WO2000001406A1

WO2000001406A1 - Medicinal utilization of heparin cofactor ii

Info

Publication number: WO2000001406A1
Application number: PCT/JP1999/003646
Authority: WO
Inventors: Minoru Tsukada; Takashi Gotoh; Teruaki Imada
Original assignee: Welfide Corporation
Priority date: 1998-07-07
Filing date: 1999-07-05
Publication date: 2000-01-13
Also published as: AU4397599A

Abstract

Utilization of heparin cofactor II in preventing and treating diseases caused by the abnormal acceleration of the functions of macrophages, pulmonary epithelial cells and/or synovial cells, in particular, blood coagulation promoting effect and cytokine producing effect (for example, articular diseases, lung diseases, diseases in association with vascular failure); and utilization of heparin cofactor II in producing preventives/remedies for the above diseases. The preventives/remedies containing heparin cofactor II can be topically administered to a joint, the respiratory tract, around a vascular failure, etc. and achieve a therapeutic effect at the target site in a low HCII dose.

Description

Description Heparinkov actor II for pharmaceutical applications

The present invention relates to a novel medicinal use of heparin cofactor II (hereinafter abbreviated as HCII). More particularly, the present invention relates to the use of HC II for the prevention and treatment of diseases involving macrophages, lung epithelial cells and / or synovial cells. The present invention also relates to the above-mentioned agent for local administration, which comprises HCII as an active ingredient. Background art

HCII is a plasma glycoprotein that has a blood coagulation inhibitory effect, and is known to inhibit proteases such as thrombin mainly in vitro (i /? Vitro) in the presence of dermatan sulfate and a large amount of heparin (Tollefsen et al., J.

Biol. Chem., 258: 6713-6716, 1983). Therefore, the present inventors have determined that HCII is different from antithrombin III (hereinafter abbreviated as A）), which exhibits an antithrombin action in the presence of heparan sulfate, and is specific at a site where a large amount of dermatan sulfate is present in vivo. It is thought that HCII alone may be administered in vivo (in vivo), and that HCII exhibits anticoagulant effects in specific organs, tissues or cells. It has been clarified that systemic administration is effective in the prevention and treatment of various diseases such as sepsis, diseases causing abnormal blood flow, and organ disorders such as liver, lung, kidney, and brain (EP-7815) No. 58).

However, the mechanism of its therapeutic effect has not yet been elucidated in many cases, and no suggestion has been given as to the possibility of further pharmaceutical use of HCII. Furthermore, although HCII is expected to be able to act specifically in vivo when administered alone, systemic administration requires large doses to achieve an effective therapeutic effect. May not be obtained.

Therefore, an object of the present invention is to search for a further pharmaceutical use of HCII, that is, a novel therapeutic effect of HCII for a disease, and to clarify the mechanism of the therapeutic effect. Another object of the present invention is to provide an HCII preparation which provides a selective therapeutic effect at a site to be treated by local administration of a low dose of HCII, thereby treating said disease. To allow safer use of HCII in Disclosure of the invention

The present inventors have concluded that HCII has a remarkable prophylactic and therapeutic effect on joint diseases such as rheumatoid arthritis and osteoarthritis, and that the prophylactic and therapeutic effect can be obtained by combination use of ΑΤΠΙ and Z or pelinastatin Has been found to be further enhanced.

Further, the present inventors have conducted research on the mechanism of the therapeutic effect, and found that HCII is a macrophage present in the joint capsule (a connective tissue membrane present around the joint) and a cell of synovial cells or macrophages. It has been found that it suppresses the function, that is, the abnormal increase of serine protease producing action and cytokine producing action, and suppresses the proliferation of these cells.

Therefore, the present inventors have considered, among other diseases for which the therapeutic effect of HCII is known, a disease caused by abnormal dysfunction of cells performing the same cell function as macrophage synovial cells, specifically, Pulmonary epithelial cells present in the alveoli, macrophages in the abdominal cavity, macrophages appearing around the site of vascular injury, are caused by abnormal enhancement of thrombin and other serine proteinase-producing, blood clotting, and cytokine-producing effects Similarly, the mechanism of HCII treatment for pulmonary diseases and diseases associated with vascular disorders Investigated Nism. As a result, it was also found that HCII exerts a therapeutic effect on these diseases by similarly suppressing the abnormal enhancement of the above-mentioned cell functions of the lung epithelial cells ゃ Macular phage.

Based on these findings, the present inventors have investigated the administration of the above-mentioned joint disease, pulmonary disease and vascular disease to the joint cavity in which synovial cells are present and the alveoli in which pulmonary epithelial cells are present. Local administration of HCII in the respiratory tract and around the site of vascular injury where migratory macrophages are present, the present invention succeeded in obtaining at least the same preventive and therapeutic effects as systemic administration of HCII. It was completed.

That is, the present invention is as follows.

(1) Macrophages, pulmonary epithelial cells or synovial cells containing pharmaceutically effective amount of HCII and pharmaceutically acceptable carrier, especially serine protease producing action, blood clotting activity activating action A preventive and therapeutic agent for a disease caused by abnormally high activity of at least one of and cytokine production.

(2) Prevention of diseases caused by abnormally increased serine protease production in macrophages, pulmonary epithelial cells or synovial cells around the body, which contain a pharmaceutically effective amount of HCII and a pharmaceutically acceptable carrier. Therapeutic agent.

(3) The agent for preventing and treating a disease according to the above (1) or (2), wherein the disease is a joint disease, a lung disease or a vascular disorder.

(4) An agent for preventing and treating joint diseases, comprising a pharmaceutically effective amount of HCII and a pharmaceutically acceptable carrier.

(5) The agent for preventing or treating a disease according to any one of the above (1) to (4), which is in a form for local administration, particularly for administration to a joint, an airway or a site around a vascular disorder.

(6) The preventive or therapeutic agent for any of the above-mentioned diseases 1 to 5, further comprising a pharmaceutically effective amount of ΑΤΙΠ and / or ΑΤΙΠrinastatin.

(7) Macrophages, pulmonary epithelial cells or synovial cells have cell functions, especially serine protease generation, blood coagulation activation and cytokine production. Use of HCII for the prevention and treatment of a disease caused by at least one action of hyperactivity.

(8) Use of H C II for prevention and treatment of a disease caused by abnormally increased production of serine protease in macrophages, pulmonary epithelial cells or synovial cells in vivo.

(9) The use of the above item 7 or 8, wherein the disease is a joint disease, a lung disease or a vascular disorder.

(10) Use of HCII for prevention and treatment of joint disease.

(11) The use according to any of the above items 7 to 10, wherein HCII is administered locally, particularly around a joint, an airway or a site of vascular injury.

(12) The use according to any one of the above items 7 to 11, which is used in combination with と and Z or ゥ linastatin.

(13) Diseases caused by abnormal enhancement of cell functions of macrophages, lung epithelial cells or synovial cells, in particular, at least one of serine oral protease production, blood coagulation activation and cytokine production Use of HCII for the manufacture of prophylactic and therapeutic agents for cancer.

(14) Use of HCII for the manufacture of a prophylactic and therapeutic agent for a disease caused by abnormally increased production of serine protease in macrophages, pulmonary epithelial cells or synovial cells in vivo.

(15) The use of the above item 13 or 14, wherein the disease is a joint disease, a lung disease or a vascular disorder.

(16) Use of HCII for production of a prophylactic and therapeutic agent for joint disease.

(17) The use according to any one of the above items 13 to 16, wherein the agent for preventing and treating a disease is in a form for local administration, particularly for administration to a joint, a respiratory tract or a site around a vascular lesion.

(1 8) the use of any of the above 1 3-1 7 the disease preventive and therapeutic agent further contains AT 111 and _/ / or © Rinasutachin pharmaceutically effective amount.

(19) The agent for preventing and treating the disease of the above 1 or 6, and the prevention and treatment of the disease Therapeutic agent is used for the treatment of diseases caused by abnormally enhanced macrophages, lung epithelial cells or synovial cells, in particular, the production of serine protease, at least one of blood coagulation activation and cytokine production. Commercial package containing a package insert stating that it can or should be used for prevention and treatment.

(20) The agent for preventing or treating a disease of the above 2 or 6, and the agent for preventing and treating the disease, are capable of abnormally increasing the production of serine protease in macrophages, lung epithelial cells or synovial cells in vivo. A commercial package containing a package insert stating that it can or should be used in the prevention and treatment of the resulting disease.

(21) Includes the agent for preventing or treating the disease of 4 or 6 above, and the package insert stating that the agent for preventing or treating the disease can or should be used for the prevention and treatment of joint disease Commercial package. BEST MODE FOR CARRYING OUT THE INVENTION

HC II has a prophylactic and therapeutic effect on diseases caused by abnormally enhanced cell functions of macrophages, lung epithelial cells or synovial cells. Tissue factor is expressed on the cell surface in the presence of cytokines released or released from these cells as macrophages, lung epithelial cells or synovial cells, and promotes blood coagulation. Stimulation of thrombin and other serine proteases to produce cytokines, and lung epithelial cells and synovial cells stimulate their own cell growth by stimulation of thrombin and the like, but are not limited thereto. .

Preferably, in the present invention, the disease caused by abnormally enhanced cell functions of macrophages, lung epithelial cells or synovial cells includes at least one of serine protease generation, blood coagulation activation and cytokine production. These are diseases caused by abnormal enhancement of one of the actions, for example, abnormal functioning of synovial cells and synovium-derived macrophages present in the joint cavity, such as rheumatoid arthritis and osteoarthritis. Disease caused by hyperplasia, acute respiratory distress syndrome (ARDS), idiopathic respiratory distress syndrome (IRDS), etc., pulmonary disease caused by abnormal dysfunction of lung epithelial cells present in the alveoli, postoperative disorders (Eg, restenosis after PTCA), atheroma, and the like, which are caused by abnormal dysfunction of macrophages existing around the site of vascular injury.

The HCII used in the present invention is not particularly limited as long as it is derived from mammals such as humans, monkeys, pests, pomas, dogs, puppies, mice, and rats. Are preferably used. Moreover, as long as it is purified to the extent that it can be used as a medicine, it may be natural or artificial. Natural products can be purified from known whole blood of mammals such as humans, whole plasma, plasma fraction, serum or serum squeezed from coagulated blood using known means. A method for purifying HCII from human plasma is described in, for example, Blinder et al. (Biol. Chem., 264: 5128-5133, 1989), Japanese Patent Application Laid-Open No. 9-186697, and the like.

Artificial ones include natural HCII (see, for example, Blinder et al., Biochemistry, 27: 752-759, 1988) or mutant HCII that retains or improves antithrombin activity (eg, EP—4243 51 And those obtained from cultures of host cells transformed with a recombinant vector containing DNA encoding the DNA, and those obtained by chemical synthesis.

The agent for preventing and treating diseases of the present invention is obtained by appropriately mixing HCII with necessary components such as pharmaceutically acceptable carriers (eg, excipients, diluents, etc.), and injecting, injecting, tablets, capsules, and tablets. It can be formulated into any commonly used dosage form such as a preparation and can be administered orally or parenterally.

The agent for preventing and treating diseases of the present invention is preferably formulated into a dosage form generally used for topical administration. For example, for topical administration to joints, HCII is formulated into a liquid formulation together with a pharmaceutically acceptable carrier, or is prepared as a solid formulation such as powders, granules, tablets, etc. Sterile purified water, physiological food Salt water). In particular, prepare and store HCII together with a pharmaceutically acceptable carrier as a lyophilized sample, and dilute it at the point of use with distilled water for injection, for example, so that the HCΠ concentration will be approximately 0.01-10000 units1. It is preferable to use them.

Other pharmaceutically acceptable carriers that can be added to the agent for preventing and treating diseases of the present invention include, for example, buffers (which are not particularly limited as long as they maintain a physiologically preferable pH value), and the like. Examples include tonicity agents (these are not particularly limited as long as they maintain a physiologically isotonic salt concentration), and stabilizers (eg, saccharides such as mannitol and sorbitol), but are not particularly limited thereto.

Preferably, the agent for preventing and treating diseases of the present invention can be locally administered to a site to be treated, for example, a joint, a respiratory tract, or a vascular disorder site. In this case, the dose of HCII varies depending on the degree of disease progression, the severity of the patient (patient), tolerance to drugs, the species of animal, etc., but it is usually 5 to 100 000 units (0.1 2002000 units (in terms of Z kg), preferably about 50-25000 units (in terms of 1-500 units in terms of Z kg), and this amount can be administered once or in several divided doses. The agent for preventing and treating diseases of the present invention can be administered using an administration route such as oral, intravenous or intravenous, in addition to local administration. In this case, the dose of HCII varies depending on the degree of disease progression, the severity of the patient (patient), tolerance to drugs, body weight, animal species, etc., but usually 1 to 10,000 units / day for an adult. It is about kg body weight, preferably about 10 to 2000 units Zkg body weight, and this amount can be administered once or in several divided doses (In the present invention, the titer of HCII is in the presence of heparin. The antithrombin activity of HCII was measured by the synthetic substrate method, and a calibration curve was prepared using の with a known titer, and one unit of ΑΤΠΙ was regarded as one unit of HCII ΑΤΠΙ One unit was 1 m 1 of normal human plasma Equivalent to the amount contained in).

The agent for preventing and treating diseases of the present invention is more preferably used in combination with ΑΤΠΙ and Z or pelinastatin. ΑΤΙΠ and / or pelinastatin It may be formulated into an HCII formulation and formulated, or may be formulated individually and administered sequentially or simultaneously. When formulated separately, ΑΤΙΠ and ゥ linastatin can be used together with necessary components such as pharmaceutically acceptable carriers (eg, excipients, diluents, etc.), as well as injections, tablets, capsules, syrups, etc. Can be formulated into any of the commonly used dosage forms and can be administered orally or parenterally. If HCII is administered topically, ΑΤΙΠ and pelinastatin can also be formulated in a form for topical administration. For example, for topical administration to joints, ATIII or pelinastatin may be prepared as a liquid formulation together with pharmaceutically acceptable excipients, or prepared as a solid formulation such as powders, granules, tablets, etc. Water, sterile purified water, physiological saline, etc.). In particular, ΑΤΠΙ or pelinastatin is prepared and stored as a lyophilized sample together with a pharmaceutically acceptable carrier, and when used, for example, the AT III concentration is adjusted to about 0.01 to 10,000 units / m1 with distilled water for injection. Or, the concentration of pelinastatin is about 10 to 50,000 units / m1 (the titer of pelinastatin was applied to trypsin 2 / ig, and the amount that inhibited the enzyme activity of 1 μg of trypsin was defined as 1 unit of pelinastatin). It is preferable to use it after diluting it. Examples of the pharmaceutically acceptable carrier include the same carriers as in the above HCII preparation.

When HCII is used in combination with ATIII and / or pelinastatin, the dosage of each component varies depending on the route of administration, disease progression, patient (patient) severity, drug tolerance, body weight, animal species, etc. In the case of systemic administration such as oral, intravenous, and intraarterial administration, HCII per adult day is usually: ~ 10000 units / kg body weight, ATIII and pelinastatin, respectively, 1-10000 units Zkg body weight and 10-20000 units / kg body weight, preferably HC II 10-2000 units Z kg body weight, AT III And pelinastatin are 10-2000 units Zkg body weight and 10-10000 units Zkg body weight, respectively. In addition, in the case of local administration such as local administration of joints, HCII is usually about 5 to 100,000 units, and Nastatin is about 5 to 100,000 units and about 500 to 100,000 units, respectively, preferably HCII is about 50 to 25,000 units, and ΑΤΠΙ and perinastatin are about 50 to 25,000 units and about 5000 to 100,000 units, respectively.

It is desirable to start administration of the agent for preventing and treating diseases of the present invention immediately after the onset of the disease or at a time when the onset of the disease does not occur but there is a possibility of the onset. It is also desirable to administer an appropriate dose every day or every one to several days until healing is achieved. In addition, in the case of a disease with a poor prognosis, administration may be continued for a certain period after cure. Hereinafter, the present invention will be described in more detail with reference to examples. However, these are merely examples, and do not limit the scope of the present invention. The HCII, ATIII and perinastatin used in the following examples were obtained according to the methods described in JP-A-9-286797, EP-339919 and JP-A-7-278015, respectively. The prepared one was used. Example 1 Effect of HCII on heron carrageenan arthritis

A heron (Japanese white, male, 3 to 4 months old) was administered lml of 1% lagedin-added saline twice every 7 days into the knee joint cavity of the left hind limb. The knee joint diameter in the horizontal direction was measured with a vernier caliper before and after the second dose of force-lagenin, and the ratio (%) of the joint diameter after the second dose to the joint diameter before the force-lagenin was calculated to swell. Degree. Choose a heron with the same degree of swelling and divide it into 7 groups of 9 birds per group. HCII 10 units (group H), AΤΠΙ10 units (group A), ゥ linastatin 3000 units (group U), HCII 5 units + ATIII 5 Unit (H + A group), HCII 5 units + ゥ linastatin 3000 units (H + U group), ΑΤΠΙ 5 units + ゥ linastatin 3000 units (A + U group) or HCII 5 units + AT III 5 units + ゥ linastatin 3000 units (H + A + U group) was administered into the left knee joint cavity three times in total every other day from one day after the second administration of lagenin. A control to which only saline was administered was used as a control. Two, four, and six days after the start of administration, the left knee joint diameter was measured, and the swelling (%) was calculated as the swelling degree based on the joint diameter before the administration of tyrageenin. After the final measurement of the joint diameter, the patella pad was cut, lml of cold saline was injected into the joint cavity, and the joint cavity was sufficiently spread.Then, 0.5 ml of the joint fluid 0.5 ml was injected using a syringe. Collected. The acid phosphatase activity in the synovial fluid was measured using an acid phosphatase activity measurement kit (manufactured by Sigma) according to the attached protocol. Further, the degree of thrombus formation, the degree of synovial cell proliferation, and the degree of bone destruction were measured by conventional methods. Table 1 shows the results.

table 1

Effects of HCII, ΑΤΠΙ and ゥ rinastatin on ゥ heron arthritis model

Relative swelling relative to normal of 100

The degree of histological changes was evaluated on a 6-point scale, with 0 being normal and 5 being the most severe (the figures were the average of 9 birds). Joint swelling and acid phosphatase activity of HCII, ΑΤΠΙ, and ナ linastatin ( It is an indicator of synovial cell damage), improved thrombosis, synovial cell proliferation, and bone destruction. The effect is further enhanced by the combination of any two or all of the three drugs. Example 2 Enhanced effect of HCII in the presence of macrophages, lung epithelial cells or synovial cells

Macrophages were collected intraperitoneally or from atherogenic vessels. Synovial cells were obtained from synovium obtained by synovectomy from rheumatic patients. Pulmonary epithelial cells were isolated from rat lungs by conventional methods. Some macrophages, synovial cells and lung epithelial cells were cultured to obtain cultures (free and released).

(Experiment 1) Enhance HCII antithrombin effect in the presence of macrophages, lung epithelial cells or synovial cells

5 nM thrombin solution to HCII (final concentration 1 U / m 1), HCII + peritoneal Makurofu § one di (final concentration 1 0 ⁶ 1111), or HCII + peritoneal macrophages cultures (final concentration 10 ⁶ (converted) Zm l) was added and the mixture was incubated at 37 ° C for 30 minutes, and then the thrombin activity was measured by a spectrophotometer using the synthetic substrate method. Similar experiments were performed using macrophages, synovial cells or lung epithelial cells (and their respective cultures) collected from the plaque-forming vessels instead of the peritoneal macrophages (and their cultures). Was done. Table 2 shows the results.

Table 2

Effect of macrophages and lung epithelial cells on the antithrombin effect of HCII

And synovial cell effects

Relative activity with thrombin activity as 100 when thrombin alone (no additives) HCII slightly inhibited thrombin activity. The addition of macrophages or cultures collected from the intraperitoneal cavity significantly enhanced the inhibitory effect of HCII on thrombin. Similar results were obtained for macrophages, synovial cells and lung epithelial cells collected from the plaque-forming vessels.

(Experiment 2) Promotion of coagulation activity by macrophages, lung epithelial cells or synovial cells and inhibition of coagulation by HCII.

In peritoneal macrophages containing solution (1 0 ⁶ 71 ^ 1), after incubation of endotoxin solution (1 mu g / m 1) was added 3 7 ° C in 3 hours, to the mixture 1 0 0 1, human The coagulation time was measured by adding 100 μg / l plasma and 100 μl of CaCl ₂ solution (25 mM). A material obtained by adding C a C 1 ₂ of 1 UZM 1 prior to addition HCII, were compared clotting times in the non-additive ones. Similar experiments were performed using macrophages, synovial cells or lung epithelial cells collected from the plaque-forming vessels instead of peritoneal macrophages. Table 3 shows the results.

Table 3

Increased coagulation by macrophages, lung epithelial cells and synovial cells, and suppression of hypercoagulation by HCII

In the presence of endotoxin-stimulated macrophages, plasma clotting time (reperfusion time) was significantly shortened and hypercoagulation was observed. For HCII addition This shortening of the coagulation time was significantly improved. These results suggested that HCII also exerts an antithrombin action on thrombin generated on macrophages. Similar results were obtained with macrophages, synovial cells, and lung epithelial cells collected from the plaque formation vessels.

(Experiment 3) Effects of HCII on proliferation of synovial cells and lung epithelial cells

1 U / ml of thrombin was added to synovial cells or lung epithelial cells and cultured at 37 ° C. The expression of thrombin receptor 1 day later and the number of cells 4 days later were measured. Receptor expression and cell proliferation were compared between those with and without the addition of HC 11 during thrombin stimulation. Table 4 shows the results.

Table 4

Effect of HCII on synovial cell and lung epithelial cell proliferation and thrombin receptor expression

¹ Relative value with the degree of proliferation without thrombin stimulation as 100

⁽² ) Relative value based on expression without thrombin stimulation The proliferation of synovial cells and lung epithelial cells was promoted by thrombin stimulation as compared to those without stimulation, and the expression of thrombin receptor was also increased. On the other hand, cell proliferation and receptor expression were significantly suppressed by the addition of HCII.

(Experiment 4) Effect of HCII on site force production of macrophages, lung epithelial cells or synovial cells

Thrombin (1 nmo 1 ZL for macrophage stimulation, 100 nm for others) o1 / L) was added to peritoneal macrophages, macrophages collected from the plaque-forming blood vessels, lung epithelial cells or synovial cells, and cultured at 37 ° C. TNF, IL-16, GM—CSF Was examined. The expression of each of the above cytokines was compared between the case where HCII was added during thrombin stimulation and the case where HCII was not added. Table 5 shows the results.

Table 5

Effect of HCII on cytokine production by macrophages, synovial cells and lung epithelial cells

Cytokine produced by each cell at the time of thrombin stimulation:: Percentage of each cytokine produced by each cell at the time of addition of HCII Cytokine production was increased by thrombin stimulation at all cells, but the addition of HCII was not This was suppressed. Industrial applicability

According to the present invention, HCII exhibits an antithrombin activity (anticoagulant activity) in the presence of macrophages, lung epithelial cells or synovial cells, and also has an inhibitory effect on the proliferation of these cells and an inhibitory effect on the production of site force. Therefore, it is useful for prevention and treatment of diseases involving macrophages, lung epithelial cells or synovial cells. In addition, the agent for preventing and treating diseases of the present invention is extremely useful because topical administration can provide excellent preventive and therapeutic effects with low doses of HCII. This application is based on Japanese Patent Application No. 191977 filed in Japan, filed in Japan, the contents of which are incorporated in full herein.

In addition, references, including patents and patent applications, cited herein are hereby incorporated by reference to the same extent as if their entire contents were disclosed.

Claims

The scope of the claims

1. A prophylactic and therapeutic agent for diseases caused by abnormal cell function of macrophages, lung epithelial cells or synovial cells, comprising heparin cofactor II as an active ingredient.

2. The agent for preventing and treating diseases according to claim 1, wherein the cell function is at least one action selected from the group consisting of a serine protease generating action, a blood clotting activity activating action, and a cytokine producing action.

3. A preventive and therapeutic agent for a disease caused by abnormally increased production of serine protease in a macrophage, pulmonary epithelial cell or synovial cell peripheral region, which contains heparin cofactor II as an active ingredient.

4. The disease preventive or therapeutic agent according to any one of claims 1 to 3, wherein the disease is selected from the group consisting of joint disease, lung disease, and diseases associated with vascular disorders.

5. A prophylactic and therapeutic agent for joint diseases containing heparin cofactor II as an active ingredient.

6. The preventive or therapeutic agent according to any one of claims 1 to 5, which is in a form for topical administration.

7. The disease preventive and therapeutic agent according to claim 6, which is in a form for administration to a joint, an airway, or a site around a vascular disorder.

8. The preventive or therapeutic agent for a disease according to any one of claims 1 to 7, further comprising antithrombin II and / or perinastatin.

9. Use of heparin cofactor II for the prevention and treatment of diseases caused by abnormal hyperfunction of macrophages, lung epithelial cells or synovial cells.

10. The use according to claim 9, wherein said cell function is at least one action selected from the group consisting of a serine protease producing action, a blood clotting activity stimulating action and a cytokine producing action.

1 1. For the prevention and treatment of diseases caused by abnormally increased production of serine protease in macrophages, pulmonary epithelial cells or synovial cells around the body. Use of Ncofactor II.

1 2. Use according to any of claims 9 to 11, wherein said disease is a joint disease, a lung disease or a vascular disorder.

1 3. Use of Heparinkov actor II for prevention and treatment of joint disease.

14. The use according to any one of claims 9 to 13, wherein heparin cofactor II is administered locally.

1 5. Use according to claim 14, characterized in that palincofactor II is administered around joints, airways or vascular lesions.

1 6. Use according to any of 9 to 15 above, characterized in that it is used in combination with antithrombin III and / or pelinastatin.

1 7. Use of heparin cofactor II for the manufacture of a prophylactic and therapeutic agent for diseases caused by abnormal cell function of macrophages, lung epithelial cells or synovial cells.

1 8. The use according to claim 17, wherein said cell function is at least one action selected from the group consisting of a serine protease producing action, a blood clotting activity activating action, and a cytokine producing action.

1 9. Use of heparin cofactor II for the manufacture of a prophylactic and therapeutic agent for diseases caused by abnormally increased production of serine protease in macrophages, pulmonary epithelial cells or synovial cells in vivo.

20. Use according to any one of claims 17 to 19 wherein said disease is a joint disease, a lung disease or a vascular disorder.

21. Use of heparin cofactor II for the manufacture of a prophylactic and therapeutic agent for joint disease.

22. The use according to any one of claims 17 to 21, wherein said agent for preventing and treating diseases is in a form for topical administration.

23. Use according to claim 22, wherein said agent for preventing and treating diseases is in a form for administration around joints, airways or sites of vascular injury.

24. A pharmaceutically effective amount of antithrombin ΠΙ in which the agent for preventing and treating the disease is pharmaceutically effective and Use according to any one of claims 17 to 23 further comprising Z or pelinastatin.

25. The agent for preventing or treating a disease according to claim 1 or 8, and the agent for preventing and treating the disease, wherein the agent for preventing and treating the disease is caused by an abnormal cell function of macrophages, lung epithelial cells or synovial cells. A commercial package containing a package insert stating that it can or should be used for the product.

26. The agent for preventing and treating a disease according to claim 3 or 8, and the agent for preventing and treating the disease, wherein the agent for preventing and treating the disease is abnormal in the production of serine protease in macrophages, lung epithelial cells or synovial cells in vivo. A commercial package containing a package insert stating that it can or should be used in the prevention and treatment of diseases caused by hyperactivity.

27. It is stated that the agent for preventing or treating a disease according to claim 5 or 8 and that the agent for preventing and treating a disease can or should be used for the prevention and treatment of a joint disease Commercial package containing package inserts.