JP2021066691A - Therapeutic agent for chronic lung disease/acute respiratory distress syndrome - Google Patents

Abstract

To provide a new therapeutic strategy useful for the treatment of chronic lung disease (particularly pediatric chronic lung disease).SOLUTION: There is provided a therapeutic agent containing fibrin derived-peptide Bβ15-42 as an active ingredient.SELECTED DRAWING: None

Description

The present invention relates to peptide preparations. More specifically, the present invention relates to a therapeutic agent containing a fibrin-derived peptide as an active ingredient and its use.

Chronic lung disease (CLD), especially chronic lung disease in newborns, is a serious and frequent complication of neonatal care and preterm infants receiving artificial ventilation for respiratory problems such as respiratory distress syndrome. Chronic lung lesions found in a group (see, eg, Non-Patent Document 1). Increased vascular permeability and infiltration of various inflammatory substances are involved in the formation of the pathology of CLD. With advances in neonatal care, the survival rate of infants with a birth weight of less than 1,500 g in developed countries has increased from less than 70% to more than 80% over the last 20 years, but the prevalence of CLD is gestational age 28. The rate is still high at 53.2% for babies under a week and 40% for babies with a birth weight of less than 1,000 g.

An internationally advocated definition of neonatal chronic lung disease in 2001 stated that "preterm infants <32 weeks gestation required more than 21% oxygen therapy for 28 days or more before 36 weeks of modification or discharge. It says "infant" and is classified according to its oxygen dependence. Chronic lung disease may require home oxygen therapy even after discharge, and is an important disease in consideration of the medical economy, such as hospitalization for respiratory infections in early childhood. In addition, chronic lung disease has a major problem of deterioration of respiratory function not only in newborns and infants but also in adolescence.

So far, neonatal chronic lung disease has become emphysematous due to dysplasia of lung tissue due to lung immaturity and surfactant deficiency, plus damage such as infection, patency of the arterial duct, oxygen toxicity, and artificial ventilation. However, in recent years, neonatal chronic lung disease is not only a mere lung injury, but also various injuries in the process of developing immature lungs going out of the womb and growing. It is thought that the development of the alveoli and vascular system has stopped.

Treatments for this disease are expected to be symptomatic treatments such as limiting oxygen concentration, limiting water content, reducing the water load on the pulmonary circulation with diuretics, administering bronchodilators and respiratory stimulants, and anti-inflammatory and anti-edema effects. The administration of steroids has been carried out. For example, Patent Document 1 proposes a pharmaceutical composition applied to intratracheal administration in combination with a steroid agent and pulmonary surfactant in order to reduce the risk of respiratory distress syndrome patients suffering from chronic lung disease in newborns. However, since steroids are feared to have side effects on the central nervous system during the growth period, the current situation is that short-term small doses are rescued only for severe cases. As described above, chronic lung diseases are treated as symptomatic treatments, and no therapeutic agents and treatment methods aiming at the cure of the diseases have been reported. The research group of the present inventors has proposed a new therapeutic strategy for chronic lung disease using Muse cells, which are a type of pluripotent stem cells (Patent Document 2).

JP-A-2007-262664 International Publication No. 2018/025973 Pamphlet Japanese Patent No. 4181874

Jobe, A.H. & Bancalari, E. Am J Respir Crit Care Med 163, 1723-29. Wolf, T. et al., Lancet. 2015 Apr 11; 385 (9976): 1428-35.

There is a great need to establish new treatments for chronic lung disease (CLD), especially neonatal chronic lung disease (BPD). Therefore, it is an object of the present invention to provide a new therapeutic strategy effective for the treatment of CLD.

In the course of research under the above issues, the present inventors _{focused on the fibrin-derived peptide Bβ 15-42} (therapeutic component symbol: FX06). FX06 is a synthetic peptide derived from fibrin E1 fragment that suppresses leukocyte infiltration and leakage of water out of blood vessels by binding to VE-cadherin present at the intercellular binding site of vascular endothelial cells (for example, Patent Document 3). reference). FX06 has been studied for various diseases and its clinical application is advancing. It has been reported that administration of FX06 to patients with Ebola hemorrhagic fever improved vascular permeability (see, for example, Non-Patent Document 2), and it can be expected to suppress water leakage to the outside of blood vessels also in the lungs. Therefore, the effect of FX06 on CLD was examined in detail using model animals. As a result, the administration of FX06 was found to have therapeutic effects such as reduction of inflammation, improvement of respiratory function, suppression of alveolar development arrest, and improvement of pulmonary hypertension. That is, FX06 was found to be extremely effective in treating CLD. The model animal used in the experiment reproduced the pathophysiology of CLD by high oxygen load, but showed phenotypes such as increased respiratory rate and decreased oxygenation ability, and was associated with acute respiratory distress syndrome (ARDS). It is also considered to be useful for drug evaluation. In addition, considering the relationship between CLD and ARDS (particularly, commonality such as increased vascular permeability and pulmonary dysfunction due to decreased oxygen gas exchange capacity at the alveolar level due to infiltration of inflammatory cells) , FX06 can be expected to be applied to ARDS in addition to CLD.
Based on the above results and considerations, the following inventions are provided.
[1] A therapeutic agent for chronic lung disease or acute respiratory distress syndrome, which contains the fibrin-derived peptide Bβ _{15-42 as an active ingredient.}
[2] Chronic pulmonary disease is a disease selected from the group consisting of bronchopulmonary dysplasia (BPD), Wilson-Mikiti syndrome (WMS), neonatal protracted pulmonary hypertension (PPHN) and neonatal hypertension. 1] The therapeutic agent according to.
[3] The therapeutic agent according to [1] or [2], wherein the fibrin-derived peptide Bβ _{15-42 comprises the amino acid sequence shown in SEQ ID NO: 1.}
[4] Use of _{fibrin-derived peptide Bβ 15-42} for producing therapeutic agents for chronic lung disease or acute respiratory distress syndrome.
[5] A method for treating chronic lung disease or acute respiratory distress syndrome, which comprises the step of administering a therapeutically effective amount of the fibrin-derived peptide Bβ _{15-42 to a patient suffering from chronic lung disease or acute respiratory distress syndrome.}

Experimental protocol. Newborn rats were bred under high oxygen load conditions to create a chronic lung disease model. FX06 was administered intraperitoneally and its effect was investigated. The results of evaluating the ratio of alveolar walls in the lung tissue of chronic lung disease model rats in the FX06-administered group (FX06), the saline-only-administered group (vehicle), and the room-fed group (sham) are shown. The higher the proportion of alveolar wall, the denser the alveolar wall is and the more developed the lung tissue. The results of evaluating the white blood cell count in the bronchoalveolar lavage fluid of chronic lung disease model rats of the FX06-administered group (FX06), the physiological saline-administered group (vehicle), and the room-breeding group (sham) are shown. The higher the white blood cell count, the stronger the infiltration of inflammation into the alveoli. The cardiac evaluation of the chronic lung disease model rat of the FX06 administration group (FX06), the physiological saline-only administration group (vehicle), and the room-reared group (sham) is shown. The vertical axis shows the weight of the right ventricular wall divided by the weight of the left ventricular wall and the septum. The higher the ratio, the stronger the thickening of the right ventricular wall, that is, the higher the pulmonary hypertension. The results of evaluating the tidal volume of chronic lung disease model rats in the FX06-administered group (FX06), the saline-only-administered group (vehicle), and the room-reared group (sham) are shown. The short-term group was tested on 15-day-old rats, and the long-term group was tested on 29-day-old rats. The higher the ventilation volume, the better the lung function. The results of evaluating the respiratory rate of chronic lung disease model rats in the FX06 administration group (FX06), the physiological saline-only administration group (vehicle), and the room-reared group (sham) are shown. The lower the respiratory rate, the better the lung function. The results of evaluation of airway contraction resistance of chronic lung disease model rats in the FX06-administered group (FX06), the physiological saline-only-administered group (vehicle), and the room-breeding group (sham) are shown. The lower the resistance, the better the respiratory function. The results of evaluating lung compliance, elastance, and airway resistance of chronic lung disease model rats in the FX06-administered group (FX06), the saline-only-administered group (vehicle), and the room-air-reared group (sham) are shown. .. The higher the compliance, the better the elastance and the lower the airway resistance, the better the lung function. The results of administration of FITC fluorescent lectin to chronic lung disease model rats in the FX06-administered group (FX06), the physiological saline-only group (vehicle), and the room-reared group (sham) were evaluated by electron microscopy. Shown. The more FITC fluorescent lectin (green in the original figure) infiltrates into the alveoli, the stronger the increase in vascular permeability.

The present invention relates to a medicament for chronic lung disease (CLD) or acute respiratory distress syndrome (ARDS), that is, a therapeutic agent for chronic lung disease or acute respiratory distress syndrome (hereinafter, also referred to as "therapeutic agent of the present invention"). The therapeutic agent of the present invention is applicable to the treatment or prevention of chronic lung disease or acute respiratory distress syndrome. "Therapeutic agent" refers to a drug that exhibits a therapeutic or prophylactic effect on a target disease or condition. Therapeutic effects include alleviating (mitigating) the symptoms or associated symptoms characteristic of the target disease / condition, preventing or delaying the exacerbation of the symptoms, and the like. The latter can be regarded as one of the preventive effects in terms of preventing aggravation. Thus, therapeutic and prophylactic effects are partly overlapping concepts, difficult to distinguish clearly, and the practical benefits of doing so are small. A typical prophylactic effect is to prevent or delay the recurrence of symptoms characteristic of the target disease / condition. As long as it shows some therapeutic effect or preventive effect on the target disease / pathological condition, or both, it corresponds to a therapeutic agent for the target disease / pathological condition.

The therapeutic agent of the present invention contains fibrin-derived Bβ peptide _15-42 (FX06) as an active ingredient. FX06 consists of amino acids 15 to 42 of the Bβ polypeptide chain of human fibrinogen and has the following amino acid sequence.
NH ₂ -GHRPLDKKREEAPSLRPAPPPISGGGYR-COOH (SEQ ID NO: 1)

FX06 can be prepared by a known peptide synthesis method (for example, solid phase synthesis method, liquid phase synthesis method) or a genetic engineering method. If an automatic peptide synthesizer is used, the target peptide can be easily and quickly synthesized.

Although not bound by theory, in view of the experimental results shown in the Examples section below and previous reports on FX06, at least part of the effect of the therapeutic agent of the present invention is VE- on the vascular endothelium. It is thought to be brought about by the action of acting on cadherin to enhance its adhesiveness and suppressing the increase in vascular permeability and the anti-inflammatory action. Because of this mechanism of action, the therapeutic agent of the present invention can be expected to have a high therapeutic effect on chronic lung disease and acute respiratory distress syndrome.

The above peptides may be modified in some way as long as the activity required for the therapeutic agent of the present invention is maintained. That is, in one aspect of the present invention, a modified product of the above peptide (hereinafter referred to as "modified peptide") is used as an active ingredient. The "modified peptide" in the present invention means that a part (may be a plurality of sites) of a specific peptide as a basic structure is replaced with another atomic group or the like, or another molecule is added. A compound having a structure different from that of the peptide, at least in part, by modification. Those skilled in the art can design modified products such as the above-mentioned peptide-based substituents by using well-known or conventional means. In addition, based on such a design, the desired modified product can be prepared by using well-known or conventional means.

As a typical example of the modified peptide, a peptide derivative in which a part of the side chain (atom or atomic group) is replaced with another atom or atomic group in the amino acid residue constituting the peptide can be mentioned. Such peptide derivatives can be prepared by any manufacturing process designed to give the peptide derivative as the final product. Therefore, if the peptide derivative of interest is a peptide in which a part (for example, an atomic group that is a part of a side chain) is apparently substituted by a specific atomic group, the peptide derivative of interest is this. Even if it is produced by a substitution reaction using the specific atomic group using an apparently basic peptide as a starting material, or, for example, an appropriate substitution reaction using a peptide having another structure as a starting material, etc. (in some cases, a plurality of them). It may be a process). Examples of other atoms or atomic groups here include hydroxyl groups, halogens (fluorine, chlorine, bromine, iodine, etc.), alkyl groups (methyl group, ethyl group, n-propyl group, isopropyl group, etc.), hydroxyalkyl groups (hydroxyalkyl groups, etc.). Examples thereof include a hydroxymethyl group, a hydroxyethyl group, etc.), an alkoxy group (methoxy group, ethoxy group, etc.), an acyl group (formyl group, acetyl group, malonyl group, benzoyl group, etc.) and the like.

The modified peptide also includes those in which the functional groups in the constituent amino acid residues are protected by appropriate protecting groups. As the protecting group used for such a purpose, an acyl group, an alkyl group, a monosaccharide, an oligosaccharide, a polysaccharide and the like can be used. Such protecting groups are linked by an amide bond, an ester bond, a urethane bond, a urea bond, or the like, depending on the peptide site to which the protecting group is attached, the type of protecting group used, and the like.

As another example of the modified peptide, one that has been modified by the addition of a sugar chain can be mentioned. In addition, various peptide derivatives classified into alkylamines, alkylamides, sulfinyls, sulfonylamides, halides, amides, aminoalcohols, esters, aminoaldehydes, etc. by substituting the N-terminal or C-terminal with other atoms are also modified. It is one of the peptides.

The therapeutic agent of the present invention is applied to the treatment of chronic lung disease or acute respiratory distress syndrome. In Japan, in 1996, a research group of the Ministry of Health, Labor and Welfare reported that "chronic lung injury" in newborns began in the neonatal period due to lung abnormalities other than congenital malformations, and respiratory distress symptoms that required oxygen administration began in the neonatal period. "Chronic lung disease" is defined as "a disease that continues beyond", and "chronic lung disease" is referred to as "diffuse opacity on chest radiographs" in order to characterize chronic lung disease in low-birth-weight infants, who account for the majority of lung disorders. If there is a chronic lung disorder with obvious abnormal findings such as images and foamy shadows, "the disease types are classified as I to VI as shown below based on background factors and chest X-ray findings.

I. Chronic neonatal lung injury preceded by neonatal respiratory distress syndrome (RDS) that presents diffuse foamy or irregular cord emphysema-like opacities on chest X-rays beyond 28 days of age II. Chronic neonatal pulmonary disorder preceded by RDS, showing diffuse opaque images on chest X-ray for more than 28 days after birth, but not foamy opacities or irregular cord-like emphysema-like opacities III. Chronic neonatal emphysema not preceded by RDS, with high suspicion of prenatal infections such as high IgM levels in cord blood, chorioamnionitis, and funisitis, and diffuse foam on chest X-rays beyond 28 days of age Those with umbilical or irregular cord emphysema-like shadow IV. Chronic neonatal pulmonary disorder not preceded by RDS, with unknown prenatal infection but presenting diffuse foamy or irregular cord emphysema-like opacities on chest X-rays beyond 28 days of age III'. Chronic neonatal emphysema not preceded by RDS, with high suspicion of prenatal infection such as high IgM level of cord blood, chorioamnionitis, and funisitis, and diffuse impermeability on chest X-ray beyond 28 days after birth Those that show an image but do not lead to foamy or irregular cord emphysema-like shadows V. Chronic neonatal pulmonary disorder not preceded by RDS, showing diffuse opaque images on chest X-ray for more than 28 days after birth, but not foamy or irregular cord emphysema-like shadows VI. Those that are not classified into any of the above I to V

The diagnosis of chronic lung disease is made by chest X-ray and the main symptoms of hyperventilation in respiratory distress syndrome, as described in the above criteria, but after denying the possibility of other respiratory diseases. Exclusion diagnosis is the basis.

In general, chronic neonatal pulmonary disease is a condition in which the development of alveolar and vascular system is suppressed due to known risk factors such as immaturity of the lung, oxygen toxicity, artificial ventilation, inflammation, infection, and patent ductus arteriosus. Bronchopulmonary dysplasia (BPD), Wilson-Mikiti syndrome (WMS), neonatal prolongation, but not limited to chronic lung disease as an applicable disease of the present invention. Pulmonary hypertension (PPHN), neonatal hypertension, etc. can also be included. Bronchopulmonary dysplasia (BPD) was first reported by Northway et al. In 1967, and is generally another name for chronic lung disease in Europe and the United States.

Chronic obstructive pulmonary disease in newborns is a common disease in preterm infants, and is a disease in which respiratory disorders requiring oxygen persist even after 28 days of age or 36 weeks of modification. The etiology of chronic lung disease is as described above, but it is largely caused by hyperoxygen therapy (long-term high-concentration oxygen absorption, high-pressure ventilator management, etc.) and inflammation. In the context of inflammation (infection), prenatal infections such as chorioamnionitis and funisitis contribute to the pathogenesis of chronic lung injury, which may also be the subject of the present invention. Chorioamnionitis is one of the infectious diseases in which inflammation spreads to the amniotic membrane surrounding the foetation and causes placental inflammation. When chorioamnionitis occurs, inflammatory substances become high in the womb, which causes exfoliation of the bronchi and alveolar epithelium, a decrease in substances necessary for the development and regeneration of alveolar structure, and is thought to cause chronic lung damage. Has been done.

In the above, the description has focused on chronic bronchopneumonia in newborns, but the therapeutic agent of the present invention is not limited to newborns, but children other than newborns (infants, toddlers, school children, adolescents) or adults can also be treated. For example, it is expected to be applied to the treatment of acute fine bronchitis, acute pneumonia, acute bronchopneumonia, bronchial asthma and the like. The therapeutic agent of the present invention is also applicable to the treatment of acute respiratory distress syndrome (ARDS). ARDS is a type of respiratory failure (called acute lung injury (ALI) in relatively mild cases), sepsis, heavy blood transfusions, severe pneumonia, chest trauma, pulmonary embolism, pancreatitis, mechanical ventilation, inhalation of toxic gas, It develops due to excessive intake of drugs. ARDS is a disease that requires urgent treatment and prompt intervention is desired. It usually develops within 24-48 hours of the causative event, but it may take several days (about 4-5 days) to develop. In consideration of such circumstances, the therapeutic agent of the present invention may be used prophylactically. As in the case of chronic lung disease, the treatment target is not particularly limited, that is, a child (newborn, infant, infant, school child, adolescent) or an adult can be treated.

The therapeutic agent of the present invention can be formulated according to a conventional method. In the case of formulation, other components that are acceptable in the formulation (for example, carriers, excipients, buffers, emulsifiers, suspensions, painkillers, stabilizers, preservatives, preservatives, saline, etc.) ) Can be contained. As the excipient, lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used. As the buffer, phosphate, citrate, acetate and the like can be used. As the emulsifier, gum arabic, sodium alginate, tragant and the like can be used. As the suspending agent, glycerin monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used. As the pain-relieving agent, benzyl alcohol, chlorobutanol, sorbitol and the like can be used. Propylene glycol, ascorbic acid and the like can be used as the stabilizer. As the preservative, phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben and the like can be used. As the preservative, benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.

The dosage form for formulation is also not particularly limited. Examples of dosage forms are injections, infusions, inhalants, inhalation aerosols, inhalation powders, tablets, powders, fine granules, granules, capsules and syrups. The therapeutic agent of the present invention is administered to a subject by injection (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, intraperitoneal, etc.), infusion, transpulmonary, nasal or oral (oral) depending on the dosage form. Will be done. Preferably, administration is parenteral, that is, by injection, infusion, pulmonary, nasal or the like. The routes of administration are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination. The therapeutic agent of the present invention contains an amount of an active ingredient necessary for obtaining the expected therapeutic effect (that is, a therapeutically effective amount). The amount of the active ingredient in the therapeutic agent of the present invention generally varies depending on the dosage form, but the amount of the active ingredient is set in the range of, for example, about 0.001% by weight to about 99% by weight so that a desired dose can be achieved.

The dose of the therapeutic agent of the present invention is set so as to obtain the expected therapeutic effect. Symptoms, patient age, gender, weight, etc. are generally considered in the setting of therapeutically effective doses. Those skilled in the art can set an appropriate dose in consideration of these matters. For example, the dose can be set so that the daily amount of the active ingredient in a newborn baby is, for example, 0.1 mg / kg to 200 mg / kg, preferably 2 mg / kg to 100 mg / kg. An example of the dose for an adult (body weight of about 60 kg) is 1 mg to 5 g, preferably 50 mg to 1.35 g, as the amount of the active ingredient per day. As the administration schedule, for example, once to several times a day (for example, twice, three times, four times), once every two days, once every three days, or the like can be adopted. In preparing the administration schedule, the patient's medical condition and the duration of effect of the active ingredient can be taken into consideration.

Treatment with another drug (eg, an existing therapeutic agent) may be performed in parallel with treatment with the therapeutic agent of the present invention, or treatment with an existing therapeutic agent (for example, surgical resection) may be combined with treatment with the therapeutic agent of the present invention. You may.

As is clear from the above description, the present application is a therapeutic method characterized by administering a _{therapeutically effective amount of the fibrin-derived peptide Bβ 15-42 (FX06) to a patient with chronic lung disease or acute respiratory distress syndrome.} Also provided.

The effect of FX06 on chronic lung disease was examined using model animals.

1. 1. Preparation of chronic lung disease model rat and administration of FX06 (Fig. 1)
The experimental animal protocol used in this study was approved by the Animal Care and Use Committee of Nagoya University School of Medicine. Pregnant SD rats were obtained from Japan SLC Co., Ltd. (Shizuoka, Japan). Immediately after birth (within 24 hours), mother and pups are allowed free access to food and water during the experiment and are subjected to a high oxygen load chamber (animal with oxygen controller and sensor adapter). It was bred in a chamber) under a 12-hour light-dark cycle. The temperature in the animal room and cage was always maintained at 23 ° C. Surrogate mother rats were replaced every two days because mother rats were also injured by hyperoxygenation.

FX06 was intraperitoneally administered once daily at a dose of 4.8 mg / kg for 14 days to the treatment group of the above model rats at the stage of 5 days of age. In the control group (vehicle), only the same volume of saline was administered instead of FX06. Rats to which neither FX06 nor saline was administered and which were not subjected to high oxygen load were included in the untreated group (sham). In the following experiments, 15-day-old and 29-day-old rats were used for various evaluations as a short-term group and a long-term group, respectively. Rats were exposed to high oxygen concentration (80%) until the age of 15 for short-term evaluation, and then exposed to normal oxygen concentration (21%) until the age of 29 for long-term evaluation.

2. Pulmonary tissue evaluation The lung tissue of chronic lung disease model rats was evaluated as follows. The model rats in the short-term and long-term groups described above were euthanized, physiological saline was injected from the right ventricle to perfuse the pulmonary blood vessels, and then the lungs were inflated with a 4% paraformaldehyde aqueous solution via a tracheal catheter (20 cmH). ₂ O, 20 minutes). The lungs were removed, fixed in a 4% paraformaldehyde solution for 18 to 24 hours (4 ° C), and then cut into each lung lobe. The carved lung lobes were dehydrated with an aqueous ethanol solution and xylene, embedded in paraffin, and the lung lobes were cut into sections having a thickness of 5 μm and subjected to hematoxylin-eosin staining (HE staining) to prepare specimens. Using an inverted microscope (manufactured by Olympus, model number IX83), place 100 grids (x10 locations x 10 sections) on the microscope software (Stereo Investigator), and under each grid is either space or lung tissue. I confirmed. We evaluated what percentage of the 100 grids were lung tissue. Normally, it occupies about 40% in normal lung tissue, and the alveolar space becomes larger as the lung tissue is damaged. As shown in FIG. 2, in rats in the short-term group (15 days of age), the FX06-treated group (FX06) showed a significant therapeutic effect (significant development of lung tissue) as compared with the control group (vehicle). It was.

3. 3. Measurement of the number of inflammatory cells in alveolar lavage fluid In chronic lung disease, an increase in the number of inflammatory cells is observed, and it was examined whether the number of these cells decreased by administration of FX06. After euthanizing the short-term group of rats, the blood vessels were perfused with saline from the pulmonary artery, and 0.4 mL (0.2 mL x 2 times) of saline was injected through the intubated tracheal cannula to wash the alveolar cells (0.2 mL). BAL) was performed, and the BAL solution (BALF) was collected. The number of white blood cells in BALF was measured by the following method. Specifically, 20 μL of Turk solution was added to 10 μL of bronchoalveolar lavage fluid for staining, and the total number of cells was measured using a Baker-Turk hemocytometer. Then, Turk's solution and bronchoalveolar lavage solution were mixed and the number of white blood cells was measured with an electron microscope.
The results are shown in FIG. The white blood cell count in the FX06 treatment group (FX06) was significantly lower than that in the control group (vehicle), indicating that the infiltration of inflammation into the alveoli was suppressed.

4. Cardiac evaluation (pulmonary hypertension evaluation)
The therapeutic effect of FX06 on chronic lung disease was evaluated using a rat heart. The heart was taken out from the model rat of the long-term group, separated into two parts, the right ventricular wall (RV) and the septum + left ventricular wall (IVS + LV), and then sufficiently dried in a dryer (60 ° C., 48 hours). Was weighed. Persistent pulmonary hypertension causes the right ventricular wall to thicken (= become heavier). The values in the sham group are normal, but the values in the chronic lung disease (vehicle group) are significantly increased, and thickening of the right ventricle is observed (Fig. 4). The values in the FX06-administered group were close to those in the Sham group, indicating that the thickening of the right ventricular wall was suppressed (that is, the pulmonary hypertension was reduced) (Fig. 4).

5. Evaluation of respiratory function (Whole Body Plethysmography)
The therapeutic effect of FX06 on chronic lung disease was indirectly evaluated by placing rats in a chamber for measuring respiratory rate and ventilation volume. In the short-term group, the tidal volume is normal in the Sham group, but the value in the chronic lung disease (vehicle group) is significantly reduced. The values in the FX06-administered group are close to those in the Sham group, indicating that lung function is good (Fig. 5). Respiratory rate increased in the chronic lung disease (vehicle group), indicating deterioration of lung function, but not in the FX06-administered group (Fig. 6). In the airway contraction index that indirectly evaluated airway resistance, the Sham group showed normal values, the chronic lung disease (vehicle group) had an increase in airway resistance, and the FX06-administered group did not show an increase in lung function. The improvement can be seen (Fig. 7).

6. Evaluation of lung function (flexiVent)
The therapeutic effect of FX06 on chronic lung disease was evaluated by directly measuring and evaluating lung function by inserting a cannula into the trachea and connecting it to flexivent. Compliance was normal in the Sham group, significantly decreased in the chronic lung disease (vehicle group), and not decreased in the FX06-administered group (Fig. 8). Elastance showed a normal value in the Sham group, showed an increasing tendency in chronic lung disease (vehicle group), and did not increase in the FX06 administration group. Airway resistance showed normal values in the Sham group, tended to increase in chronic lung disease (vehicle group), and did not increase in the FX06-administered group. These results indicate that the FX06-administered group has an effect of improving lung function.

7. Evaluation of vascular permeability We evaluated vascular permeability by injecting FITC lectin into the veins of rats and examining the degree of leakage to the alveoli with an electron microscope. Leakage of lectin to the outside of blood vessels including alveoli was not observed in the Sham group and FX06 administration group, and leakage of lectin to the alveoli and out of blood vessels was observed in the chronic lung disease (vehicle group) (Fig. 9). That is, it can be seen that the increase in vascular permeability was suppressed in the FX06 administration group.

The therapeutic agent of the present invention is used for the treatment of chronic lung disease (CLD) or acute respiratory distress syndrome (ARDS). In particular, it is suitable for the treatment of chronic lung disease in newborns, that is, bronchopulmonary dysplasia (BPD), and provides a new therapeutic strategy for BPD.

As mentioned above, the pathophysiology of CLD is lung injury due to inflammation caused by various factors and increased vascular permeability. According to the therapeutic agent of the present invention containing FX06 as an active ingredient, it is possible to perform treatment aiming at "suppression of increase in vascular permeability" which has not been achieved in conventional treatment strategies. Moreover, since FX06 also has an anti-inflammatory effect in addition to its vascular permeability inhibitory effect, it is possible to suppress the main pathological conditions of CLD from both sides, and it is possible to provide a highly effective treatment method.

The present invention is not limited to the description of the embodiments and examples of the above invention. Various modifications are also included in the present invention as long as those skilled in the art can easily conceive without departing from the description of the scope of claims. The contents of the papers, published patent gazettes, patent gazettes, etc. specified in this specification shall be cited by reference in their entirety.

Claims (5)

A therapeutic agent for chronic lung disease or acute respiratory distress syndrome, which contains the fibrin-derived peptide Bβ _{15-42 as an active ingredient.} According to claim 1, the chronic lung disease is a disease selected from the group consisting of bronchopulmonary dysplasia (BPD), Wilson-Mikiti syndrome (WMS), neonatal protracted pulmonary hypertension (PPHN) and neonatal hypertension. The listed therapeutic agent. The therapeutic agent according to claim 1 or 2, wherein the fibrin-derived peptide Bβ _15-42 comprises the amino acid sequence shown in SEQ ID NO: 1. Use of _{fibrin-derived peptide Bβ 15-42} to produce therapeutic agents for chronic lung disease or acute respiratory distress syndrome. A method of treating chronic lung disease or acute respiratory distress syndrome, comprising the step of administering a therapeutically effective amount of the fibrin-derived peptide Bβ _{15-42 to a patient suffering from chronic lung disease or acute respiratory distress syndrome.}

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