JP5530635B2 - 腸管癒着抑制剤 - Google Patents
腸管癒着抑制剤 Download PDFInfo
- Publication number
- JP5530635B2 JP5530635B2 JP2008558089A JP2008558089A JP5530635B2 JP 5530635 B2 JP5530635 B2 JP 5530635B2 JP 2008558089 A JP2008558089 A JP 2008558089A JP 2008558089 A JP2008558089 A JP 2008558089A JP 5530635 B2 JP5530635 B2 JP 5530635B2
- Authority
- JP
- Japan
- Prior art keywords
- intestinal
- adhesion
- ifn
- intestinal adhesion
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 206010000050 Abdominal adhesions Diseases 0.000 title claims description 235
- 239000003112 inhibitor Substances 0.000 title claims description 44
- 108010074328 Interferon-gamma Proteins 0.000 claims description 126
- 102100037850 Interferon gamma Human genes 0.000 claims description 125
- 238000001356 surgical procedure Methods 0.000 claims description 22
- 230000003472 neutralizing effect Effects 0.000 claims description 16
- 210000000936 intestine Anatomy 0.000 claims description 10
- 238000010254 subcutaneous injection Methods 0.000 claims description 3
- 239000007929 subcutaneous injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 110
- 230000009545 invasion Effects 0.000 description 74
- 238000000034 method Methods 0.000 description 74
- 230000014509 gene expression Effects 0.000 description 73
- 238000010171 animal model Methods 0.000 description 56
- 210000001035 gastrointestinal tract Anatomy 0.000 description 56
- 108020004999 messenger RNA Proteins 0.000 description 54
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 45
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 45
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 42
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 37
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 37
- 102100024304 Protachykinin-1 Human genes 0.000 description 33
- 238000004519 manufacturing process Methods 0.000 description 32
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 30
- 102000006381 STAT1 Transcription Factor Human genes 0.000 description 30
- 241000699666 Mus <mouse, genus> Species 0.000 description 27
- 102000003141 Tachykinin Human genes 0.000 description 27
- 108060008037 tachykinin Proteins 0.000 description 27
- 239000000126 substance Substances 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 22
- 210000001744 T-lymphocyte Anatomy 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 21
- 230000000968 intestinal effect Effects 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 16
- 238000010586 diagram Methods 0.000 description 16
- 210000000581 natural killer T-cell Anatomy 0.000 description 16
- 101800000399 Neurokinin A Proteins 0.000 description 15
- 101800000923 Neuropeptide K Proteins 0.000 description 15
- 102000005886 STAT4 Transcription Factor Human genes 0.000 description 15
- 108010019992 STAT4 Transcription Factor Proteins 0.000 description 15
- 102000013968 STAT6 Transcription Factor Human genes 0.000 description 15
- 108010011005 STAT6 Transcription Factor Proteins 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 15
- 238000013424 sirius red staining Methods 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 14
- 101150108167 TAC1 gene Proteins 0.000 description 13
- 230000008569 process Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000012216 screening Methods 0.000 description 8
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 230000008595 infiltration Effects 0.000 description 7
- 238000001764 infiltration Methods 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 238000007912 intraperitoneal administration Methods 0.000 description 7
- 238000010186 staining Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 230000003480 fibrinolytic effect Effects 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 230000002980 postoperative effect Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000003753 real-time PCR Methods 0.000 description 6
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 5
- 206010016654 Fibrosis Diseases 0.000 description 5
- 101800003906 Substance P Proteins 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 239000003527 fibrinolytic agent Substances 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 238000002350 laparotomy Methods 0.000 description 5
- 210000004698 lymphocyte Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 102100037346 Substance-P receptor Human genes 0.000 description 4
- 101710097909 Substance-P receptor Proteins 0.000 description 4
- 102000040945 Transcription factor Human genes 0.000 description 4
- 108091023040 Transcription factor Proteins 0.000 description 4
- 238000002679 ablation Methods 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- 238000004043 dyeing Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000017423 tissue regeneration Effects 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 208000031737 Tissue Adhesions Diseases 0.000 description 3
- 210000000683 abdominal cavity Anatomy 0.000 description 3
- 210000004534 cecum Anatomy 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 238000003633 gene expression assay Methods 0.000 description 3
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 3
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 102400000097 Neurokinin A Human genes 0.000 description 2
- HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 description 2
- 230000029662 T-helper 1 type immune response Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005485 electric heating Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000012239 gene modification Methods 0.000 description 2
- 230000005017 genetic modification Effects 0.000 description 2
- 235000013617 genetically modified food Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000035800 maturation Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 206010033675 panniculitis Diseases 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 235000020083 shōchū Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 210000004304 subcutaneous tissue Anatomy 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 101100368700 Caenorhabditis elegans tac-1 gene Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 238000000018 DNA microarray Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 101000609260 Mus musculus Plasminogen activator inhibitor 1 Proteins 0.000 description 1
- 101000801487 Mus musculus Tissue-type plasminogen activator Proteins 0.000 description 1
- 229940123821 Neurokinin 1 receptor antagonist Drugs 0.000 description 1
- 102000003797 Neuropeptides Human genes 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010034650 Peritoneal adhesions Diseases 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- 238000010802 RNA extraction kit Methods 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 208000024340 acute graft versus host disease Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 210000003236 esophagogastric junction Anatomy 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 102000057308 human HGF Human genes 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 208000003243 intestinal obstruction Diseases 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000014725 late viral mRNA transcription Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- PFPSZGPAQFBVHZ-UHFFFAOYSA-N n-(3-chlorophenyl)-2-[(4-phenyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]acetamide Chemical compound ClC1=CC=CC(NC(=O)CSC=2N(C(C=3C=CN=CC=3)=NN=2)C=2C=CC=CC=2)=C1 PFPSZGPAQFBVHZ-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 description 1
- -1 or SP Proteins 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000004876 tela submucosa Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/249—Interferons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5082—Supracellular entities, e.g. tissue, organisms
- G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/52—Assays involving cytokines
- G01N2333/555—Interferons [IFN]
- G01N2333/57—IFN-gamma
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Genetics & Genomics (AREA)
- Cell Biology (AREA)
- Urology & Nephrology (AREA)
- Food Science & Technology (AREA)
- Pathology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Microbiology (AREA)
- Toxicology (AREA)
- Surgery (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Animal Husbandry (AREA)
- Biodiversity & Conservation Biology (AREA)
Description
本発明に係る実験動物の腸管癒着を形成する方法は、実験動物の腸管を焼灼する焼灼工程を含み、上記焼灼工程では、上記腸管に与えられる侵襲の程度が一定になるように熱量を制御すればよい。
本発明に係る腸管癒着抑制剤のスクリーニング方法は、下記の(i)〜(iii)の工程を含み、(i)実験動物の腸管の少なくとも一部の部位を焼灼する工程;(ii)上記実験動物に被験物質を投与する工程;(iii)腸管癒着の形成を確認する工程;上記(i)の工程では、上記実験動物が有する腸管に、IFN−γの発現を誘導する熱量の熱を与えればよい。
本発明に係る腸管癒着抑制剤は、IFN−γ阻害物質を含むものであればよい。また、投与時期については、腸管が侵襲される手術の1日前から当該手術の30分後までの間がよい。
後述する実施例では、以下の方法で、各マウスに対して腸管癒着形成のための手術類似侵襲(以下、単に「手術類似侵襲」と表記する)を施術した。
adhesion score0;癒着無し。
adhesion score1;一箇所の薄い膜状の癒着の形成。
adhesion score2;二箇所以上の薄い癒着の形成。
adhesion score3;局所的に厚い癒着の形成。
adhesion score4;播種状に付着した厚い癒着の形成又は二箇所以上の局所的に厚い癒着の形成。
adhesion score5;極めて厚く血管新生も認められる癒着の形成又は二箇所以上の、播種状に付着した厚い癒着の形成。
(使用動物)
正常マウスとしてBALB/cを用いた。BALB/cはJackson Laboratoryから購入した。
まず、BALB/c群に上記手術類似侵襲を施した。次に、当該手術類似侵襲を施術する直前及び施術後経時的に、BALB/cを開腹して焼灼部位を含む組織を切除して、パラフィン固定を行なった後、3μmの厚さに薄切りした。なお、以下、マウスの表記の後に「群」と付した場合、10匹〜15匹を一群とする当該マウス群を示すものとする。
(使用動物)
本実施例では、正常マウスとしてBALB/cを用いた。また、BALB/cからCD4+T細胞を除去したマウス(以下、「anti−CD4Ab」と表記する)を用いた。
まず、BALB/c群及びanti−CD4Ab群に上記手術類似侵襲を施術した。
CD4+T細胞は、上述のように2種類に分類される。ここでは、CD4+T細胞のうち、iNKT細胞の腸管癒着に対する関与を検討した。
本実施例では、iNKT細胞欠損マウス(以下、「NKT-/-」と表記する)及びNKT-/-にBALB/c由来のCD4+T細胞を1匹当たり1×107個、尾静脈より移入したマウス(以下、「NKT-/-+WTCD4T」と表記する)を用いた。
まず、NKT-/-群及びNKT-/-+WTCD4T群に上記手術類似侵襲を施術した。次に、施術から7日経過後に開腹して腸管癒着の形成を肉眼で観察して、adhesion scoreにより腸管癒着の程度を評価した。その結果を図5に示す。図5は、上記手術類似侵襲施術後のNKT-/-群及びNKT-/-+WTCD4T群の腸管癒着形成を評価した結果を示す図であり、比較のため実施例2で行なった、BALB/c群に対する上記手術類似侵襲の施術の結果をも示している。
本実施例では、IFN−γが腸管癒着形成に関与する因子であることを確認した。
本実施例では、正常マウスとしてC57BL/6を用いた。また、IFN−γ欠損マウス(以下、「IFNγ-/-」と表記する)及びIFNγ-/-に対して、施術一日前に浸透圧ポンプを皮下に装着させて、1週間で1匹当たり100μgのIFN−γを投与したマウス(以下、「IFNγ-/-+IFNγ」と表記する)を用いた。IFNγ-/-は、東京大学医科学研究所 岩倉洋一郎教授より恵与された。
まず、C57BL/6群に上記手術類似侵襲を施術した。次に、施術後の焼灼部位から経時的にmRNAを精製した。そして、精製したサンプルをreal time PCRに供して、IFN−γをコードするmRNA(以下、「IFN−γmRNA」と表記する。)の発現量を測定した。なお、上記mRNAの精製には、RNA抽出キット(QIAGEN社製RNeasy Mini Kit、品番74106)を用いた。
本実施例では、腸管癒着形成に対するIFN−γの関与を詳細に確認した。
本実施例では、実施例3で用いたNKT-/-に、IFNγ-/-由来のCD4+T細胞を移入したマウス(以下、「NKT-/-+IFNγ-/-CD4T」と表記する)を用いた。
まず、NKT-/-+IFNγ-/-CD4T群に上記手術類似侵襲を施術した。次に、施術から7日経過後に開腹して腸管癒着の形成を肉眼で観察して、adhesion scoreにより腸管癒着の程度を評価した。その結果を図9に示す。図9は、上記手術類似侵襲後の、NKT-/-+IFNγ-/-CD4T群の腸管癒着形成を評価した結果を示す図であり、比較のため実施例2で行なった、NKT-/-+WTCD4T群に対する上記手術類似侵襲の施術の結果をも示している。
本実施例では、腸管癒着形成に対するIFN−γの関与について、IFN−γの細胞内シグナル伝達に必須の転写因子であるSTAT1を欠損させたマウスを用いて、より詳細に確認した。
本実施例では、STAT1を欠損させたマウス(以下、「STAT1-/-」と表記する)、STAT4を欠損させたマウス(以下、「STAT4-/-」と表記する)及びSTAT6を欠損させたマウス(以下、「STAT6-/-」と表記する)を用いた。
まず、STAT1-/-群、STAT4-/-群及びSTAT6-/-群に上記手術類似侵襲を施術した。
本実施例では、substance Pを含むタキキニンによるIFN−γ産生の機構を確認した。上述のように、substance Pを含むタキキニンは、手術等の物理的刺激が加わることで、神経末端から分泌される神経伝達因子の一つである。
本実施例では、substance Pを含むタキキニンの産生を制御する遺伝子であるtac1を欠損させたマウス(以下、「Tac1-/-」と表記する。)を用いた。Tac1-/-は、Jackson Laboratoryから購入した。
まず、Tac1-/-群に、上記手術類似侵襲を施術した。
本実施例では、腸管癒着形成にSTAT1が関与するメカニズムについて、STAT1とtPA及びPAIとの関係等から確認した。
本実施例では、正常マウスとしてBALB/cを用いた。また、実施例6に記載のSTAT1-/-を用いた。
腸管癒着形成に関与するメカニズムを明らかにするため、まず、腸管癒着形成に対するtPA及びPAIの関与を確認した。
次に、腸管癒着形成に対するSTAT1及びPAIの関与を検討した。
本実施例では、IFN−γ産生を阻害することにより、腸管癒着の形成を抑制できるか否かを確認した。
本実施例ではBALB/cを用いた。
IFN−γ阻害物質としてHGFを用いて、HGFの投与と、BALB/cの腸管癒着形成との関係を調べた。
HGF20μgをPBSに溶解して200μlに調整した溶液の投与時期を変更した以外は、実施例9に記載した方法と同じ方法で、腸管癒着形成の抑制効果を確認した。投与時期としては、手術類似侵襲の施術から30分、1、3、5日後とした。それぞれの投与時期、実施例9の投与時期(施術の1日前)、及び比較のためPBSのみを投与した結果を図17に示す。図17は、HGFの投与時期と腸管癒着形成との関係を調査した結果を示す図であり、横軸は投与時期を示し、縦軸はAdhesion Scoreを示す。なお、PBSのみの投与は施術の1日前に行なった。なお、HGFについてはペプロテック社から購入したヒトHGFをPBSに調整して使用した。
本実施例では、IFN−γ阻害物質としてIFN−γ中和抗体を用い、該IFN−γ中和抗体を、2mg/bodyとなるように投与した以外は実施例9に記載した方法と同じ方法で、腸管癒着形成の抑制効果を確認した。
本実施例ではタキキニンがIFN−γの産生を誘導するか否か確認した。
Claims (1)
- HGF及びIFN−γ中和抗体からなる群より選ばれる少なくとも1つのIFN−γ阻害物質を含むことを特徴とする腸管が侵襲される手術の1日前から当該手術の術前までの間のみに静脈注射又は皮下注射によって投与するための腸管癒着抑制剤。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008558089A JP5530635B2 (ja) | 2007-02-14 | 2008-02-13 | 腸管癒着抑制剤 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007033904 | 2007-02-14 | ||
JP2007033904 | 2007-02-14 | ||
PCT/JP2008/052299 WO2008099829A1 (ja) | 2007-02-14 | 2008-02-13 | 実験動物の腸管癒着を形成する方法、腸管癒着実験動物の製造方法、腸管癒着抑制剤のスクリーニング方法及び腸管癒着抑制剤 |
JP2008558089A JP5530635B2 (ja) | 2007-02-14 | 2008-02-13 | 腸管癒着抑制剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2008099829A1 JPWO2008099829A1 (ja) | 2010-05-27 |
JP5530635B2 true JP5530635B2 (ja) | 2014-06-25 |
Family
ID=39690057
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2008558089A Active JP5530635B2 (ja) | 2007-02-14 | 2008-02-13 | 腸管癒着抑制剤 |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP5530635B2 (ja) |
WO (1) | WO2008099829A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2019078344A1 (ja) * | 2017-10-20 | 2020-09-17 | 学校法人兵庫医科大学 | 抗il−6受容体抗体を含有する術後の癒着を抑制するための医薬組成物 |
US11851486B2 (en) | 2017-05-02 | 2023-12-26 | National Center Of Neurology And Psychiatry | Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA025493B1 (ru) * | 2011-05-17 | 2016-12-30 | Акционерное Общество "Фармасинтез" | Соединения, фармацевтические композиции и способ профилактики и лечения спаечного процесса |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11511160A (ja) * | 1995-08-18 | 1999-09-28 | ザ・ビクトリア・ユニバーシティ・オブ・マンチェスター | インターフェロン−ガンマインヒビター含有医薬組成物 |
JP2003517007A (ja) * | 1999-12-15 | 2003-05-20 | エントレメッド インコーポレイテッド | 内皮細胞増殖阻害組成物および方法 |
-
2008
- 2008-02-13 JP JP2008558089A patent/JP5530635B2/ja active Active
- 2008-02-13 WO PCT/JP2008/052299 patent/WO2008099829A1/ja active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11511160A (ja) * | 1995-08-18 | 1999-09-28 | ザ・ビクトリア・ユニバーシティ・オブ・マンチェスター | インターフェロン−ガンマインヒビター含有医薬組成物 |
JP2003517007A (ja) * | 1999-12-15 | 2003-05-20 | エントレメッド インコーポレイテッド | 内皮細胞増殖阻害組成物および方法 |
Non-Patent Citations (6)
Title |
---|
JPN6012047913; 玉熊正悦, 他.: 現代医療 Vol.14, No.12, 19821210, p.2407-2411, (株)現代医療社 * |
JPN6013030991; Surgery Vol.140,No.3, 2006, p441-447 * |
JPN7012003725; REED, K.L., et al.: 'A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increas' Proceedings of the National Academy of Sciences of the United States of America Vol.101, No.24, 20040615, p.9115-9120 * |
JPN7012003726; KUROIWA, T., et al.: 'Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic func' The Journal of Clinical Investigation Vol.107, No.11, 200106, p.1365-1373 * |
JPN7012003727; PITTAWAY, D.E., et al.: 'A comparison of the CO2 laser and electrocautery on postoperative intraperitoneal adhesion formation' FERTILITY AND STERILITY Vol.40, No.3, 198309, p.366-368 * |
JPN7012003728; 森本悟一: '電気メス使用の結腸縫合創治癒に及ぼす影響に関する実験的研究' 日本消化器外科学会雑誌 Vol.13, No.10, 198010, p.1174-1185 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11851486B2 (en) | 2017-05-02 | 2023-12-26 | National Center Of Neurology And Psychiatry | Method for predicting and evaluating therapeutic effect in diseases related to IL-6 and neutrophils |
JPWO2019078344A1 (ja) * | 2017-10-20 | 2020-09-17 | 学校法人兵庫医科大学 | 抗il−6受容体抗体を含有する術後の癒着を抑制するための医薬組成物 |
JP7235249B2 (ja) | 2017-10-20 | 2023-03-08 | 学校法人兵庫医科大学 | 抗il-6受容体抗体を含有する術後の癒着を抑制するための医薬組成物 |
US11692037B2 (en) | 2017-10-20 | 2023-07-04 | Hyogo College Of Medicine | Anti-IL-6 receptor antibody-containing medicinal composition for preventing post-surgical adhesion |
Also Published As
Publication number | Publication date |
---|---|
WO2008099829A1 (ja) | 2008-08-21 |
JPWO2008099829A1 (ja) | 2010-05-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Carlson et al. | Cardiac macrophages adopt profibrotic/M2 phenotype in infarcted hearts: Role of urokinase plasminogen activator | |
Chung et al. | Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands | |
JP2010143935A (ja) | 血管新生を減少させる方法 | |
JP2009528977A (ja) | 慢性線維形成性疾患を治療するための物質および方法 | |
KR20200083503A (ko) | Tim-3 경로와 pd-1 경로의 이중 저해제 | |
JP2009538274A (ja) | Cxcl13またはcxcr5のアンタゴニストの創傷または線維症疾患の治療のための使用 | |
US20120315279A1 (en) | Compositions and method of modulating growth factor function | |
Al Heialy et al. | T cell–induced airway smooth muscle cell proliferation via the epidermal growth factor receptor | |
JP5530635B2 (ja) | 腸管癒着抑制剤 | |
WO2012064967A2 (en) | Cancer cell-derived receptor activator of the nf-kb ligand drives bone and soft tissue metastases | |
US9068004B2 (en) | TWEAK/Fn14 system regulates skeletal muscle atrophy and regeneration | |
EP3747440A1 (en) | Method for destroying cellular mechanical homeostasis and promoting regeneration and repair of tissues and organs, and use thereof | |
US10160805B2 (en) | Methods of treating inflammatory bowel disease by administering tumor necrosis factor-like ligand 1A or an agonistic death-domain receptor 3 antibody | |
US20140255404A1 (en) | Pulmonary hypertension | |
Tian et al. | A combination of chitosan, cellulose, and seaweed polysaccharide inhibits postoperative intra-abdominal adhesion in rats | |
US20220218874A1 (en) | Compositions and methods of modulating endochondral ossification and bone formation | |
US20060276385A1 (en) | Anti-inflammatory agents and methods of their use | |
KR101748120B1 (ko) | 나노입자-유리체 기반 단백질 복합체를 유효성분으로 포함하는 혈관신생억제용 조성물 및 이의 용도 | |
US12011446B2 (en) | Method of using MeK inhibitor to prevent radiation induced fibrosis | |
CN111662972A (zh) | Traf3通过抑制il-17信号防治关节炎 | |
US20230159629A1 (en) | Compositions and method of modulating growth factor function | |
Jia et al. | Pingyangmycin-regulated expressions of adhesion molecules in human venous malformation endothelial cells | |
CN111840545B (zh) | 依鲁替尼作为血管抑制剂的作用、降低其副作用的药物及其用途 | |
WO2018119080A1 (en) | Compositions and methods for treating hepatic disorders | |
Rabinovitch | Pathology of pulmonary hypertension |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100930 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120911 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121106 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130625 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130821 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140401 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140421 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5530635 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |