrome by inhibiting the expression of, reducing the vascular permeability of bronchial alveoli, and inhibiting the expression of cytokines and cell adhesion molecules that cause inflammation of lung tissue. have.

1 is a graph showing the measured values of total inflammatory cells, macrophage, lymphocytes, neutrophils, and eosinophils present in alveolar lavage fluid after inhaling lipopolysaccharide (LPS) in mice. to be.

Figure 2 is a graph measuring airway resistance (Rrs) while administering methacholine to the trachea of the incision through the ventilator.

Figure 3 shows the inhalation of lipopolysaccharide (LPS) in lung tissue induced acute lung injury, after administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) in lung tissue. The photograph shows the results of Western blot analysis of the expression changes of vascular endothelial growth factor.

4 is a graph quantifying the expression of vascular endothelial growth factor in lung tissue by Western blot method, using a densitometer (#, p <0.05, versus SAL + VEH; *, p <0.05 versus LPS + VEH).

FIG. 5 shows Evans Blue Die after inhalation of lipopolysaccharide (LPS) and administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) to mice induced with acute lung injury. It is a graph measuring vascular permeability using (#, p <0.05, versus SAL + VEH; *, p <0.05 versus LPS + VEH).

Figure 6 is a graph showing the correlation between the concentration of vascular endothelial cell growth factor and vascular permeability in bronchoalveolar lavage fluid, respectively.

Figure 7 shows the inhalation of lipopolysaccharide (LPS) in lung tissue induced acute lung injury after administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) and then in lung tissue. It is a photograph showing the result of analyzing the expression change of interleukin-1b (IL-1b) by Western blot method.

FIG. 8 shows inhalation of lipopolysaccharide (LPS) and administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240) to mice induced with acute lung injury. It is a photograph showing the result of analyzing the expression change of interleukin-8 (IL-8) by Western blot method.

Figure 9 shows inhalation of lipopolysaccharide (LPS) in lung tissue induced acute lung injury after administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240). It is a photograph showing the results of Western blot analysis of the expression changes of tumor necrosis factor-alpha (TNF-a).

Figure 10 shows inhalation of lipopolysaccharide (LPS) in lung tissue induced acute lung injury after administration of 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (AS 605240). It is a photograph showing the results of Western blot analysis of the expression changes of cell adhesion molecules (VCAM-1).

Claims

A pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome containing 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione (Cas No: 648450-29-7) of Chemical Formula 1.

[Formula 1]

The method of claim 1,

Treatment of acute lung injury and acute respiratory distress syndrome by the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione is introduced into the lung tissue macrophages, lymphocytes, neutrophils, and eosinophils Pharmaceutical composition for the treatment of acute lung injury and acute respiratory distress syndrome, characterized in that it is carried out by inhibiting.

The method of claim 1,

Treatment of acute lung injury and acute respiratory distress syndrome by the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione is characterized by suppressing the expression of vascular endothelial growth factor (VEGF) A pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome.

The method of claim 1,

Treatment of acute lung injury and acute respiratory distress syndrome by the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione is performed by reducing vascular permeability of bronchoalveolar alveoli. And pharmaceutical compositions for treating acute respiratory distress syndrome.

The method of claim 1,

Treatment of acute lung injury and acute respiratory distress syndrome caused by 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione is interleukin-1b (IL-1b) and interleukin-8 (IL-8). , And a pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome, characterized in that it is performed by inhibiting the expression of tumor necrosis factor-alpha (TNF-a).

The method of claim 1,

Treatment of acute lung injury and acute respiratory distress syndrome by the 5- (6-quinosalinylmethylene) -2,4-thiazolidinedione results in the expression of vascular cell adhesion molecule (VCAM-1). A pharmaceutical composition for treating acute lung injury and acute respiratory distress syndrome, characterized in that it is carried out by inhibiting.

The method of claim 1,

The composition is acute lung injury and acute respiration, characterized in that the formulation of any one selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and injections. Pharmaceutical composition for the treatment of difficulty syndrome.

A method of treating acute lung injury and acute respiratory distress syndrome disease in a mammal, except human, comprising administering the pharmaceutical composition according to claim 1 to a mammal, except human.

The method of claim 8,

The pharmaceutical composition is administered by intraperitoneal injection, characterized in that for treating acute lung injury and acute respiratory distress syndrome disease.