JP2003284774A - Material for improving function of respiratory organ - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a material for improving the function of a respiratory organ by detoxifying or removing a superantigen derived from Staphylococcus aureus or Group A streptococcus, which has an action of inhibiting the function of the respiratory organ, and a method for clarifying blood with the material. <P>SOLUTION: The material for improving the function of a respiratory organ removes or detoxifies substances inhibiting the function of the respiratory organ in blood. A blood-clarifying column packed with the material, which can remove or detoxify these substances inhibiting the function of the respiratory organ, is produced to clarify the blood. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a material for losing (detoxifying) or removing the toxin activity of a substance that suppresses respiratory function. In particular, by binding to a substance that suppresses the function of the respiratory system present in a high-concentration protein solution such as blood, a drug that detoxifies its toxin activity, or the function of the respiratory system present in a high-concentration protein solution, It is preferably used as a blood purification column that removes substances that suppress.

[0002]

2. Description of the Related Art Pneumonia, lung cancer, sepsis and the like may cause death due to a decrease in oxygen concentration in blood due to a decrease in respiratory function. Among them, in septicemia and pneumonia caused by infectious diseases, Gram-negative bacteria, Gram-positive bacteria or bacterial components of these bacteria that have flowed into the blood from the infection site produce various mediators to cause systemic inflammation, and this inflammatory reaction If it increases, it becomes impossible to maintain the homeostasis of the living body due to acute respiratory failure. Furthermore, continuous progress is seen in severe sepsis, septic shock, and multiple organ dysfunction syndrome.

The basis of respiratory failure treatment is respiratory assistance such as high-concentration oxygen inhalation and artificial respiration, and treatment of underlying diseases. In the treatment of patients with acute respiratory failure, the pH value should generally not fall below 7.3 on the basis of arterial blood gas findings, and PaO ₂ > 50 Tor.
Oxygen is administered to keep r. However, respiratory management has no therapeutic effect on the underlying disease of respiratory dysfunction,
Further, the oxygen concentration cannot be increased to 100% or more. Antibiotics are given if the infection is the cause, but the condition may not improve. Further, even if the inflow of the respiratory function-suppressing substance is continuous, detoxification of the suppressing substance and removal to the outside of the body are not performed, and if the respiratory management is stopped in that state, the blood oxygen concentration decreases again.

[0004]

DISCLOSURE OF THE INVENTION In the present invention, attention is focused on a substance that suppresses respiratory function, which has not been considered in the prior art, the substance is identified, and there is an affinity for the inhibitor, In addition, the present inventors have conducted a study from the viewpoint of producing a material that removes its toxicity outside the body by detoxifying or adsorbing it. The present inventors also derived substances that suppress respiratory function, particularly Staphylococcus aureus or group A streptococcus. It was found that a substance having activity as a superantigen of erythrocyte has a function of suppressing respiratory function, and a medical antidote or a medical adsorbent having a high affinity with these respiratory function suppressing substances. A blood purification material using the material and the adsorbent material and a blood purification column filled with the material were invented and derived from conventional respiratory failure, particularly infectious diseases such as pneumonia and sepsis. It has succeeded in providing a blood purification method using a treatment material and the material for respiratory failure.

[0005]

The present invention has the following constitution in order to solve the above problems. (1) A material for improving the function of the respiratory system, which is characterized by removing or detoxifying a respiratory function suppressing substance in blood. (2) The material for improving the function of the respiratory system according to (1), wherein the respiratory function suppressing substance is a substance derived from bacteria. (3) The material for improving respiratory function according to (2), wherein the bacterium is Staphylococcus aureus or group A streptococcus. (4) The material for improving the function of the respiratory system according to any one of (1) to (3), wherein the respiratory function suppressing substance is a superantigen. (5) The material for improving the function of the respiratory system according to any one of (1) to (4), which has a urea bond, a thiourea bond or an amide bond. (6) Insoluble in water (1) to (5)
A material for improving respiratory function according to any one of 1. (7) The respiratory function-inhibiting substance is a substance that reduces the oxygenation efficiency of blood in the lungs (1) to
The material for improving the function of the respiratory system according to any one of (6). (8) A blood purification material (1) to
The material for improving the function of the respiratory system according to any one of (7). (9) A blood purification column, which is filled with the material for improving the function of the respiratory organ according to any one of (1) to (8).

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides a material for detoxifying or removing a respiratory function-inhibiting substance, as a material that enables supplementary treatment of respiratory management. In the present invention, “detoxification” refers to detoxification of toxins in blood, and “removal” refers to removal of substances from blood by adsorption or detoxification.

In the present invention, a respiratory coefficient (also referred to as a lung failure index; hereinafter abbreviated as RI) was used to evaluate respiratory function. When the lung is damaged, the arterial blood oxygen partial pressure (hereinafter abbreviated as P _aO2 ) decreases, so P _aO2 and alveolar air oxygen partial pressure (hereinafter abbreviated as P _AO2 ) do not match, and P _AO2 And P _aO2 (alveolar-arterial blood oxygen partial pressure range alveo
lar-arterial O ₂ pressure
difference; hereinafter, abbreviated as A-aD _O2 . ) Rises. A-aD _O2 is one of the indexes of the oxygenation efficiency of the lung, and an increase in A-aD _O2 means that gas exchange in the lung is not successful (the oxygenation efficiency is decreased). is doing. P _AO2 is approximately P _AO2 = P _IO2 − (P
Calculated as _aCO2 / R). R is the respiratory quotient, usually calculated as 0.8, and P _IO2 is the _inspired oxygen partial pressure, 37 ° C.
Then 713mmHg × F _IO2 (F _IO2 is the oxygen concentration in the intake air)
Calculated by RI is a value obtained by dividing A-aD _O2 , which increases depending on F _IO2 , by P _aO2 at that time for correction, and is represented by RI = A-aD _O2 / P _aO2 .
33 or less (Goldfarb MA, et a
1: AmJ Surg 219: 255-258, 19
75. ). In an ideal lung, A-aD _O2 = RI = 0, and an increase in RI means that A-aD _O2 is increased and respiratory function is suppressed.

The respiratory function-suppressing substance to be removed may be any substance that exists in blood and suppresses respiratory function,
Examples include, but are not limited to, chemicals, pharmaceuticals, endogenous proteins, and exogenous toxin proteins. In the present invention, bacterial toxins are particularly preferable for removal.
Bacteria may be those that produce toxins that suppress respiratory function, such as Escherichia coli, Pseudomonas aeruginosa, Gram-negative bacteria such as Klebsiella pneumoniae, Staphylococcus epidermidis, Streptococcus, Bacillus subtilis, etc. Examples include positive bacteria, but are not limited thereto. Particularly in the present invention, Staphylococcus aureus and A
Superantigen-producing bacteria such as group streptococci are preferred as targets.

Unlike conventional antigens, superantigens bind to major histocompatibility antigen class II (hereinafter abbreviated as MHC class II) on antigen presenting cells without undergoing a processing process in antigen presenting cells. In addition, it is a compound that stimulates T cells having a specific V region by forming a complex with MHC class II to abnormally activate the immune system, and when fever, rash, blood pressure decrease and food poisoning occur. It is said to cause vomiting or induction of autoimmune diseases. As a superantigen, Staphylococcal enterotoxin A, which is a Staphylococcus aureus exotoxin,
B, C, D, E, H or toxic shock syndrome toxin-1 (hereinafter abbreviated as TSST-1), streptococcal pyrogenic exotoxin A which is group A streptococcal exotoxin, and certain viral proteins and plant proteins It has been confirmed that there are more than a dozen types, including, but may be specified in the future. Up to now, activation of immunity by superantigen has been reported, but the present inventors have newly found that administration of superantigen to animals induces respiratory failure.

The material for improving the function of the respiratory system used in the present invention may be any material having an affinity for the respiratory function-suppressing substance, and may be an antibody or peptide specifically recognizing these substances or chemically. There are various possible low molecular structures such as the functional groups of the affinity chromatography to be synthesized, but there is no particular limitation.

A method for obtaining a peptide that specifically binds to a specific substance is described in "Sato. A et al., Biochemi.
story, 35, 10441-10447, 199.
The peptide library described in “6 years” can be used. To obtain a peptide library for obtaining a peptide that specifically binds to a respiratory function-suppressing substance by this method, for example, a respiratory function-suppressing substance is used. The filamentous bacteriophage in which the random sequence is added to the amino terminus of the pIII region is seeded on a Petri dish in which is immobilized, and incubated, and only the phage bound to the respiratory function inhibitor is eluted. The method is not particularly limited to this. An antibody that specifically recognizes a specific substance can be prepared by using the method described in "Seikagaku Chemistry Experimental Course 5 Immunobiochemistry Research Method by the Japanese Biochemical Society, Tokyo Kagaku Dojin Shuppan". To obtain a monoclonal antibody that specifically recognizes a function-suppressing substance, for example, a respiratory function-suppressing substance is used in a mouse, such as BALB / c.
When the antibody titer rises, spleen cells or lymph node cells are fused with myeloma cells to produce a hybridoma, and a hybridoma that produces a monoclonal antibody that specifically recognizes a respiratory function-suppressing substance is used. It may be screened, but is not particularly limited to this method. Also,
As a method for obtaining a polyclonal antibody that specifically recognizes a respiratory function-suppressing substance, for example, a respiratory function-suppressing substance is administered to mammals such as rats, mice, and rabbits, and blood is collected when the antibody titer rises. A method for obtaining antiserum is used, but the method is not particularly limited to this method. If purification of the antibody from the antiserum is required, it can be purified by a selective precipitation fractionation method based on the difference in solubility, a fractionation method based on the difference in charge, a fractionation method based on the difference in molecular weight, or a combination thereof. can do.

[0012] The chemically synthesized functional group that binds to affinity chromatography may be any functional group that binds to a respiratory function-suppressing substance, but is more preferably inexpensive and is a chemically synthesized low molecule that is easy to sterilize. A structure is used, and more preferably, a structure having a urea bond, a thiourea bond or an amide bond is used. The structure following the urea bond, thiourea bond or amide bond is not particularly limited, and propane, hexane, octane,
Although aliphatic compounds such as dodecane and alicyclic compounds such as cyclohexane and cyclopentane can be used,
Considering the high affinity, aromatic compounds such as benzene, naphthalene and anthracene are more preferably used.
Derivatives such as bromoheptane, chlorocyclohexane, methylbenzene, chlorobenzene, nitrobenzene, diphenylmethane and chloronaphthalene are also preferably used.
A structure having an amino group, a hydroxyl group or a carboxyl group can also be used. For example, as a structure having an amino group, aminohexane, monomethylaminohexane, dimethylaminohexane, aminooctane, aminododecane, aminodiphenylmethane, 1- (3-aminopropyl) imidazole, 3-amino-1-propene, aminopyridine, Aminobenzenesulfonic acid, tris (2-aminoethyl) amine, etc., diaminoethane,
Diethylenetriamine, triethylenetetramine, tetraethylenepentamine, dipropylenetriamine, polyethyleneimine, N'-methyl-2,2'diaminodiethylamine, N-acetylethylenediamine, 1,2-
A compound having a plurality of amino groups such as bis (2-aminoethoxyethane) (may be referred to as polyamine)
Is used. Further, as the structure having a hydroxyl group, hydroxypropane, 2-ethanolamine, 1,3 diamino-2-hydroxypropane, hydroxybutanone,
Hydroxybutyric acid, hydroxypyridine and the like, glucose, glucosamine, galactosamine, maltose, cellobiose, sucrose, agarose, cellulose, chitin, sugars such as chitosan, oligosaccharides, sugars such as polysaccharides or derivatives thereof can be used. It is not limited to these. Further, as the structure having a carboxyl group, β-alanine, n-caproic acid, isobutyric acid, γ-amino-β-hydroxybutyric acid and the like can be used. Most preferably, the material of the present invention can have an aromatic compound and an amino group or a hydroxyl group as a structure following a urea bond, a thiourea bond or an amide bond.

Further, polyurea, polythiourea and polyamide having a plurality of urea bonds, thiourea bonds and amide bonds in the molecular structure can also be used as the material of the present invention. Also in this case, any of the above structures can be used as the structure following the urea bond, the thiourea bond, and the amide bond, but most preferably, both a hydroxyl group, an amino group or a carboxyl group and an aromatic compound are used. You can

Since the material of the present invention may be any of a monomer, an oligomer and a polymer, a material obtained by polymerizing the above structure or a part thereof is also included in the material of the present invention. That is, as the above structure or a part thereof, a synthetic polymer such as nylon, polymethylmethacrylate, polysulfone, polystyrene, polyethylene, polyvinyl alcohol, polytetrafluoroethylene, cellulose, collagen, chitin, chitosan, or a derivative thereof is included. Natural polymers and the like are preferably used. That is, it is preferable to introduce a urea bond or / and a thiourea bond or / and an amide bond into the homopolymerized, copolymerized or blended synthetic polymer or natural polymer. In addition, metals, ceramics,
Those obtained by coating an inorganic material such as glass with a suitable polymer are also suitably used.

The material of the present invention can be synthesized by reacting an isocyanate compound or an isothiocyanate compound with an amino compound when introducing a urea bond or a thiourea bond into an aliphatic compound or an aromatic compound. When introducing an amide group into an aliphatic compound and an aromatic compound, for example, a method of reacting an acid, an acid chloride or an acid anhydride with an amino compound can be used. The mixing ratio of the amino compound and the isocyanate compound, the isothiocyanate compound, the acid, the acid chloride or the acid anhydride can be arbitrarily selected, and is usually 1 mol of the isocyanate compound, the isothiocyanate compound, the acid, the acid chloride or the acid anhydride. 0.1 to 10 mol of amino compound is preferably used. Examples of the isocyanate compound or the isothiocyanate compound include ethyl isocyanate, stearyl isocyanate, n-butyl isocyanate, iso-butyl isocyanate and n-butyl isocyanate.
Propyl isocyanate, methyl isothiocyanate,
Any of aliphatic isocyanate compounds or isothiocyanate compounds such as ethyl isothiocyanate, n-butyl isothiocyanate, benzyl isothiocyanate, hexamethylene diisocyanate, cyclohexyl isocyanate, cyclohexyl thioisocyanate and cyclohexyl diisocyanate can be used, but more preferably Phenyl isocyanate, chlorophenyl isocyanate, fluorophenyl isocyanate, bromophenyl isocyanate, nitrophenyl isocyanate, tolyl isocyanate, methoxyphenyl isocyanate, 1-naphthyl isocyanate,
4,4 'diphenylmethane diisocyanate, 3,
3 ', 5,5' tetraethyl 4,4 'diisocyanato diphenylmethane, phenyl isothiocyanate, chlorophenyl isothiocyanate, fluorophenyl isothiocyanate, nitrophenyl isothiocyanate, tolyl isothiocyanate, methoxyphenyl isothiocyanate, 1-naphthyl isothiocyanate, etc. The aromatic isocyanate compound or isothiocyanate compound is used. As the acid chloride, for example, any of aliphatic acid chlorides such as isovaleryl chloride, stearoyl chloride, cyclohexanecarbonyl chloride, and 6-chloronicotinic acid chloride can be used, but more preferably benzoyl chloride, 3, 4-
Aromatic acid chlorides such as dichlorobenzoyl chloride, nitrobenzoyl chloride, 4-chlorobenzoyl chloride, 4-toluoyl chloride and benzo- [b] thiophene-2-carbonyl chloride can be used. As the acid anhydride, for example, acetic anhydride, succinic anhydride, phthalic anhydride, benzoic anhydride, etc. can be preferably used. The amino group of the amino compound used in the present invention may be a primary amino group, a secondary amino group or a tertiary amino group. Examples of the amino compound include ammonia, sec-octylamine and 1- (3-
Aminopropyl) imidazole, 3-amino-1-propene, aminopyridine, aminobenzenesulfonic acid, tris (2-aminoethyl) amine and the like can be preferably used. Further, a polyamino compound or an amino compound having a hydroxyl group or a carboxyl group, which can introduce a urea bond, a thiourea bond or an amide bond, can be preferably used. Examples of the polyamino compound include diaminoethane, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, dipropylenetriamine, N'-methyl-2,2'diaminodiethylamine, polyethyleneimine, N-acetylethylenediamine, 1,2-bis ( Any of 2-aminoethoxy) ethane and the like can be used. As the amino compound having a hydroxyl group, 2-ethanolamine, 3-
Propanolamine, 6-hexanolamine, 1,3
Aliphatic amines such as diamino-2-hydroxypropane, 2- (2-aminoethoxy) ethanol, 2- (2-aminoethylamino) ethanol, glucamine, N-methyl-1,3-diaminopropanol, or 4-amino Aromatic amines such as phenol, diaminophenol, aminohydroxypyrimidine, diaminohydroxypyrimidine and diaminohydroxypyrazole, or amino acids such as serine and tyrosine are used. In addition, epichlorohydroline and amino compounds, or 1,
It is also possible to synthesize an amino compound having a hydroxyl group from a compound having only a hydroxyl group or a compound having only an amino group by reacting 3 dibromo-2-hydroxypropane. Also, when introducing a urea bond, a thiourea bond or an amide bond into the sugar, the same method as above can be used. That is, in the case of a sugar having an amino group such as chitosan or glucomisan, the above-mentioned isocyanate compound, isothiocyanate compound, acid, acid chloride or acid anhydride can be reacted. In the case of a sugar that does not have an amino group, such as cellulose, after the hydroxyl group of the sugar is activated using epichlorohydrin, tresyl chloride, etc., it is reacted with ammonia, diaminoethane, etc. to introduce an amino group. Then, using this amino group, a urea bond, a thiourea bond, or an amide bond can be introduced into the sugar. As the amino compound having a carboxyl group, for example, β-alanine, 4-amino-n-butyric acid, γ-amino-β-hydroxy-n-butyric acid, 6-amino-n-capronsan and the like can be used.

Further, when the material of the present invention is an oligomer or polymer, a method of reacting an amino group with an oligomer or polymer having an active ester group of a carboxylic acid such as an isocyanate group, a carboxyl group or a succinimide group is preferable. Used.
Further, an oligomer or polymer having an amino group, or ammonia, diaminoethane, 1,3 diaminopropane, 1,3 diamino-2-hydroxypropane, 1,2
-Bis (2-aminoethoxy) ethane, tris (2-aminoethyl) amine, 2- (2-aminoethylamino)
An oligomer in which an amino group is introduced with ethanol,
It is also a preferable method to react the polymer with the above-mentioned isocyanate compound, isothiocyanate compound, acid, acid chloride or acid anhydride. In addition, it is preferable to control the reaction time, the reaction temperature, the mixing ratio, or the like, or to use a protecting group so that the acid chloride or the isocyanate compound does not react with a group other than the amino group. Functional groups such as an amino group, an isocyanate group, a carboxylic acid active ester group such as a carboxyl group or a succinimide group, an acid chloride group, and an acid anhydride group can be introduced into an oligomer or a polymer as required.

Further, when the material of the present invention is polyurea or polythiourea, a method of reacting a polyisocyanate compound or polyisothiocyanate compound with a polyamino compound can be used. Usually, the amount of the reagent is 0.1 to 1 with respect to 1 mol of the polyisocyanate compound or the polyisothiocyanate compound.
0 mol of polyamine is preferably used. As the polyisocyanate compound or polyisothiocyanate compound, hexamethylene diisocyanate, cyclohexyl diisocyanate, tolylene diisocyanate,
4,4 'diphenylmethane diisocyanate, 3,3'
5,5 ′ tetraethyl 4,4 ′ diisocyanatodiphenylmethane, xylene diisocyanate, methylenebis (4-phenylisothiocyanate) and the like are preferably used. Further, as the polyamino compound, diaminoethane, diaminopropane, 1,3 diamino-2-hydroxypropane, N′-methyl 1,3-diamino-2-propanol, diaminophenol, N, N′-diaminopiperazine, diethylenetriamine, triamine Ethylenetetramine, tetraethylenepentamine, polyethyleneimine, dipropylenetriamine, N'-methyl-2,2'-
Diaminodiethylamine and the like can be preferably used. Further, when the material of the present invention is polyamide, for example, a method of polycondensing polycarboxylic acid and polyamine can be used. In addition, polyurea, polythiourea,
In any of the polyamides, polyisocyanate,
A method of finally obtaining polyurea, polythiourea, and polyamide by sequentially introducing each functional group one by one without using polyisothiocyanate, polycarboxylic acid, or the like is also preferably performed.

All of the above reactions are normally carried out at a reaction temperature of 0 to 150 ° C. and a reaction time of 0.1 to 24 hours. A reaction solvent is not always necessary, but it is generally carried out in the presence of a solvent. Solvents that can be used include aliphatic hydrocarbons such as methanol, ethanol, isopropyl alcohol, n-butanol, hexane, acetone, N, N dimethylformamide and dimethyl sulfoxide, aromatic hydrocarbons such as benzene, toluene and xylene. , Halogenated hydrocarbons such as dichloromethane, chloroform and chlorobenzene, and ethers such as diethyl ether, tetrahydrofuran and dioxane. After the reaction, the reaction solution is subjected to usual post-treatments such as filtration and concentration, if necessary, after column chromatography,
It can be purified by an operation such as recrystallization. Also,
In the case of a water-insoluble material, washing with a glass filter or the like is also a preferable method.

Among the materials of the present invention, the water-insoluble one is preferably used as a column for removing respiratory function-inhibiting substances. The shape is not particularly limited, but when it is used as a column, beads, fibers, hollow fibers, yarn bundles, yarns, nets, knitted fabrics, woven fabrics and the like are preferable. Further, the present material can be used not only alone but also further fixed to an appropriate material, or mixed with other materials to be used as one column or a coating material. The operations such as immobilization or mixing may be performed before or after being processed into the above shape. When the column using the material of the present invention is used as a column for extracorporeal circulation, blood drawn out of the body may be directly passed through the column or may be used in combination with a plasma separation membrane or the like.

As a method for treating respiratory failure, a compound having a structure having an affinity for a respiratory function-suppressing substance may be administered into blood, or may be made water-insoluble, and blood may be circulated through a blood column to be removed. However, there is no particular limitation.

[0021]

EXAMPLES Example 1: Preparation of material having affinity with respiratory function-suppressing substance 50% by weight sea component (46% by weight mixture of polystyrene and 4% by weight polypropylene) and 50% by weight island component ( Polypropylene) and US Pat. No. 4,661,260
The sea-island type composite fiber (thickness: 2.6 denier, number of islands: 16) described in Example 1 of 50 g of N-methylol-α-
Chloroacetamide, 400 g nitrobenzene, 40
The mixture was reacted with a mixed solution of 0 g of 98% sulfuric acid and 0.85 g of paraformaldehyde at 20 ° C. for 1 hour. After that, the fiber was washed with nitrobenzene, then the reaction was stopped with methanol, and further washed with methanol to obtain α-chloroacetamide methylated crosslinked polystyrene fiber (hereinafter abbreviated as AMPSt fiber).

Next, tetraethylenepentamine 6.3
g, tert-butylamine (7.2 g) was washed with 500 ml of N, N dimethylformamide (hereinafter abbreviated as DMF), and the fiber was added to a solution of 500 ml of DMF in which 2.3 g of 4-chlorophenylisocyanate was dissolved. Was carried out at 25 ° C for 1 hour. Then, it was washed on the glass filter with 1000 ml of DMF and further with 1000 ml of distilled water to obtain a urea bond-incorporated AMPSt fiber (abbreviated as UAMP fiber).

Here, using the produced UAMP fiber,
An adsorption test of toxic shock syndrome toxin-1 (hereinafter abbreviated as TSST-1 manufactured by Toxin Technology), which is a superantigen derived from Staphylococcus aureus, was performed. 0.1M of TSST-1 containing 0.15 sodium chloride and 5 mg / ml bovine serum albumin (fraction V) (manufactured by Seikagaku Corporation) to a concentration of 1 ng / ml
It was dissolved in a sodium phosphate buffer (pH 7.4) to give a solution to be adsorbed. UAMP 0.1g to this adsorbed solution 1
The mixture was added to the mixture, and the adsorption reaction was performed at 37 ° C. for 2 hours while swirling. The TSST-1 concentration before and after adsorption was measured.
(Table 1) Table 1. TSST-1 adsorption test using urea-bonded fibers

[0024]

[Table 1]

As described above, it was confirmed that the concentration of TSST-1 was lowered, and it was shown that a fiber having a high adsorption rate for TSST-1 was prepared.

Example 2 Treatment of Respiratory Failure Rabbits Using Respiratory Function Inhibitory Substance-Adsorbed Fibers Prepared in Example 1 Rabbits (3 kg; male, New Zealand White)
After anesthesia with Nembutal "(Dainippon Pharmaceutical Co., Ltd.), endotracheal intubation was performed, and blood gas findings showed arterial oxygen saturation (SaO ₂ ).
Was controlled by a ventilator so that the ratio would be 90%. In addition, "muscurax" (manufactured by Sankyo) as a muscle relaxant in physiological saline was adjusted to 0.25 mg / ml and adjusted to 1 ml /
It was continuously administered from the femoral vein at a dose of kg / hr. In addition, 5 ml / kg / of "Hespander" (manufactured by Kyorin Pharmaceutical) as an infusion solution
It was continuously administered from the femoral vein for hr. As a continuous anesthesia, the exhaled breath was also mixed with 1% of isoflurane.

In order to reproduce the respiratory failure state due to sepsis, a cecal ligation and stab incision was performed, and TSST-1-producing Staphylococcus aureus was intraperitoneally administered. The number of administered bacteria is 6 × 10 ⁸ c
It was set to fs / kg. After the administration, the abdomen was sutured. After that, the blood gas in the artery was measured for 8 hours. RI as a respiratory function
Was measured.

The following two kinds of treatments were performed on the rabbits to which this TSST-1-producing Staphylococcus aureus was administered. (1) 3 of administration of TSST-1 producing Staphylococcus aureus
After a lapse of time, blood purification was carried out by an ordinary method by an extracorporeal circulation method using a column filled with the TSST-1 adsorbing fiber produced in Example 1. (2) Extracorporeal circulation using a polypropylene tube was performed by a conventional method from 3 hours after the administration of TSST-1 producing Staphylococcus aureus.

For extracorporeal circulation, an indwelling needle was inserted into the femoral artery and femoral vein to secure blood vessels, and blood was circulated using a circulation pump. Heparin was used as an anticoagulant. The blood flow rate was 10 ml / min. Table 2. Changes in blood TSST-1 concentration and RI

[0030]

[Table 2]

As described above, administration of TSST-1-producing Staphylococcus aureus increased RI with the increase of blood TSST-1 concentration and caused respiratory failure.
When blood purification was performed using a column packed with ST-1 adsorbent fiber, increases in TSST-1 concentration and RI were suppressed, and deterioration of respiratory function could be suppressed. In particular, it was shown that the oxygenation efficiency of the lung was improved, and respiratory failure could be treated.

[0032]

INDUSTRIAL APPLICABILITY According to the present invention, by selectively detoxifying or removing a substance that suppresses respiratory function even in a solution having a high protein concentration, it is possible to prevent the deterioration of respiratory function or to reduce the decreased function. Materials and treatment methods could be provided to restore and improve lung oxygenation efficiency. Provided is a drug or a column for blood purification, which can treat or prevent deterioration of respiratory function due to sepsis or the like, since the respiratory function-suppressing substance existing in blood can be detoxified or removed using the material of the present invention. It has become possible.

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Claims (9)

[Claims] 1. A material for improving the function of the respiratory system, which is characterized by removing or detoxifying a respiratory function suppressing substance in blood. 2. The material for improving the function of the respiratory system according to claim 1, wherein the respiratory function-inhibiting substance is a substance derived from bacteria. 3. The material for improving the function of the respiratory system according to claim 2, wherein the bacterium is Staphylococcus aureus or group A streptococcus. 4. The material for improving the function of the respiratory system according to any one of claims 1 to 3, wherein the respiratory function suppressing substance is a superantigen. 5. The material for improving the function of the respiratory system according to any one of claims 1 to 4, which has a urea bond, a thiourea bond or an amide bond. 6. The method according to claim 1, which is insoluble in water.
5. A material for improving the function of the respiratory system according to any one of 5 to 5. 7. The material for improving the function of the respiratory system according to any one of claims 1 to 6, wherein the respiratory function suppressing substance is a substance that reduces the oxygenation efficiency of blood in the lungs. 8. A material for improving the function of the respiratory system according to any one of claims 1 to 7, which is a blood purification material. 9. A blood purification column, which is filled with the material for improving the function of the respiratory system according to any one of claims 1 to 8.