CN105457017A - Application of progranulin (PGRN) in treatment of sepsis - Google Patents
Application of progranulin (PGRN) in treatment of sepsis Download PDFInfo
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- CN105457017A CN105457017A CN201610017964.6A CN201610017964A CN105457017A CN 105457017 A CN105457017 A CN 105457017A CN 201610017964 A CN201610017964 A CN 201610017964A CN 105457017 A CN105457017 A CN 105457017A
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- YIEDSISPYKQADU-UHFFFAOYSA-N n-acetyl-n-[2-methyl-4-[(2-methylphenyl)diazenyl]phenyl]acetamide Chemical compound C1=C(C)C(N(C(C)=O)C(=O)C)=CC=C1N=NC1=CC=CC=C1C YIEDSISPYKQADU-UHFFFAOYSA-N 0.000 description 1
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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
Abstract
The invention provides application of progranulin (PGRN) in preparation of drugs for treating, or diagnosing or preventing sepsis. The survival rate of sepsis is effectively increased. By means of the application, a new target spot is found for treating, diagnosing and preventing sepsis, and new technological breakthrough is brought.
Description
Technical field
The present invention relates to technical field of pharmaceutical biotechnology, the medicinal usage that particularly PGRN is new.
Background technology
Sepsis (sepsis) refers to that its state of an illness is dangerous, and case fatality rate is high, and sickness rate is ever-increasing trend by infecting the systemic inflammatory response syndrome (systemicinflammatoryresponsesyndrome, SIRS) caused.According to statistics, the whole world has 1,800 ten thousand people's morbidities every year.In the U.S., sepsis patient mortality rate accounts for 17% of inpatient.And in China, the incidence rate of a serious Sepsis of polycentric Epidemiological study display ICU is 8.68%, mortality rate is up to 44.7%.In recent years, although anti-infective therapy and multiple organ support therapy technology achieve significant progress, the case fatality rate of Sepsis is still up to 30% ~ 70%, and in shock patients, its mortality rate is then up to 70% ~ 90%.Sepsis treatment cost is high, and medical resource consumption is large, has a strong impact on the quality of life of the mankind, causes grave danger to human health.To this, Europe serious symptom association, serious symptom association of the U.S. and international sepsis forum initiation " campaign of rescue sepsis " (survivingsepsiscampain, SSC), within 2002, the multiple tissue of American-European countries is jointly initiated and signs " Barcelona declaration ", and formulate based on the evidence-based medical studied sepsis further, constantly update treatment of sepsis guide and SSC guide, to improve the remedy measures of Sepsis, reduce the mortality rate of Sepsis.
Sepsis is a kind of systemic inflammatory response syndrome, generation evolution and the pathomechanism of the autoimmune disease caused from other non-infective agents are all different, sepsis further develops and often causes multiple organ dysfunction syndrome, causing multiple organ dysfunction syndrome, is the main cause causing death.
Because sepsis mechanism is very complicated, relate to the series of physiological and pathological processes such as infection, inflammation, immunity, blood coagulation and histologic lesion.Infect and cause the inflammatory factor discharged to transfer whole body various kinds of cell and multiple organ systems by neuro-endocrine-immune system, constitute complicated network, Cascaded amplification, restricts mutually.Therefore clinical economics is very difficult, still lacks effective clinical means at present.Current quality method is based on antibacterial therapy and the Comprehensive Treatment that changes for each system, but still is difficult to achieve the desired result, and mortality rate still remains high.In view of sepsis is by infecting the systemic inflammatory response syndrome caused, the immunologic function disorder that its runaway inflammatory factor causes causes patient's multiple organ dysfunction and one of main causes of death.
Progranulin (Progranulin, PGRN), is also granulin/epithelinprecursor, proepithelin, acrogranin, or prostatecancercell-derivedgrowthfactor, by GRN gene code.
Summary of the invention
The object of the invention is to, in the complicated regulated and control network of sepsis, search out new treatment, diagnosis, prevention target spot, bring new breakthrough to pyemic control.
The object of the invention is to be realized by following measures:
The purposes of progranulin (Progranulin, PGRN) in preparation treatment, diagnosis or prevention medication for treating pyemia.
Preferably, the purposes of progranulin (Progranulin, PGRN) in preparation treatment, diagnosis or prevention medication for treating pyemia, dosage is 0.1-10g/kg.
The invention provides progranulin (PGRN) application in pyemic treatment, diagnosis, prevention, giving ectogenic PGRN can have remarkable therapeutical effect to sepsis, can significantly improve its survival rate.
The present invention finds that PGRN disappearance causes the reduced capability of body bacteria removal, and spleen lymphocyte apoptosis increases, and the multiple organ inflammation damnifications such as liver lung kidney are increased the weight of, and by giving ectogenic PGRN albumen, can significantly improve the survival rate of mice.
Accompanying drawing explanation
Fig. 1: in sepsis patient blood, PGRN test experience: A is sepsis patient blood specimen of growing up, and B is the plasma specimen of child's sepsis patient.
PGRN test experience in Fig. 2 animal sepsis models: A specimen is serum, B is that small stream liquid is filled with in abdominal cavity
Fig. 3 bacterial loads is tested: A, B, C represent blood respectively, small stream liquid and spleen specimen are filled with in abdominal cavity
The pathology of each organ injury of Fig. 4 detect
The Lymphocyte Apoptosis experiment of spleen in Fig. 5 mouse sepsis model
The survival rate of Fig. 6 sepsis animal model detects
After Fig. 7 gives ectogenic PGRN albumen, survival rate detects.Wherein A experimental subject is WT mice, and B is PGRN
-/-mice
Fig. 8 CLP modeling process figure
Macrophage result in Fig. 9 Flow cytometry PLF
Figure 10 sepsis model gives survival rate result after PGRN.
Detailed description of the invention
The following stated is the preferred embodiments of the present invention, but the present invention is not limited to following examples.Described method is conventional method if no special instructions.Described raw material all can obtain from open commercial sources if no special instructions.
Embodiment 1
The foundation (Cecal Ligation paracentesis Cecalligationandpuncture, CLP) of sepsis animal model
Laboratory animal: it is male for testing mice used, and body weight is 18-22g, about 6-8 week age.Raise at Medical University Of Chongqing Experimental Animal Center SPF (SpecificPathogenFree) level laboratory.This experiment mice used is SPF level laboratory animal.Wild type C57BL/6 mice (Wildtype, WT) buys from Medical University Of Chongqing's Experimental Animal Center, the PGRN knock out mice (PGRN of C57BL/6 Background sources
-/-) buy from the TheJacksonLaboratory of the U.S..
Method: grow up C57 mice, with the pentobarbital sodium intraperitoneal injection of anesthesia mice of 100 microlitres 1.5%, is fixed on operation panel, abdominal part Pet electric clipper shaves hair, sterilization skin, does the long otch of 1cm in abdomen center, cecal ligation, with No. 26 syringe needle punctures, as Fig. 8.Last sew up wound, sterilization skin.(concrete reference: DanielRittirsch, PeterAWard, etal.Immunodesignofexperimentalsepsisbycecalligationandp uncture.NatProtoc.2009; 4 (1): 31-36).This modeling method is the classical modeling method of sepsis animal model, and this modeling method studies pyemic goldstandard animal model at present.
The mensuration of bacterial loads:
By mouse modeling after 24 hours, anesthetized mice, fixing, get peritoneal lavage fluid (Peritoneallavagefluid respectively, PLF), cardiac blood and spleen, get 100 microlitre bed boards after peritoneal lavage fluid and blood being done 10 times of serial dilutions, the first homogenate of spleen, then get 100 microlitre bed boards after doing 10 times of serial dilutions, after 18-24 hour, count the clump count on blood agar plate.
Result as shown in Figure 3, compared with WT mice, PGRN
-/-mice is after setting up sepsis model, and its PLF, has higher bacterial loads in blood and spleen, the reduced capability of its body bacteria removal, and PGRN disappearance is unfavorable for that antibacterial is removed.
The pathology of each organ injury detect:
Respectively by WT mice and PGRN
-/-mice builds sepsis model, after 6 hours and 24 hours by mouse anesthesia after put to death, get lung, liver,spleen,kidney, in 4% paraformaldehyde, fix 24--48 hour, carry out respectively dewatering, waxdip, embedding, section, after HE dyeing under microscope microscopy.
Result as shown in Figure 4, compared with WT, PGRN
-/-the each organ injury of mice obviously increases the weight of, and from the visible significantly increased inflammation of pathological section, inflammatory cell infiltration, albumen inflammatory exudation, organizes congestion and edema, the performances such as necrocytosis.The cell injury situation of following biochemical indicator reflection, wherein ALT and AST is the index of reflection hepatic injury, and it is serious that ALT and AST raises prompting stem cell injuries.LDH is the index of reflection kidney, lungs and myocardial damage, and LDH raises and illustrates that damage is heavier.
By WT mice and PGRN
-/-after mouse modeling, put to death after 6h and 24h is by mouse anesthesia respectively, get spleen, after 4% paraformaldehyde fixes 24 hours, carry out dewatering, waxdip, paraffin embedding, section, then use TUNEL method (DAB colour developing) detect apoptosis, result as shown in Figure 5: compared with WT mice, PGRN
-/-apoptosis of spleen significantly increases, and 24 hours less than 6 time more obvious, lymphocytic apoptosis when PGRN disappearance exacerbates sepsis.
Survival rate is tested:
Mice is built sepsis model, and caecum large portion ligation, makees severe sepsis model, the Survival of observed and recorded mice, and every day observes twice, and Continuous Observation 2 weeks, to mice no longer death.
Result as shown in Figure 6, compared with WT, PGRN
-/-mouse survival rate significantly reduces.Show as PGRN
-/-mice is being set up within sepsis model three days all dead, and survival rate reduces to 0, and WT mice still can long-term surviving after setting up sepsis model.Illustrate that PGRN disappearance is unfavorable for the existence of mice in sepsis.
ELISA detects the PGRN in sample: as depicted in figs. 1 and 2, PGRN all expresses and significantly raises result in pyemic patient and animal body.
External source PGRN is to pyemic therapeutic effect:
PGRN (the mice PGRN albumen (RecombinantMouseProgranulin) of restructuring buys the R & D company from the U.S.)
Modeling injected in mice 20 μ gPGRN is given within 2 hours through abdominal cavity after modeling, then by wound suture, sterilization skin.The Survival of observed and recorded mice, every day observes twice, and Continuous Observation 2 weeks, to mice no longer death.
No matter result as shown in Figure 7, after modeling, is WT mice or PGRN
-/-mice, gives the survival rate that ectogenic PGRN all can significantly improve mice.
As Fig. 7 (A), WT mice is divided into three groups, matched group (sham operated rats), treatment group (sepsis model) and non-treatment group (sepsis model), as can be seen from the figure, non-treatment group 5 days mices after modeling are all dead, and PGRN treatment group still can keep the survival rate of about 50% after 10 days in modeling.
As Fig. 7 (B), use PGRN
-/-mice is repeated above-mentioned experiment and has drawn consistent result, and namely PGRN treatment group still can keep the survival rate of about 50% after two weeks in modeling, until mice is not in death.But not final all dead after the mouse modeling for the treatment of group, survival rate reduces to 0.
Above two groups of experiments all illustrate that PGRN has good therapeutic effect to mouse sepsis.
The detection of macrophage in PLF:
By WT mice and PGRN
-/-mice sets up sepsis model, gets PLF respectively 6 hours and 24 hours, and with the anti-CD11b antibody labeled cells of the anti-F4/80 antibody of PE labelling and APC labelling, the macrophage ratio in Flow cytometry PLF, result as shown in Figure 9.Then giving WT mouse peritoneal injects after the macrophage in Mice Body knocks out by 200 μ lClophosome, then sets up sepsis model, and then gives PGRN treatment, and result as shown in Figure 10.
Compared with WT mice, PGRN
-/-mice is after modeling, and the macrophage in PLF significantly reduces, i.e. PGRN
-/-mice raises the reduced capability of macrophage.
Late Cambrian PGRN of the present invention as the pyemic effect of Drug therapy, by with WT mice and PGRN
-/-after mouse modeling, the experiment such as bacterial loads and survival rate finds the protective effect that PGRN plays a role in sepsis, and injecting ectogenic PGRN can play significant therapeutical effect to sepsis, significantly improves its survival rate.This therapeutic effect is significantly objective, has good potential applicability in clinical practice.
Claims (2)
1. the purposes of progranulin in preparation treatment, diagnosis or prevention medication for treating pyemia.
2. the purposes of progranulin in preparation treatment, diagnosis or prevention medication for treating pyemia, dosage is 0.1-10g/kg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610017964.6A CN105457017A (en) | 2016-01-12 | 2016-01-12 | Application of progranulin (PGRN) in treatment of sepsis |
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|---|---|---|---|
| CN201610017964.6A CN105457017A (en) | 2016-01-12 | 2016-01-12 | Application of progranulin (PGRN) in treatment of sepsis |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015096858A1 (en) * | 2013-12-23 | 2015-07-02 | Mediagnost Gesellschaft für Forschung und Herstellung von Diagnostika GmbH | Method for detecting a systemic inflammation and test system |
| US20150316548A1 (en) * | 2012-11-28 | 2015-11-05 | Universitaet Des Saarlandes | Progranulin as marker for autoimmune disorders |
-
2016
- 2016-01-12 CN CN201610017964.6A patent/CN105457017A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150316548A1 (en) * | 2012-11-28 | 2015-11-05 | Universitaet Des Saarlandes | Progranulin as marker for autoimmune disorders |
| WO2015096858A1 (en) * | 2013-12-23 | 2015-07-02 | Mediagnost Gesellschaft für Forschung und Herstellung von Diagnostika GmbH | Method for detecting a systemic inflammation and test system |
Non-Patent Citations (2)
| Title |
|---|
| HTTP://CORDIS.EUROPA.EU/PROJECT/RCN/196475_EN.HTML: "Validation of Progranulin as biomarker in diagnostics and prognosis of sepsis", 《互联网》 * |
| 刘露: "生长因子PGRN在内毒素炎症应答中功能的初步研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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Application publication date: 20160406 |