JP2015168665A - Inhibitor for exacerbation of bleeding and/or inflammation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an agent for preventing and/or treating the bleeding exacerbation caused by bleeding exacerbation-causing oral bacteria.SOLUTION: This invention provides an inhibitor for exacerbation of bleeding and/or inflammation, comprising an inhibition material that inhibits the interaction between collagen-binding protein (CBP) on the body surface of an oral bacterium and collagen exposed at a damage site of tissue.

Description

  The present invention relates to a hemorrhagic and / or inflammation exacerbation inhibitor comprising an inhibitor that inhibits the interaction between collagen-binding protein (CBP) and collagen on the surface of oral bacteria, and inhibits the function of the collagen-binding domain of CBP. It relates to a binding inhibitor.

Examples of conditions involving bleeding due to blood vessel damage include bleeding due to trauma and blood vessel rupture, bleeding during childbirth, intracerebral hemorrhage, etc. In the case of injury or subarachnoid hemorrhage, severe damage may occur due to neurological symptoms caused by cerebral vasospasm induced by bleeding.
In order to improve the prognosis of bleeding, not only effective bleeding treatment (hemostasis) but also prevention and suppression of bleeding exacerbation is necessary, and it is also important to diagnose the risk of exacerbation of bleeding. is there.

  In recent years, it has been pointed out that oral bacteria are involved in various systemic diseases. For example, Streptococcus mutans, a cariogenic bacterium, is also known as a causative agent of bacteremia and infective endocarditis, and bacterial DNA of S. mutans is detected from heart valve and aortic aneurysm specimens Therefore, the relationship with cardiovascular diseases has also been reported (Non-patent Document 1). In addition, among S. mutans, those having a collagen binding protein (CBP) have been reported to promote exacerbation of cerebral hemorrhage and inflammatory colitis (Patent Documents 1 and 2 and Non-Patent Document 2).

International Publication No. 2010/113627 International Publication No. 2001/111790

Nakano et al., 2008, Japanese Dental Science Review, 44: 29-37 Nakano et al., Nature communications, 2 (2011): 485.

  The present invention is based on the idea that if the interaction between collagen-binding protein (CBP) possessed by oral bacteria and collagen can be inhibited, it can contribute to effective bleeding treatment (hemostasis), its inhibitory substance, and An object of the present invention is to provide an agent for preventing and / or treating bleeding exacerbation caused by the oral bacteria.

  The present inventors studied the effect of Streptococcus mutans, which is a cariogenic bacterium present in blood, on systemic diseases, and the collagen binding protein possessed by S. mutans is a site of vascular endothelial injury that is a bleeding site. That binds to exposed collagen and accumulates at the site of injury, delays healing of the bleeding site, and S. mutans with collagen-binding protein is taken up by hepatocytes and Kupffer cells and inflammatory cytokines Focused on the fact that it causes the secretion of. Therefore, further research was conducted, and it was found that a peptide of about 10-20 having the same amino acid sequence as a part of the collagen-binding protein can attenuate the interaction between CPB and collagen. The present invention has been completed.

That is, the present invention relates to the following.
[1] A bleeding and / or inflammation exacerbation inhibitor comprising an inhibitor that inhibits the interaction between collagen binding protein (CBP) on the surface of oral bacteria and collagen.
[2] The hemorrhage and / or inflammation exacerbation inhibitor of [1], wherein the oral bacteria is Streptococcus mutans.
[3] The hemorrhage and / or inflammation exacerbation inhibitor of [1] or [2], wherein the inhibitor inhibits the binding between type I collagen and CBP.
[4] The bleeding and / or [1] to [3], wherein the inhibitor inhibits the interaction between type I collagen and CBP containing the sequence represented by SEQ ID NO: 139 or a functional equivalent thereof. Or an inflammation exacerbation inhibitor.
[5] The hemorrhage and / or inflammation exacerbation inhibitor of [1] to [4], wherein the inhibitor is a substance that binds to the collagen binding domain of CBP.
[6] The bleeding and / or inflammation exacerbation inhibitor of [1] to [5], wherein the inhibitor is an antibody.
[7] The hemorrhage and / or inflammation exacerbation inhibitor of [1] to [4], wherein the inhibitor is a partial sequence of the collagen binding domain sequence of CBP.

  According to the present invention, it becomes possible to prevent exacerbation of bleeding and / or inflammation by CBP-bearing oral bacteria that are exacerbation factors of bleeding and / or inflammation. It is considered that oral bacteria present in the blood act on exacerbation of bleeding and inflammation caused by oral bacteria. Especially in the case of bleeding, it does not occur site-specifically but can occur at the site of bleeding throughout the body, and when bleeding exacerbation occurs in places that are difficult to find or that are difficult to perform surgical treatment, There is a high possibility of becoming serious. The agent of the present invention prevents the exacerbation of bleeding by inhibiting the interaction between oral bacteria and collagen exposed at the bleeding site, and also has no site-specific effect, so its existence is not recognized. It is possible to prevent exacerbation of bleeding even in bleeding sites, bleeding in organs and brains where local treatment is difficult.

FIG. 1 is a graph showing the inhibitory effect of the antibody of the present invention on the ability to bind collagen of hemorrhagic and / or inflammation-enhanced oral bacteria. The horizontal axis represents the amount of antibody added, and “−” represents a negative control. The vertical axis represents the relative collagen binding ability when the collagen binding ability of the bacterium when no antibody is added is taken as 100%. It can be seen that as the amount of the antibody added increases, the relative collagen binding ability decreases.

The present invention will be described in detail below.
(1) Bleeding and / or inflammation exacerbation inhibitor of the present invention In one aspect, the present invention is a bleeding comprising an inhibitor that inhibits the interaction between collagen binding protein (CBP) and collagen on the surface of oral bacteria. And / or an inflammation exacerbation inhibitor.

  In the present invention, “oral bacteria” means bacteria that are resident in the oral cavity and are synonymous with “oral bacteria”. The oral bacterium in the present invention is not particularly limited as long as it has a collagen binding protein on the surface of the cell. Streptococcus downei, Streptococcus anginosus, Streptococcus sanguinis, Streptococcus oralis, Streptococcus gordonii, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotellamelaninogenica, Fusobacterium nucleatum, Bacterionero aceticum Streptococcus sobrinus and the like, more preferably Streptococcus mutans, which is known to have CBP that binds to type I collagen on the surface of the cells. In the present invention, oral bacteria that can become bleeding exacerbation factors are particularly referred to as “bleeding-enhancing oral bacteria”, and oral bacteria that can be inflammation-exacerbating factors are referred to as “inflammation-enhancing oral bacteria”.

  In the present invention, “collagen binding protein (CBP)” means a protein having the property of interacting and binding to collagen which is a biological protein. A region that interacts with collagen in the collagen-binding protein sequence is particularly referred to as a “collagen-binding domain”.

  In general, “bleeding” is classified into “ruptured bleeding” and “leaky bleeding” depending on the cause, but the bleeding and / or inflammation exacerbation inhibitor of the present invention is preferably used particularly for broken bleeding. it can. Disruptive hemorrhage is caused by the rupture of the blood vessel wall due to various causes such as trauma, rupture of an aneurysm, lesion erosion from surrounding tissues, and usually occurs in the blood vessel wall due to platelet aggregation, blood coagulation reaction, etc. There is a mechanism in the body that stops bleeding by closing the hole. For example, at the site where ruptured bleeding has occurred, type I collagen is exposed in the damaged vascular endothelium, and von Willebrand factor (vWF) binds to the exposed collagen. Blood platelets aggregate and adhere by binding to exposed collagen and vWF bound to collagen. The blood coagulation reaction proceeds by releasing various active substances from the aggregated platelets or by activating the platelet aggregates by shear stress stimulation from the bloodstream. In addition, the exposed collagen itself activates the XII coagulation factor, whereby the blood coagulation cascade proceeds.

  The mechanism by which oral bacteria cause exacerbation of bleeding is not completely clarified, but collagen-binding proteins present on the surface of oral bacteria that are exacerbations of bleeding interact with collagen exposed at the site of injury. It is thought to be caused by acting. That is, when oral bacteria are bound to collagen, vWF and platelets cannot be bound, and activation of the XII coagulation factor by collagen is also inhibited, so that the hemostatic mechanism is not activated. .

  In addition, the mechanism of inflammation exacerbation caused by oral bacteria is not completely clarified, but oral bacteria that are inflammation exacerbating factors are mediated by collagen binding protein (CBP) present on the surface of the cells. It is thought that these cells are taken up by interaction with hepatocytes and promote the secretion of inflammation-inducing cytokines such as IFNγ. Examples of the inflammation exacerbated by the inflammation-promoting oral bacteria include, but are not limited to, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.

  The exacerbation inhibitor of bleeding and / or inflammation of the present invention contains a substance that inhibits the interaction between collagen and CBP present on the surface of cells of bleeding and / or inflammation-increasing malignant oral bacteria. It prevents the oral bacteria from interacting with exposed collagen and hepatocytes at the site of vascular endothelial injury, thereby promoting normal activation of the hemostatic mechanism and preventing the initiation of inflammatory signals. Generally, it is known that type I collagen is exposed at the damaged site of the vascular endothelium. Therefore, in one embodiment of the present invention, the inhibitor of the present invention can inhibit the binding between type I collagen and CBP.

  In one embodiment of the present invention, the bleeding exacerbation inhibitor contains a substance that inhibits the binding between CBP and type I collagen present on the surface of S. mutans cells. One of the anchor proteins of S. mutans, CBP (also referred to as Cnm) is a type I collagen binding protein with a molecular weight of about 120 kDa, a collagen binding domain (CBD, residues 152-316), a B repeat domain ( Residues 328-455) and the LPXTG motif (residues 507-511) (Sato et al., 2004, Journal of Dental Research, 83 (7): 534-539). The CBP gene possession frequency of S. mutans is about 10-20%, and CBP positive strains are known to be expressed mainly in serotypes f and k (Nakano et al., 2007, J. Clin. Microbiol., 45: 2616-2625).

  According to the study by the present inventors, in CBP possessed by S. mutans, it is clear that the CBD and LPXTG motifs are highly conserved among strains, but the number of B repeat domain repeats varies from strain to strain. (Nomura et. Al., 2009, J. Med. Microbiol., 58: 469-75). Therefore, in one embodiment of the present invention, the inhibitory substance inhibits the interaction between type I collagen and CBP containing the sequence represented by SEQ ID NO: 139 or a functional equivalent thereof.

  In the present invention, the “functional equivalent” of a specific sequence means one having a function equivalent to the function of the molecule represented by the sequence. For example, in the case of a functional equivalent of the sequence of S. mutans CBD, as described above, CBD is known to be highly conserved among strains. Therefore, the CBD present in the CBP of each S. mutans strain is functional. It is considered to be included in the physical equivalent. The functional equivalent of a specific amino acid sequence includes an amino acid sequence having high homology with the amino acid sequence. In general, an amino acid sequence having a homology of 70% or more, preferably 80% or more, more preferably 90% or more, more preferably 95% or more of homology with a specific amino acid sequence Included in the functional equivalent of a sequence.

  Functional equivalents of a particular nucleic acid sequence include nucleic acids that hybridize under stringent conditions to the complementary sequence of the nucleic acid sequence. “Stringent conditions” refers to conditions under which only specific hybridization occurs and non-specific hybridization does not occur. Such conditions are usually conditions such as hybridization at 37 ° C. and washing treatment at 37 ° C. with a buffer containing 1 × SSC and 0.1% SDS, preferably hybridization at 42 ° C. and Conditions such as washing at 42 ° C. with a buffer containing 0.5 × SSC and 0.1% SDS, more preferably hybridization at 65 ° C. and 0.2 × SSC and 0.1% SDS. The condition is a washing treatment at 65 ° C. with a buffer solution. A functional equivalent of a specific nucleic acid sequence encoding a polypeptide includes a degenerate sequence of the sequence.

  The inhibitor contained in the hemorrhage and / or inflammation exacerbation inhibitor of the present invention is not particularly limited as long as it is a substance that can inhibit the interaction between collagen and CBP on the surface of cells of the hemorrhagic malignant oral bacteria. . “Inhibiting interaction” means reducing the interaction between substances, for example, binding to one of the interacting substances to reduce the interaction, or It includes reducing the interaction by reducing the expression level.

Substances that reduce the interaction between CBP and collagen typically include (i) CBP, preferably a substance that binds to the collagen binding domain of CBP and inhibits the binding between CBP and collagen, (ii) CBP And (iii) a substance that reduces the expression of CBP, and the like.
Examples of the substance that binds to CBP, preferably binding to the collagen-binding domain of CBP and inhibits the binding between CBP and collagen include antibodies that recognize part or all of the collagen-binding domain as an epitope.

  An antibody that recognizes part or all of CBP, preferably the collagen-binding domain of CBP as an epitope can be produced using a conventional method known in the art. As a simple method, for example, a rat is immunized with an epitope candidate polypeptide as an antigen, lymphocytes are collected from the immunized rat, and the lymphocytes and mouse myeloma cells are fused to produce an antibody-producing hybridoma. The method of obtaining is mentioned.

  Examples of the substance that binds to the collagen region to which the collagen-binding domain of CBP binds and competitively inhibits CBP include a polypeptide containing a partial sequence of the collagen-binding domain of CBP or a functional equivalent thereof. Such polypeptides can also be produced using conventional methods known in the art. Such a method includes, for example, a method of fragmenting into a peptide having a length of about 10 to 20 amino acids with respect to a known sequence and examining the binding between the peptide fragment and collagen.

  Examples of the substance that reduces the expression of CBP include polynucleotides such as siRNA and antisense nucleic acid for a nucleic acid sequence encoding CBP. Such polynucleotides can also be produced using conventional methods known in the art.

(2) Inhibitory substance of the present invention In one aspect of the present invention, a novel substance capable of inhibiting the interaction between collagen and CBP on the surface of bacterial cells of hemorrhagic and / or inflammation-enhancing oral bacteria is provided. . Accordingly, the present invention also includes such inhibitors.
As described above, the inhibitory substance of the present invention is not particularly limited as long as it is a substance that can inhibit the interaction between collagen exposed at the site of tissue damage and CBP on the surface of cells of the hemorrhagic malignant oral bacteria. Examples of such substances include, but are not limited to, for example, those that inhibit the binding between collagen and CBP by binding to CBP (such as CBP-specific antibodies), and those that bind to collagen. Examples thereof include those that inhibit the binding between CBP and collagen (for example, collagen-binding ligand) and those that inhibit the expression of CBP in oral bacteria (for example, siRNA of CBP).

  Examples of the inhibitory substance of the present invention that inhibits the binding between collagen and CBP by binding to CBP include CBP-specific antibodies and CBP-binding ligands. CBP is believed to bind collagen with a collagen binding domain (CBD) present in its sequence, and therefore, in the inhibitor of this embodiment, preferably recognizes part or all of the collagen binding domain of CBP as an epitope. However, it is not limited to this. For example, a site other than the collagen-binding domain is recognized as an epitope, but spatially hinders the binding between the collagen-binding domain and collagen, or the CBP three-dimensional structure can be changed by binding to CBP, etc. Is also included.

  As another embodiment of the inhibitor of the present invention, as a substance that inhibits the binding between CBP and collagen by binding to collagen, for example, a partial sequence peptide of the collagen binding domain of CBP or a functional equivalent thereof, etc. For example, a collagen-binding ligand. Since the inhibitor of this embodiment has a property of binding to collagen, it does not adversely affect the role of collagen in coagulation such as platelet aggregation, binding to vWF, activation of coagulation factor XII, etc. desirable.

As a result of examining the possibility that the amino acid sequence forming the primary structure of a protein having the property of binding to collagen contains a sequence that interacts with collagen, the present inventors exert particularly strong inhibitory activity. Finding that there are 13 peptide sequences of ˜16 amino acids in length, there is a consensus sequence (FLNINNE: SEQ ID NO: 138) common to 5 of them, and that 5 sequences contain sequences similar to such consensus sequences Newly found. Accordingly, the present invention in one aspect relates to the 13 inhibitory peptide sequences of Table 1 having such inhibitory activity, preferably 10 inhibitory peptide sequences having the consensus sequence. Here, the “sequence similar to the consensus sequence” means a sequence in which about 1 to 3 amino acids are deleted, substituted, or added in the consensus sequence. It is preferably substituted with the same class of amino acids. There are several amino acid classifications depending on the property of interest, but all are known in the art, and those skilled in the art can readily understand amino acid classifications. For example, phenylalanine (F) is classified as an aromatic amino acid among neutral amino acids, and examples of the same class of amino acids include tyrosine (Y) and tryptophan (W). Leucine (L) and isoleucine (I) are classified as aliphatic amino acids among neutral amino acids, and examples of the same class of amino acids include glycine (G), alanine (A), and valine (V). Asparagine (N) is classified as an acetic acid amino acid amide among neutral amino acids, and examples of the same class of amino acids include glutamine (Q). Glutamic acid (E) is classified as an acidic amino acid, and aspartic acid (D) and the like are listed as amino acids of the same class.

  Examples of the inhibitor of the present invention, which inhibits the expression of CBP in oral bacteria, include siRNA against CBP.

(3) Treatment and prevention method of bleeding exacerbation of the present invention The present invention provides a novel hemorrhage and / or inflammation exacerbation inhibitor, and therefore, in one aspect of the present invention, bleeding and / or inflammation in a subject A method for preventing and / or treating an exacerbation of a disease comprising the step of administering to a subject in need thereof an effective amount of the bleeding and / or inflammation exacerbation inhibitor of the present invention is also included in the present invention. Is included.
The “subject” in the present invention may be any individual organism as long as it can possess bleeding and / or inflammation-promoting oral bacteria, but preferably human and non-human mammals (eg, mice, Rats, guinea pigs, hamsters and other rodents, chimpanzees and other primates, cows, goats, sheep and other cloven-hoofed animals, horses and other terrestrial eyes, rabbits, dogs and cats, etc., and more preferably humans Individual. The subject may or may not have a bleeding site, but possesses hemorrhagic and / or inflammatory malignant oral bacteria.

  The bleeding and / or inflammation exacerbation inhibitor of the present invention used in the prevention / treatment method of the present invention includes any of those described herein. The effective amount in the present invention is, for example, an amount that delays or stops the progress of bleeding. In addition, an amount that does not cause adverse effects exceeding the benefits of administration is preferred. Such an amount can be appropriately determined by tests in model animals such as mice and rats, and such test methods are well known to those skilled in the art. The specific dose of the active ingredient depends on various conditions relating to the subject in need thereof, such as severity of symptoms, general health status of the subject, age, weight, subject sex, diet, timing and frequency of administration, It can be determined in consideration of the drug used in combination, the response to treatment, the dosage form, compliance with the treatment, and the like.

Moreover, as an administration method, any known appropriate administration method can be used, such as intraarterial administration, intravenous administration, intraoral administration, and the like to a site where hemorrhagic malignant oral bacteria can exist. Particularly preferred is intravenous administration.
One aspect of the prevention / treatment method of the present invention further includes a step of selecting a subject having bleeding-enhancing malignant oral bacteria as a subject of prevention / treatment before the administering step.

All patents, applications and other publications mentioned herein are hereby incorporated by reference in their entirety.
EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to these Examples. In the following examples, the term “collagen binding protein” or “CBP” simply means the collagen binding protein of DDBJ accession number: AB1026892.

Experimental Example 1: Search for binding inhibitory peptides
Based on published information on the primary structure of collagen binding protein derived from Streptococcus mutans (DDBJ accession number: AB1026892), collagen binding protein derived from Staphylococcus aureus (PDBj accession number: 2F6A) and collagen protein, etc. Using the technique, it was divided into peptides of appropriate length. Thereby, for AB1026892, a total of 69 sequences from the N-terminal side alignment, 31 sequences from the C-terminal side extended alignment, and 38 sequences from the C-terminal side extension alignment, and 2F6A, a total of 38 sequences, from the N-terminal side alignment to 29 sequences, A total of 111 sequences were obtained: 4 sequences derived from collagen protein. Furthermore, these sequences were subjected to primary evaluation. As a result, 64 sequences obtained by further shortening and enhancing the activity of several hit sequences were combined to obtain a partial peptide of the primary sequence of the protein or a 137 sequence which is a similar sequence. .

Experimental Example 2: Measurement of Collagen Binding Inhibitory Activity Regarding the 137 sequences obtained in Experimental Example 1, the collagen binding ability of CBP-bearing bacteria when these peptides are allowed to act is measured, and the binding ability of the control is compared to 100%. Thus, the collagen binding inhibitory activity of each peptide was calculated.
(1) Preparation of samples For the measurement, Streptococcus mutans TW871 and TW295 strains, which are CBP-bearing bacteria, were used (for details of the strain, Fujiwara et al., Eur. J. Oral Sci. 109, 330-334 (2001 )reference). The bacterial suspension was adjusted with PBS so that OD ₅₀₀ = 1.0, and the bacterial suspension further diluted 10 times was used as the bacterial solution. The peptide of Experimental Example 1 was added to 1 ml of the prepared bacterial solution so as to have a final concentration of 10 μM, and reacted while rotating at about 20 rpm at room temperature for 1 hour. As a control, the TW871 strain was used without being mixed with the peptide, and the TW295 strain was used by being mixed with the peptide.

(2) Measurement of collagen binding capacity 200 μl of 96-well tissue culture plate (Becton Dickinson) mixed with sterile distilled water added with 0.1M acetic acid and type I collagen (Sigma) at a ratio of 9: 1 And incubated overnight at 4 ° C. Thereafter, the plate was washed 3 times with PBS, 200 μl of PBS containing 5% bovine serum albumin was added, and the plate was blocked by incubating at 37 ° C. for 1.5 hours. The wells were washed with PBS supplemented with 0.01% Tween 20 (Wako Pure Chemical Industries), then seeded with 200 μl of the bacterial solution prepared in (1) and cultured at 37 ° C. for 3 hours. Thereafter, the plate was washed 3 times with PBS, 200 μl of 25% formaldehyde was added, and the mixture was allowed to stand at room temperature for 30 minutes and fixed. After further washing with PBS three times, 200 μl of a solution obtained by adding 0.05% crystal violet (Wako Pure Chemical Industries) to sterile distilled water was added and allowed to stand at room temperature for 1 minute, and again washed with PBS three times. Absorbance (OD ₅₉₅ ) was measured by adding 7% acetic acid. The absorbance of the control was 100%, and the binding inhibitory activity of each peptide was calculated by increasing or decreasing the absorbance. The results are shown in the table below.

As shown in the above table, peptides having the property of inhibiting the binding between CBP and collagen were observed among the peptides. Among them, 13 peptides showing strong inhibitory activity (collagen binding ability of 80% or less) were confirmed. Among them, a consensus sequence (FLNINNE (SEQ ID NO: 138)) common to 10 sequences or a similar sequence was found.
In addition, since the primary sequence possessed by the peptide exhibiting inhibitory activity is considered to be the primary sequence involved in the interaction between collagen and CBP, an antibody having such primary sequence as an epitope also contains collagen and CBP. It is thought that the interaction of can be inhibited.

(3) Preparation of antibody A monoclonal antibody that recognizes CBP was prepared by a conventional method. Briefly, 10 week old female rats were immunized with 53 μg GST-CBP protein and boosted with 40 μg GST-CBP protein 18 days later. Lymphocytes were collected from the iliac lymph nodes of immunized rats and fused with mouse myeloma cells SP2 by the PEG method to prepare hybridomas. As a result, a hybridoma producing an antibody that specifically recognizes CBP was obtained.
It is considered that an antibody that specifically recognizes the partial peptide obtained in Experimental Example 1 can also be obtained by the same method.

(4) Measurement of Collagen Binding Inhibitory Ability of Antibody Collagen binding inhibitory ability of the monoclonal antibody prepared in (3) was measured. The ability to inhibit collagen binding was performed by modifying (2). That is, in the preparation of the bacterial solution of (1), a predetermined amount of monoclonal antibody was added instead of adding the peptide. As a control, in addition to the TW871 strain in which no antibody was added (1), the TW295 strain in which no antibody was added (2) was also used. The results are shown in the table below. Moreover, what represented the result of (2) in the graph is shown in FIG.

As can be seen from the table, when the amount of antibody added is increased, the collagen-binding ability of the bacteria is reduced accordingly. Therefore, it can be seen that the monoclonal antibody inhibits the collagen-binding ability of bacteria in a dose-dependent manner.

  According to the present invention, a novel bleeding and / or inflammation exacerbation inhibitor is provided. Such an agent contains a novel inhibitor that inhibits the interaction between collagen and CBP, and the action of such an inhibitor prevents and / or exacerbates bleeding and / or exacerbation of inflammation caused by malignant oral bacteria. / Or can be treated. Especially if the subject has a bleeding exacerbated oral bacterium, bleeding in any part of the body can be exacerbated, and thus symptoms such as diseases of the circulatory system can be exacerbated. Although there is a risk that symptoms are more likely to worsen due to exclusion or the like, the agent of the present invention is useful because these risks can be reduced.

Claims (7)

  A hemorrhagic and / or inflammation exacerbation inhibitor comprising an inhibitor that inhibits the interaction between collagen binding protein (CBP) on the surface of oral bacteria and collagen.   The hemorrhagic and / or inflammation exacerbation inhibitor according to claim 1, wherein the oral bacteria is Streptococcus mutans.   The hemorrhagic and / or inflammation exacerbation inhibitor according to claim 1 or 2, wherein the inhibitor inhibits the binding between type I collagen and CBP.   The bleeding according to any one of claims 1 to 3, wherein the inhibitory substance inhibits the interaction between type I collagen and CBP containing the sequence represented by SEQ ID NO: 139 or a functional equivalent thereof. And / or an exacerbation inhibitor of inflammation.   The hemorrhage and / or inflammation exacerbation inhibitor according to any one of claims 1 to 4, wherein the inhibitor is a substance that binds to the collagen-binding domain of CBP.   The hemorrhage and / or inflammation exacerbation inhibitor according to any one of claims 1 to 5, wherein the inhibitor is an antibody.   The hemorrhage and / or inflammation exacerbation inhibitor according to any one of claims 1 to 4, wherein the inhibitor is a partial sequence of a collagen binding domain sequence of CBP.