CN1555885A - Application of leukin 1 acceptor antagonist in medicine for preventing and treating posterior cataract - Google Patents
Application of leukin 1 acceptor antagonist in medicine for preventing and treating posterior cataract Download PDFInfo
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Abstract
An application of interleukin 1 receptor agonist in preparing the medicines for preventing and treating acquired cataract is disclosed. Said medicines can be the interleukin 1 receptor agonist IL-1RA or its synthetic medicine, or the noncompetitive IL-1 receptor blocker.
Description
Technical field:
The present invention is a kind of new application of medicine, comprises the new application of biological preparation, specifically the new application of interleukin 1 receptor antagonist IL-1RA.
Background technology:
After cataract is that present postcataract causes one of main complication of visual deterioration.Report is arranged, in adult's postcataract 2 years, have 20%～30% patient blind once again, have 43% in 5 years because of after cataract hands art once more because of after cataract; The child, the incidence rate of after cataract almost 100%.Cystitomy is present muddy the most frequently used effective ways of treatment back capsule behind the Nd:YAG laser, but laser therapy expense costliness, and often have that the intraocular lens damages, complication such as intraocular pressure rising, detachment of retina and cystoid macular edema take place.
Send out the medicine of barrier for seeking effective control back, carried out big quantity research.The medicine that barrier is sent out in propositions such as Power, intra-ocular applications control back need possess following some: (1) suppresses the propagation and the migration of lens epithelial cells effectively; (2) other organizes free of toxic effects to ophthalmic; (3) medicine need be fit to inject the anterior chamber, and its active drug concentration can be kept the sufficiently long time.Therefore, how selecting a kind of prolong drug administering mode of action time, reduce the toxic and side effects of medicine to other tissue of eye, is that the key issue in the barrier medical treatment is sent out in the back.
The present Research of chemoprophylaxis:
1. suppress with low penetration enhancer and destruction lens epithelial cell, but its corneal endotheliocyte has dissolution, can not practical application.
2. antimetabolite, as 5-FU, colchicine, methotrexate, daunorubicin etc. can suppress the mitosis of lens epithelial cell, but because their toxic action have limited application.
3. effects of heparin postoperative fibrin forms, and shortcoming is easily to cause hyphema.
4. immune drug is tested.
Although said medicine has certain effect, their toxic and side effects can't overcome, and fails in clinical practice.
In recent years develop rapidly and being extensive use of of cytobiology technology along with molecular biological, find that many cytokines play an important role in the after cataract forming process, for the formation mechanism of inquiring into after cataract provides foundation, also provide hope for effectively preventing and treat after cataract clinically.
Mechanism research
One, the many factors of the mechanism of after cataract are influential to the generation of after cataract, and wherein most importantly lens epithelial cells and post-operation inflammatory react two aspects.(1) lens epithelial cells is the composition that keeps propagation and differentiation capability in the crystalline lens to the lens epithelial cells that influences that after cataract forms.ECCE objectively is equivalent to a wound, causes the lens epithelial cells damage on the one hand; Residual on the other hand lens epithelial cells causes repair mechanism under some cytokine effects, show as dividing a word with a hyphen at the end of a line, breed and transforming to fibroblast of lens epithelial cells.Proliferation of lens epithelial cells travels to the formation that the back capsule can cause after cataract.After cataract be formed with two kinds of mechanism: one is the lens epithelial cells hypertrophy, form regenerated lens structure such as pearl-like corpusculum (Elschnigbody) and Soemmering ring, the pearl-like corpusculum is a seed capsules like cell, has contractility, causes the shrinkage muddiness of back capsule; It two is a lens epithelial cells generation fibrosis, forms fibrous membrane, and the contraction of fiber makes the back capsule form many little fold, causes visual deterioration [2].In addition, lens epithelial cells also produces extracellular matrix when breeding, dividing a word with a hyphen at the end of a line, transform, but extracellular matrix is adherent cell, pigment and protein body on the one hand, constitute epithelial cell, fibroblastic support on the other hand, epithelial cell is closely linked to each other with fibroblast, and capsule forms the fibrosis tissue in the back.Lens epithelial cells can also synthesize some cytokines, and these cytokines by inducing PGE2 synthetic, are destroyed blood-aqueous barrier on the one hand, cause inflammatory reaction; Living by the wound healing mechanism inducing fibrosis on the other hand, collagen produces, and makes the back cystic fibrosis and muddiness].(2) influencing that post-operation inflammatory reaction pair after cataract forms reaches postoperative blood-aqueous barrier destruction, inflammatory mediator release, complement activation etc. in the cataract art, also play a role in the forming process of after cataract [5].Its mechanism may be: blood-aqueous barrier destroys and causes more plasma fraction and extracellular matrix to enter the anterior chamber, deposits on the cyst membrane of back, for the adhesion propagation of lens epithelial cells on the cyst membrane of back provides suitable interior environment; In addition, a large amount of inflammatory mediators enter the anterior chamber immunoreation etc. take place.Inflammatory mediator release, complement activation and some cytokines discharge, and all stimulate proliferation of lens epithelial cells, divide a word with a hyphen at the end of a line, thereby impel the formation of after cataract.
The formation of after cataract is the process of a complexity, comes from inflammatory reaction behind the operation wound and residual lens epithelial cells.Simultaneously, the various kinds of cell factor is played a role in after cataract forms: as act on IL 1, IL 6, TNF, the TGF β at inflammation initial stage, promote the synthetic IL 1 of collagen, IL 6, TNF, bFGF, EGF, PDGF etc., bFGF, the EGF of promotion proliferation of lens epithelial cells, PDGF, IGF, TNF, IL 1, IL 6 etc., IFN, the TGF β etc. of inhibition proliferation of lens epithelial cells.Because notes are inhaled mechanicalnesses operations such as cortex, implantable artificial crystalline lens, cause the lens epithelial cells damage when ECCE, the injury repairing process promptly takes place in the residual lens epithelial cells of postoperative, the synthetic and release various kinds of cell factor.These cytokines combine with its specific receptor in vivo, both can play a role the formation cytokine network that can interact again, thereby the formation of participation after cataract separately.Along with developing rapidly of Celluar and Molecular Biology, the effect of cytokine in after cataract forms becomes the focus of people's research day by day.Simultaneously, inspire people to seek a kind ofly can the specific inhibition proliferative cell factor combine or block the formation that its medicine in conjunction with the effect that is then produced prevents after cataract with its specific receptor.The research of this respect at present begins, and waits to further develop.
Interleukin 1 family and application at present:
Interleukin 1 (interleukin1, IL 1) is once called as lymphocyte activating factor (LAF), B cell activation factor (BAF), thymocyte proliferation factor (TPF) etc., international uniform called after IL 1[1 in 1979].IL 1 can be synthesized and secretion by various kinds of cell, most importantly activatory Monocytes, other also can produce IL 1[3 as dendritic cell, langerhans' cells, epithelial cell, endotheliocyte, connective tissue cell, fibroblast, neurogliocyte [2], activatory B cell and some B cell strain].Along with advancement of science, people have had further understanding to the molecular biology characteristics of IL 1 gradually.
IL 1 is found in the acute myelogenous transudate the forties in 19th century at first, be a kind of to heat-labile protein, under the normal condition, remove the skin horn cell, outside some epithelial cell and the central nervous system cell, other cell is not all expressed IL 1m RNA, but infecting, microbial toxin, inflammatory factor, activated lymphocyte product, under the stimulation of complement and thrombin etc., nearly all nucleus all can produce IL 1, mainly contains myeloid cell (mononuclear cell, various macrophages, synovial cell and Lang Gehansi cell etc.) and lymphocyte (B cell and B cell lymphoma cell strain, helper T lymphocyte, large granular lymphocyte and NK cell) etc. [6].The IL 1 that two kinds of forms are arranged, i.e. IL 1 α and IL 1 β, its gene all are positioned on No. 2 chromosome.The IL 1 of two kinds of forms all at first is synthesized the precursor (pro IL 1) of 31kD, and proIL 1 is decomposed into the peptide of 17kD by protease, is called ripe IL 1.Ripe IL 1 α and IL 1 β are the biologic activity forms of IL 1.Although the two only has 25% amino acid identity, they activate same receptor, produce same biologic activity [6].Amphitypy IL 1 receptor (IL 1R) is arranged, and I type IL 1R (IL 1RI) is the single chain protein matter of 80kD, is present in T cell, fibroblast, endotheliocyte, chondrocyte, synovial cell and hepatocyte.II type IL 1R (IL 1RII) is the single chain protein matter of 68kD, is present in B cell, neutrophilic granulocyte and medullary cell [6].IL 1RII non-conducting and IL 1 bonded signal, but combine IL 1 with the IL 1RI competition of conducted signal, thereby be a kind of naturally occurring IL 1 antagonist.IL 1RII comes off and produces the II type IL 1R (IL 1sRII) of solubility into circulation, the latter keeps the active binding ability of membrane-bound IL 1RII and IL 1 β, but IL 1 α and IL 1ra are low-affinity, opposite solubility I type IL 1R (IL 1sRI) keeps the high-affinity of film in conjunction with IL 1RI and IL 1 α and IL 1ra, but with IL 1 β binding ability decline [7].
IL 1 has the various biological function, and 1: inducing inflammatory reaction 1) cause the release of heating, drowsiness, anorexia, neuropeptide.2) promote bone marrow to discharge neutrophilic granulocyte, induce mononuclear cell and multinuclear granulocyte chemotactic to soak into the inflammation part, discharge lysosomal enzyme; Cause basophilic granulocyte and mast cell degranulation, discharge inflammatory mediator.3) cause that hypotension, cardiac muscle suppress, shock and dead.4) induce fibroblast proliferation, induce epithelial cell, osteoblast to produce collagen protein; Induce osteoclast, fibroblast and chondrocyte etc. to discharge collagenase decomposes collagen albumen.5) increase adhesion molecule, Cycloxygenase and the isogenic expression of lipoxidase.2: immunoregulation effect 1) collaborative mitogen activates thymocyte cell and T cell; Promote thymocyte cell and T cell proliferation, express IL 2 receptors, secrete cytokines (IL 2, IL 4, IL 6, IFN γ etc.).2) promote B cell proliferation and differentiation, induce the B cell to produce the ability that IL 2, IL 4, IL 5 and IL 6 are reacted.3: participate in processes such as metabolism, hemopoietic; 4: act on various kinds of cell, induce or suppress himself with other a plurality of expression of gene as raising IL 1, IL 2, IL3, IL 4, IL 5, IL 6, IL 7, IL 8, TNF α, IFN β, IFN β 1, GM CSF, G CSF, the isogenic expression of M CSF, downward modulation Elityran and the isogenic expression of thyroid peroxidase [6,8].
IL 1ra is called as IL 1 inhibitor at first, is that [10] purifies and separates is come out from the urine of [9] and people's Myelomonocyte leukemia and other fever patients through person monocytic cell's supernatant of the pretreated cultivation of IgG.Since these IL 1 inhibitor and IL 1 competition IL 1R, thereby be known as IL 1ra, and it is first found naturally occurring cytokine inhibitor [11].IL 1ra is the acidoglycoprotein of a kind of 22～25kD, and different molecular weight is arranged owing to degree of glycosylation is different.Utilization shows that through the aminoacid sequence of the cDNA of the excretory IL 1ra of the pretreated mononuclear cell of IgG guiding it and IL 1 α have 26% amino acid identity, and with IL 1 β 19% homology [12] are arranged.The IL 1ra that expresses in horn cell and other epithelial cells lacks a guiding peptide in the structure, be that molecular weight is the non-glycosylated protein matter of 18kD.Because this kind of almost all is positioned at cell, be named as type IL 1ra (icIL 1ra) [13] in the cell, icIL 1ra has two kinds (icIL1raI and icIL 1raII), and their N end is Duoed 7 and 21 aminoacid [14] than secreting type IL 1ra respectively.The IL 1 of monocytes is called as secreting type IL 1ra (sIL 1ra), yet monocytic IL 1ra and not exclusively secretion almost have 50% to be retained in the cell [15].IL 1ra uses no any biological activity separately, does not also combine with IL 1, but can combine with I, II type IL 1R, suppresses IL 1 α and IL1 β competitively, the biological activity that mediates by IL 1R, and do not cause can detected cell effect [11].With a kind of cell, also be same cell can produce it again when producing IL 1 natural receptor antagonist IL 1ra.The ultimate density of the two that the performance of IL1 function is depended on them, this also is an important step of body cell factor network.People IL 1ra equates with IL 1 α and IL 1 β with the affinity of IL1RI type, and is suitable with IL 1 α with the affinity of IL 1RII type, but than a little less than IL 1 β many.But because IL 1R is extremely responsive to IL 1, could suppress IL 1 inductive activity far more than IL 1 and IL 1ra, IL 1ra/IL 1 value required in vitro inhibition 50%IL 1 inductive effect is different in all cases, the synovial cell is about 10 in rheumatic arthritis, surpasses 500[15 at D 10 G41 and LBRM 33 cell lines].Reorganization IL 1ra is that the molecular weight of expressing at E.Coli is the non-glycosylated protein matter of 17kD, has and natural IL 1ra identical functions [16] external, has been widely used in interior, the in vitro study of body of IL 1ra.
Though do not see clinical report as yet with reorganization IL 1ra treatment after cataract oculopathy, be some other human diseases of main virulence factor with IL 1ra treatment with IL 1, obtained effect preferably.Clinical I, the II phase of having carried out are tested confirmation, recombined human IL 1ra is safe, can improve sepsis syndrome patient's survival rate in dose dependent ground, graft versus host disease after the bone marrow transplantation of anti-corticosteroid is had the obvious treatment effect, and the carrying out property that can improve the rheumatic arthritis articular cavity is narrow, alleviate the joint erosion ratio.Although in these cases, IL 1ra has clear and definite pharmacotoxicological effect and uses potential, and because of it is a protein, using in chronic disease can a lot of difficulty of existence.Thereby have the people to propose to use transgene method, and give part or whole body application after the cDNA transfection with coding IL 1ra, make IL 1ra high expressed block the activity of IL 1, treatment is the disease of main morbidity medium with IL 1.Although the work of this respect only limits to animal experiment stage at present, shown Therapeutic Method with prospect.To encode the expression vector plasmid of Canis familiaris L. IL 1ra and the rabbit knee intracavity that liposome injects capable meniscectomy together such as Fernandes, alleviated the order of severity of experimental osteoarthritis, can measure the proteic expression of Canis familiaris L. IL1ra with ELISA and SABC method at the experiment intraarticular, inject the expression that 4 Zhou Houneng detect the IL 1ra cDNA of cloned dog at least first with the PCR method.Pan etc. [34] treat the Mus arthritis of endotaxin induction with the recombinant adenoviral vector (rAAV IL 1ra) of coding IL 1ra, proof is just sent out and the experimental arthritis of recurrence all can be suppressed by shot rAAV IL 1ra in the articular cavity, the expression of transgenic IL 1ra can continue to be present in intraarticular at least 100 days, and is activated once more by endotoxin after 80 days in rAAV IL 1ra injection.In addition; site-specific F-duction technology such as Yokoo; change IL 1ra gene over to antiglomerular basement membrane antibody inductive Masugi nephritis animal model; confirm that carrier cell accumulates in around the glomerule of inflammation really; secretion reorganization IL 1ra, the method can be protected the form of kidney and function at least 14 days.Yang etc. [36] make it in the overexpression of ischemic mice tricorn with adenovirus vector transduction IL 1ra, can reduce the expression of cerebral cortex ICAM1 (cell adhesion molecule 1), alleviate the endotheliocyte of leukocyte adhesion to ishemic part, and then the reaction that reduces inflammation, ischemic brain injury improved.The ophthalmology aspect is applied to uveitis and the keratopathy aspect is explored.
Until now, do not see as yet and use IL 1ra, be i.e. the report of interleukin 1 receptor antagonist for treating after cataract oculopathy.
Technical scheme:
The present invention is the new application of interleukin 1 receptor antagonist IL-1RA, the application in prevention and treatment after cataract medicine.
Described prevention and treatment after cataract medicine can be single interleukin 1 receptor antagonist IL-1RA, can be to serve as main part synthetic biochemical product with interleukin 1 receptor antagonist IL-1RA, can be noncompetitive IL-1 receptor blocking agent.
Description of drawings:
Before table 1. art, postoperative respectively organizes different time serum il-1 content:
The specific embodiment:
From lagophthalmos crystal ECCE, to use after the IL-1ra, the influence of IL-1 to the reaction of POE disease inquired in the dynamic change of the content of IL-1 in blood, the tear.Method is breathed out 40 of white rabbits, is divided into 5 groups: administration group, the interior administration component of anterior chamber are three groups under matched group (capable merely ECCE), the conjunctiva, 25ug/ml, 50ug/ml, 100ug/ml.Before the art, postoperative got blood and tear in 3 days, 7 days, 14 days, 28 days, adopted radioimmunity (RIA) method to detect IL-1 content.The result: administration group IL-1 concentration in blood, tear was lower than matched group in 3 days after surgery, 7 days, and three groups of administration are dose dependent in the anterior chamber, and postoperative returned to the preceding level of art in 28 days substantially.Conclusion: behind the cataract capsule outer operation in blood, the tear in the early stage after surgery inflammatory reaction of IL-1 as inflammatory mediator, play an important role, can use the early stage after surgery inflammatory reaction of IL-1ra antagonism IL-1.
Material: breathe out 40 of white rabbits, be the standard animal, every heavy 1.5 ~ 2.2Kg is divided into 5 groups at random, 8 every group.Matched group (G1): capable merely ECCE.Administration group (G2) under the conjunctiva: after the ECCE, continuous seven days, subconjunctival injection 50ug/ml IL-1ra0.1ml.The administration group finishes intracameral injection IL-1ra 0.1ml according to different three groups of 25ug/ml (G3), 50ug/ml (G4), the 100ug/ml (G5) of dividing of concentration in ECCE in the anterior chamber.Above-mentioned five groups of operations are all finished by a people under operating microscope.Before the art, postoperative got blood, tear specimen in 3 days, 7 days, 14 days, 28 days at once with the centrifugal 3min of 3000r/min, separation of serum; Filter paper with big or small uniformity is drawn tear, puts in the 0.32ml distilled water, and it is to be measured that-40 ℃ of low temperature storage are put in unification.
Method: IL-1 detects and adopts radioimmunity (RIA), is responsible for once finishing by the special messenger.
Statistical procedures: do the multilevel analysis of two factors and the t check of repeated measurement data.Total data with
-X ± s represents.
The result:
1, before the art, postoperative is respectively organized different time serum il-1 content results: there is group difference (P＜0.01) in the different disposal method.The IL-1 content trend difference (P＜0.01) that different time changes under the different disposal method.Matched group serum il-1 reached the peak in 3 days after surgery ~ 7 days, and medication group serum il-1 reached the peak in 3 days after surgery, 7 days, but peak value obviously reduces.Following expression:
2, before the art, postoperative is respectively organized different time tear IL-1 content results: there is group difference (P＜0.01) in the different disposal method.The tear IL-1 content trend difference (P＜0.05) that different time changes under the different disposal method.Matched group and medication group tear IL-1 all reached the peak in 3 days after surgery ~ 7 days, but the medication group obviously reduces than the matched group peak value.
Histological observation: in contrast eye 8 weeks of postoperative, the obvious hypertrophy of residual lens epithelial cells also travels to the back capsule; Postoperative 8 pericyte's edema extinction, the visible pearl-like corpusculum of hyperplasia that phacocyst is residual, and the ambitus has the Soemmering ring to form.In 8 weeks of experimental eye postoperative, 100ug/ml does not have obvious lens epithelial cells hypertrophy, and the obvious degeneration of residual cell, a large amount of endochylema cavitys, part shows the karyopycnosis phenomenon, along with the decline of administration concentration, the lens epithelial cells hypertrophy increases, and its effect is dense relevant with administration.Back capsule surface does not have the proliferating cells of obviously dividing a word with a hyphen at the end of a line, the obvious vacuolar degeneration of ambitus cell.Contrast eye and all no abnormal change of experimental eye retinal structure.2.2.2 transmission electron microscope Change of Ultrastructure: observe lens epithelial cells under the Electronic Speculum, the tangible cell function active state of contrast eye performance, endochylema rough endoplasmic reticulum content is abundant; The obvious vacuolar degeneration of experimental eye lens epithelial cells, dilatation of rough endoplasmic reticula, mitochondrial swelling and ridge fracture.Nucleus shows no obvious abnormalities.
IL-1 is mainly generated by mononuclear cell, various macrophage and lymphocyte, and sophisticated IL-1 is made up of 153 aminoacid.IL-1 is highly active cytokine, in＜1pg/ml concentration very strong biologic activity is arranged promptly.The IL-1 biological action is very extensive, mainly comprises the participation inducing inflammatory reaction, immunomodulating, adjusting organism metabolism.Microorganism and product thereof; Cytokine (TNF-a, IL-2, INF-r, and IL-1 itself); Endogenous factor (calcium ion, complement fragment, antigen antibody complex); Surface adhesion between the cell also can mediate IL-1 and produce.Dexamethasone, prednisone, cAMP, PGE2, TGF-β, tretinoin suppresses IL-1 and produces.IL-1 is important inflammatory mediator, and it can promote bone marrow to discharge neutrophilic granulocyte, induces mononuclear cell and multinuclear granulocyte chemotactic to soak into the inflammation part, discharges lysosomal enzyme in the part.IL-1 can cause basophilic granulocyte and mast cell degranulation, discharges inflammatory mediator.IL-1 can induce fibroblast proliferation, induces epithelial cell to produce collagen protein.IL-1ra can combine IL-1R with the IL-1 competition, thus the effect of specific inhibition of IL-6-1
[2]
Experimental data shows that IL-1 peaked in postoperative at matched group and experimental group in 3 days ~ 7 days in serum and the tear, and medication group IL-1 level is starkly lower than matched group.Administration group tear IL-1 keeps reduced levels under the conjunctiva, and administration group IL-1 level and IL-1 concentration (being dosage) are dose dependent in the anterior chamber.Each organizes level before postoperative reached art in 28 days substantially.
After cataract: the hypertrophy of lens epithelial cells is the main composition cell of posterior capsule opacification with changing life, and the activation of macrophage is the cytology basis of back capsule muddiness with transforming.Before the art, in the art, postoperative anterior ocular segment inflammation impels proliferation of lens epithelial cells, divides a word with a hyphen at the end of a line and changes life, wherein cytokine IL-1 promotes cell mitogen, plays a significant role in the proliferation of lens epithelial cells
[3,4]Wolter
[]Studies show that 3 ~ 4 days after surgery artificial intraocular lenses surfaces promptly have mononuclear cell and macrophage to adhere to macrophage to be developed by mononuclear cell.Macrophage plays important role at organism immune response in the allosome rejection; In operation, processes of wound repair, also be the effector lymphocyte who starts the earliest.Experiment confirms, macrophage can connect multiple bioactive substances such as albumen, IL-1 and the deutero-somatomedin of macrophage by eccrine fiber, these bioactive substances can be by strengthening the lens epithelial cell division, and propagation and fibrosis cause posterior capsule opacification (PCO).
Postcataract, because the destruction of blood-aqueous humor barrier, serum, some inflammatory factors etc. infiltrate the anterior chamber, the chemotaxis of these inflammatory factors, a large amount of mononuclear cells, macrophage, lymphocyte and fibroblast
[5]Produce cytokine Deng arriving inflammation effect local and by paracrine and autocrine, as IL-1, IL-6, TNF etc.The release of IL-1 further promotes mononuclear cell, macrophage, lymphocyte to arrive inflammatory mediators such as inflammation part release IL-1 again
[6]And IL-1ra is the natural agonist of IL-1, by competing the biological activity that the IL-1R receptor is blocked IL-1, the reaction that reduces inflammation, the promotion lens epithelial cell proliferation of antagonism IL-1 and the synthetic effect of collagen with IL-1, alleviate the inflammatory reaction that macrophage causes, and then reduce the generation of PCO.
Cyst membrane incision behind the Nd:YAG laser is mainly adopted in the treatment of after cataract at present, because surgery cost is higher, and complication such as artificial intraocular lenses's damage, off normal, the high intraocular pressure of postoperative, cystoid macular edema, corpus ciliare choroid seepage, detachment of retina etc. is arranged
[7]Therefore, seek the effective and medicine that have no side effect of preventing and treating posterior capsule opacification very big meaning is arranged.Ideal medicine should possess following three conditions: (1) can effectively suppress the propagation of lens epithelial cell; (2) to other histiocyte free of toxic effects of ophthalmic; (3) clinical application is convenient feasible
[8]Though antimetabolite, heparin, enzyme etc. can obviously suppress the propagation of lens epithelial cell, all eye inner tissue's cell there is more or less toxic and side effects.And the IL-1ra natural antagonist that is IL-1, just there is IL-1ra to exist among the normal human, no obvious toxic-side effects, IL-1ra obtains better curative effect in corneal allograft rejection, cornea rebirth blood vessel hypertrophy, uveitis experimentation, be a kind of medicine with good clinical value.
After cataract is the principal element that influences the postcataract vision, and present many its morbidity and inflammatory cytokine IL-1, IL-6, TNF-a of discovering are relevant.The inflammatory reaction that this experimental applications IL-1ra antagonism IL-1 causes, research IL-1 is to the effect of the early stage inflammatory reaction of cataract capsule outer operation postoperative.With IL-1 level in blood, the tear as the evaluation criterion of inflammation.
After cataract: the hypertrophy of lens epithelial cells is the main composition cell of posterior capsule opacification with changing life, and the activation of macrophage is the cytology basis of back capsule muddiness with transforming.Before the art, in the art, postoperative anterior ocular segment inflammation impels proliferation of lens epithelial cells, divides a word with a hyphen at the end of a line and changes life, wherein cytokine IL-1 promotes cell mitogen, plays a significant role in the proliferation of lens epithelial cells
[3,4]Wolter
[]Studies show that 3 ~ 4 days after surgery artificial intraocular lenses surfaces promptly have mononuclear cell and macrophage to adhere to macrophage to be developed by mononuclear cell.Macrophage plays important role at organism immune response in the allosome rejection; In operation, processes of wound repair, also be the effector lymphocyte who starts the earliest.Experiment confirms, macrophage can connect multiple bioactive substances such as albumen, IL-1 and the deutero-somatomedin of macrophage by eccrine fiber, these bioactive substances can be by strengthening the lens epithelial cell division, and propagation and fibrosis cause posterior capsule opacification (PCO).
Cyst membrane incision behind the Nd:YAG laser is mainly adopted in the treatment of after cataract at present, because surgery cost is higher, and complication such as artificial intraocular lenses's damage, off normal, the high intraocular pressure of postoperative, cystoid macular edema, corpus ciliare choroid seepage, detachment of retina etc. is arranged
[7]Therefore, seek the effective and medicine that have no side effect of preventing and treating posterior capsule opacification very big meaning is arranged.Ideal medicine should possess following three conditions: (1) can effectively suppress the propagation of lens epithelial cell; (2) to other histiocyte free of toxic effects of ophthalmic; (3) clinical application is convenient feasible
[8]Though antimetabolite, heparin, enzyme etc. can obviously suppress the propagation of lens epithelial cell, all eye inner tissue's cell there is more or less toxic and side effects.And the IL-1ra natural antagonist that is IL-1, just there is IL-1ra to exist among the normal human, no obvious toxic-side effects, IL-1ra obtains better curative effect in corneal allograft rejection, cornea rebirth blood vessel hypertrophy, uveitis experimentation, be a kind of medicine with good clinical value.
List of references:
1. Han Li Na, Shi Xiaoru, in army, etc. the rabbit intraocular lens implants the peri-operation period endothelin-1, the clinical meaning that interleukin 8 is measured. ophthalmology research, 2001,19 (4); 332
2. the Sun Wei people, Wang Huiqin. the cytokine research methodology. People's Health Publisher, 1997,1:367
3.Nippon?Ganka?Gakkai?Zasshi.1998?Aug；102(8)：531-9
4.J?Cataract?Refract?Surg.1996；22?Suppl?1：852-8
5. Hu Ming, Hao Yansheng, favour is prolonged life, etc. macrophage is to cultivating the influence of rabbit proliferation of lens epithelial cells rate and DNA synthetic ratio. Chinese Journal of Ophthalmology, 1995,31:296
6. all morning sunlight, He Shouzhi, Liang Yanjie, etc. rabbit aqueous humor cytology research behind the intraocular lens implants. Chinese Journal of Ophthalmology, 1996,32:342
7.Benezra?D，Chohen?E.Ophthalmology，1997；104：2168
8. Hu Yiqing, Chen Caigen, Zhou Shaorong, etc. the experimentation of daunorubicin prevention posterior capsule opacification. ophthalmology new development, 1998,18 (1): 23
Claims (2)
1. the new application of interleukin 1 receptor antagonist IL-1RA, the application in prevention and treatment after cataract medicine.
2. the new application of interleukin 1 receptor antagonist IL-1RA as claimed in claim 1, application in prevention and treatment after cataract medicine, described prevention and treatment after cataract medicine can be single interleukin 1 receptor antagonist IL-1RA, can be to serve as main part synthetic biochemical product with interleukin 1 receptor antagonist IL-1RA, can be noncompetitive IL-1 receptor blocking agent.
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2003
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