CN104840473A - Application of tanshinone IIA in preparation of medicine for treating tendon adhesion - Google Patents
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- CN104840473A CN104840473A CN201510238176.5A CN201510238176A CN104840473A CN 104840473 A CN104840473 A CN 104840473A CN 201510238176 A CN201510238176 A CN 201510238176A CN 104840473 A CN104840473 A CN 104840473A
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- tendon
- adhesion
- blood
- tanshinone iia
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Abstract
The invention discloses an application of tanshinone IIA in preparation of a medicament for treating tendon adhesion, and belongs to the technical field of medicines. After a rat model of the achilles tendon adhesion is prepared, the rat model is locally injected with tanshinone IIA sodium sulfonate to the achilles tendon, and the adhesion condition of the achilles tendon is compared with a blank group for histological observation and statistical analysis. The results show that the adhesion of achilles tendon in the salvia miltiorrhiza group is less than that in the blank group in gross observation, the P is less than 0.05, and the statistical difference exists; in histological observation, the number of collagen fibers and fibroblasts in the salvia miltiorrhiza group is increased compared with that of normal achilles tendon tissues, the arrangement is relatively regular, the number of collagen fibers and fibroblasts in the blank group is obviously increased, and the arrangement is irregular; the expression of TGF-beta 1 in the salvia miltiorrhiza group is obviously reduced compared with that in the blank group through Real-time PCR. These results indicate that tanshinone IIA has the effect of inhibiting the occurrence and progression of tendon adhesion, and can be used for preparing a medicament for treating tendon adhesion.
Description
Technical field
The invention belongs to medical art, relate to the application of a kind of tanshinone IIA in the medicine of preparation treatment adhesion of tendon.
Background technology
Adhesion of tendon refers to hypertrophy and the intrusion of surrounding tissue in tendon injury repair process, causes tendon dyskinesia.The postoperative adhesion of tendon of wound is one of FAQs after tendon injury, is one of still unsolved difficult problem of hands surgery, up to now still without effective solution.
The reason that adhesion of tendon occurs may be damage induce tissue Interstitial cell, the mastocyte release various active material of mechanicalness and chemical, comprise thrombin, histamine, heparin and other vaso-active substance, tissue is made to produce inflammatory reaction, capillary permeability increases, and a large amount of serosity oozes out.These exudates as the absorption that can not be decomposed, then impel fibrin to gather, and grow into while fibrocyte infiltration and new capillary vessel occur then, finally form fiber adhesion.Think that the healing of tendon is completed by inside and outside two kinds of mechanism at present.Endogenetic mechanisms refers to by Tenocyte cell hypertrophy, secretion collagen fiber reparation damage tendon; Exogenous mechanism refers to by paratenon's hypertrophy, fibroblast proliferation, produces collagen fiber reparation damage tendon.Tendon injury is light, and suture quality is good, and nutrition supply is abundant, be then main path with endogenous neurogenesis; And when tendon injury is serious, suture quality is poor, when the confession of the blood of tendon itself and synovial fluid disperse system are damaged, then exogenous reparation is preponderated formation adhesion, therefore adhesion is the inevitable outcome of the exogenous reparation of tendon.
The current discovery major cytokine relevant with tendon injury repair process comprises: transforming growth factor β (transforminggrowth factor-β, TGF-β), bone morphogenetic protein 12 (bone morphogenetic protein-12, BMP-12), type-1 insulin like growth factor (insulin-like growth factor-I, IGF-1), basic fibroblast growth factor (basicfibroblast growth factor, bFGF), VEGF (vascular endothelial growth factor, VEGF), platelet-derived growth factor (plateled derived growth factor, PDGF) etc.TGF
[1]be a relative molecular mass be 2.5 × 10
4heterodimeric protein, the mankind have TGF-β 1, TGF-β 2, TGF-β 3 three isomerss, and wherein the distribution of TGF-β 1 in the human body relation of repairing at most and with tendon injury is also the closest.Natsu etc.
[2]find that normal Tenocyte cell and stndon sheath cell can produce TGF-β 1, this factor is activated when tendon injury, and its mRNA raises obviously.Park YingJie etc.
[3]for TGF-β 1, the dosage effect of people's embryo tendon cell and the impact of time effect and TGF-β 1 cell cycle and proliferation index are observed, found that TGF-β 1 can stimulate tendon cell DNA to synthesize, and point out that TGF-β 1 can by promoting that Tendon proliferation participates in the reparation of tendon.Beredjiklian etc.
[4]by finding sheep embryo tendon injury scale-model investigation, Scarless wound healing after embryo's tendon injury, and TGF-β 1 and mRNA content thereof are starkly lower than adult tissue in embryo's environment, the Scarless wound healing mechanism of this prompting embryo may be exactly that TGF-β 1 environment of this low concentration causes.Malmstrom etc.
[5]research find TGF-β 1 by impel the raising of fibroblast and macrophage, blood vessel generation, stimulate the generation of collagen, lower the activity of matrix metalloproteinase and increase the activity of matrix metallo-proteinase inhibitor and play a role, be a cytokine played an important role in acute inflammation and wound healing, its undue expression can cause excessive scar hyperplasia and fibrosis.
Radix Salviae Miltiorrhizae is the dry root and rhizome of Lamiaceae Salvia platymiscium Radix Salviae Miltiorrhizae (Salviamiltior-rhiza bunge), has the effects such as antibacterial, antiinflammatory, blood vessel dilating, anti-platelet aggregation
[6], its effective ingredient is danshensu (p-3,4 DLAs) and TANSHINONES mainly.The sterile water solution of the sodium tanshinon IIA silate injection that tanshinone IIA obtains after sulfonation, greatly strengthen the water solublity of medicine, obtains higher curative effect.Traditional medicine is thought, blood system walked by Radix Salviae Miltiorrhizae, promoting blood circulation, and merit arrogates to oneself blood circulation promoting and blood stasis dispelling." the sensible opinion of married woman " is recorded: " Radix Salviae Miltiorrhizae simply, merit is with four things ".Li Shizhen (1518-1593 A.D.) also claims Radix Salviae Miltiorrhizae to have effect of SIWU TANG in Compendium of Material Medica.Radix Salviae Miltiorrhizae main product in Sichuan, Shanxi, Hebei, Jiangsu, the ground such as Anhui, medicinal part gets root and rhizome portion, thick with bar, interior atropurpureus and have Flos Chrysanthemi shape white point person for good, and its cold nature, bitter in the mouth, enter the heart, pericardium channel and Liver Channel.State-promulgated pharmacopoeia (version in 2005) concludes effect of Radix Salviae Miltiorrhizae for " clear away heart-fire relieving restlessness for stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow.For menoxenia, amenorrhea dysmenorrhea, lump in the abdomen, breast ventral spine pain, pyretic arthralgia pain, skin infection swell and ache, dysphoria and insomnia, hepatosplenomegaly, angina pectoris." Radix Salviae Miltiorrhizae is used to the treatment of hepatopathy, cardiovascular disease, and achieves significant curative effect because of its function of promoting blood circulation to disperse blood clots certainly.Its effective ingredient has water solublity and fat-soluble two large classes, water-soluble portion is mainly phenolic acid compound (comprising danshensu, protocatechualdehyde, salvianolic acid etc.), and fatty contents is mainly diterpene quinone (comprising TANSHINONES, cryptotanshinone etc.).Yang Wei peak etc.
[7]find, TANSHINONES can dose-dependently suppress HSC to breed, and suppresses NTx, hyaluronic acid and laminin，LN to be secreted in various degree, points out it to have anti-hepatic fibrosis effect at cellular level.Sun Xingwang etc.
[8]confirm fibroblast (hRIFs) in-vitro multiplication that sodium tanshinon IIA silate injection (DS-201) suppresses people's kidney region fibrosis to be originated, may be by the G1/S outpost of the tax office by the expression blocks cellular of cyclin E gene in T suppression cell, thus the realization of prolongation cell cycle, this remarkable inhibitory action may be one of mechanism of its treatment kidney region fibrosis.Wang Zhenling etc. are tested by Treated with Radix Salviae Miltiorrhizae hepatic fibrosis rats, think that Radix Salviae Miltiorrhizae suppresses Liver Collagen hypertrophy, can promote that the fiber degradation deposited absorbs.Collagen degradation is mainly subject to MMPs activity regulation, Wasser etc.
[9]find that Radix Salviae Miltiorrhizae can improve liver tissues of rats with hepatic fibrosis MMP mrna expression and suppress Expression of TIMP 21 (Tissue inhibitor ofmetalloproteinase 21, TIMP21) mrna expression.Liu Chenghai etc.
[10]activate with the primary culture in vitro rat HSC that TGF-β 1 stimulates, simultaneously with Radix Salviae Miltiorrhizae acid effect, found that Radix Salviae Miltiorrhizae acid T suppression cell collagen secretion, α-smooth muscle actin (α-smooth muscle actin, α-SMA) with the protein expression of plasminogen activator inhibitive factor, lower I procollagen type gene expression; And the protein expression of Smad 2,3 in T suppression cell matter and nucleus, suppresses phosphorylation and nuclear translocation thereof in Smad2 albumen born of the same parents, Radix Salviae Miltiorrhizae acid anti-hepatic fibrosis is described, suppresses the mechanism of HSC activation to be the signal transduction of suppression TGF β 1 at HSC.Wang Xiaoling etc.
[11]think that Radix Salviae Miltiorrhizae acid can suppress TGF-β 1 to promote the effect of cell NTx mrna expression and intervene the transcription factor expression of TGF-β 1 in HSC intracellular signal transduction and biological effect thereof.Radix Salviae Miltiorrhizae is also applied to wound repair field, and human fibroblasts (fibroblasts, FB) can autocrine insulin like growth factor, platelet derived growth factor, TGF-β 1 and EGF etc.
[12,13].Wherein TGF-β 1 is the important factor in processes of wound repair, and it can provide the semiochemicals of normal healing, affects all stages of agglutination.Experiment proves
[14,15]the major function of TGF-β 1 is the propagation promoting FB, regulate the balance between collage synthesis and degraded and cause extrtacellular matrix deposition, TGF-β 1 also can induce the expression of smooth muscle actin in FB, stimulate the synthesis of NTx fiber, III type collagen fiber is optionally damaged by collagenase, make I/III Collagen Type VI ratio increase, this result and the pathologic wound shrinkage to occur thereafter and cicatrization closely related.And appropriate TGF-β 1 is of value to organization healing, overexpression but likely causes cicatrix and fibrosis to be formed, and application then can reduce cicatrization with the antisense oligonucleotide of TGF-β 1 complementation
[16].
Adhesion of tendon belongs to the traditional Chinese medical science " injury of tendon and muscle ", " arthromyodynia " category.After wound, early stage hematocele becomes the stasis of blood, and expectorant agglutinates stagnant, and muscle is arrested and do not stretched, and blood network is not lived therefore ankylosis, movable unfavorable finally even wither useless need not.Current Chinese medicine mainly adopts being association of activity and inertia of theory of Chinese medical science, traditional Chinese medical science maneuver and the external application of Chinese medicine, this type of adhesion illness of fumigation and wash method Comprehensive Treatment to adhesion of tendon.Treatment skill with poking meridian method, rolling manipulation relaxing muscles and tendons and activating QI and blood in the collateral, coordinate finger sth. made by twisting, strip, pulling, loosen suffer from hands, carpal joint, tendon is loosened completely, use lift wrist kowtow fingering make tendon slide, uphold, vibrations.A brief period of time method of counting on one's fingers can make flexor tendon quick sliding, and drives wrist movable, generally within about 8 weeks after surgery, carries out, key points for operation with soft, mellow and full, carry out in proper order, avoid violence.Chinese medicine fumigation and washing has effect of thin channels and activating collaterals, blood circulation promoting and blood stasis dispelling, easing joint movement can Manipulation, and Qing Dynasty Wu Shi machine work " Li Yue Pianwen, Rhymed Discourse for Topical Remedies " is said: " reason of external treatment and the reason for the treatment of by oral administration of medicines, the medicine of external treatment and the medicine for the treatment of by oral administration of medicines, different person's method ear." damage within postoperative 6 weeks, promote swelling absorption, reviving joints alleviates contracture definite curative effect.Conventional medicine composition has: Radix Clematidis, raw river, Radix Aconiti Kusnezoffii, Squama Manis preparata, Rhizoma Pinelliae, Caulis Spatholobi, Radix Paeoniae Alba, Pine Nodular Branch, Herba Lycopodii, Herba speranskiae tuberculatae, Ramulus Cinnamomi, Chinese liquor etc.
" stasis of blood " plays important effect in the forming process of " numbness ", and the state of the stasis of blood runs through arthromyodynia all the time.Have in " Plain Questions numbness opinion " " obstruction of heart-QI person's arteries and veins is obstructed ", " disease enters deeply for a long time; to defend trip puckery in battalion; dredge during meridians; thus obstructed " sentence, other are as " passages through which vital energy circulates is incessantly popular, and ring week is endlessly; cold enters through and checks late; tears and not all right ... therefore soldier but pain " (" lift pain opinion "), " cold visitor is then blood tears among passages through which vital energy circulates, " (" carbuncle ")." hesitant pulse says numbness " (" Plain Questions normal person meteorology opinion "), " numbness be arteries and veins then blood clotting and do not flow " (" Ling Shu Miraculous Pivot or Divine Axis harmful wind ") etc.In above document " row is puckery ", " puckery and not all right ", " blood tears are then obstructed ", the existence of " stasis of blood " pointed out in words such as " blood clottings ", and next step of the stasis of blood is exactly " numbness "." medical secrets of official " opinion white tiger disease is mentioned " ... by this ailment said due to cold or exposure, stagnant through kank, vim and vigour are not all right, store between joint ... "." stagnant through kank " is namely the meaning of " stasis of blood ".Discussing arthromyodynia pathogenesis in " Lei Zheng Zhi Cai arthromyodynia " is that " good in battalion Wei Xianxu, interspaces of skin and muscles being loose, wind and cold is attacked in wetting and taking advantage of a weak point in opponent's defence, and healthy energy is hindered by heresy, can not declare row, thus be detained, coagulation of QI-blood, form numbness for a long time." point out that the starting stage of " numbness " has the state of " stasis of blood " to exist, " form numbness for a long time " afterwards.Jing-Yue Complete Works " mix to then stopping up amenorrhea network, and vim and vigour are not all right and sick is numbness by wet three gas of wind and cold." from errors in Medicine Corrected " no matter internal injury diseases caused by exogenous pathogenic factor institute the wounded QI and blood nothing but ", clearly using " blood stasis " as an important paathogenic factor and important pathogenesis link.And having a special section " arthromyodynia has blood stasis to say " discussion numbness disease to have blood stasis, wound Traditional Chinese medicine decoction for treating-ache and expelling atagnate is to control it.Can find out just have the state of " stasis of blood " to exist at the beginning of " numbness " is formed." numbness " for it " stasis of blood " gradually, the stasis of blood is to pain, fiber crops, acid, swollen " numbness ".
Analyze from etiology and pathogenesis, " stasis of blood " is also inseparable with " numbness ".Exopathogen causes the stasis of blood: " Plain Questions numbness opinion " meaning " wet three gas of wind and cold are mixed extremely, combined into numbness ".Its wind and cold is wet all can be caused " stasis of blood ", and " stasis of blood " becomes then to cause " numbness ".Predominant wind, gas is vertical and do not receive, and doing, defending gas and coagulate to some extent and cause the stasis of blood in defending gas phase.As " Plain Questions wind opinion ", " pathogenic wind and the sun all enter, and all arteries and veins Yu of row, falls apart between boundary between muscles, and with to defend gas phase dry, its road is unfavorable ... defend gas to some extent solidifying and not all right, therefore meat has also meciless." predominant cold, invade passages through which vital energy circulates, passages through which vital energy circulates is tightened up, and blood is slow, even stagnates and causes the stasis of blood.As " cold enter through and check late ", " cold visitor is then blood tears among passages through which vital energy circulates ".Preponderance of dampness, then blood moistens and gets along well, in addition damp pathogen being sticky and stagnant in nature, and wet gathering forms expectorant, and QI-blood circulation does not freely form the stasis of blood.As " wet and hold, blood moistens and gets along well, and institute thinks damp arthralgia." pathogenic heat can cause the stasis of blood outside three gas, namely Wang Qingren errors in Medicine Corrected is said: " blood heat sensation over the hands then decocts in bulk ", after blood stasis is formed, often ties mutually with pathogenic heat again and forms stagnant heat.Interior-deficiency causes the stasis of blood: discuss arthromyodynia pathogenesis in " Lei Zheng Zhi Cai arthromyodynia " for " good in seeking Wei Xianxu, interspaces of skin and muscles being loose, wind and cold is attacked in wetting and taking advantage of a weak point in opponent's defence, ".Highlight the factor of " interior-deficiency ", and clinically see that arthromyodynia with the passing of time, also present many virtual images.But all " interior-deficiency " also causes the stasis of blood.The deficiency of vital energy causes the stasis of blood: blood being the mother of qi, qi as the commander of blood, and with the passing of time, the internal organs deficiency of vital energy, the capable then blood of gas, the deficiency of vital energy then blood is unable, and exopathogenic factor wind and cold wets in addition, be then " stasis of blood " for arthromyodynia.Pathogen usually intruding into collateral in protracted disease causes the stasis of blood: prolonged illness consumption hinders healthy energy, and negative and positive of qi and blood virtual loss all can cause the stasis of blood." Plain Questions numbness opinion " " disease enters deeply for a long time, and it is puckery that battalion defends trip, and during meridians, thin event is obstructed." and YE Tian shi more clearly proposes " pathogen usually intruding into collateral in protracted disease." by above-mentioned finding; no matter be broad sense " numbness " (QI and blood is not smooth and cause meridians impatency; comprise " syndromes caused by obstructed QI in five ZANG-organs "; " five body constituents numbness " etc.); or " numbness " of narrow sense (muscle; muscles and bones, the pain numbness even swelling in joint, i.e. arthromyodynia) is all closely related with " stasis of blood ".Along with the development of modern medical techniques, the theory of " stasis of blood " is also confirmed.In the middle of clinical various disease, all have found the evidence of " stasis of blood ", syndrome of blood stasis is almost present among the various disease of each system.Promoting blood circulation by removing blood stasis is just extensive use in the middle of clinical each systemic disease also.But for a certain specified disease, the pathogenesis of its uniqueness and pathological and physiological condition, have the performance of its specific " stasis of blood ".With regard to adhesion of tendon, organize Interstitial cell, mastocyte to discharge various active material, comprise thrombin, histamine, heparin etc. and make tissue produce inflammatory reaction, capillary permeability increases, and a large amount of serosity oozes out the performance belonging to " stasis of blood "; Fibrin gathers, and grows into while fibrocyte infiltration and new capillary vessel occur then, finally forms the performance that adhesion also belongs to " stasis of blood gradually becomes numbness ".These " states of the stasis of blood " just existed before tendon completes reparation, and brought out and increased the weight of the generation of adhesion.By carrying out early intervention to healing process of tendons, use activating blood and removing stasis Method control adhesion of tendon, set up and develop " stasis of blood in numbness just " theory, for adhesion of tendon research standard, Standardization Research lay the foundation, for tcm clinical practice prescription founds the foundation that medicine provides science, there is important scientific meaning.
Chinese medicine and pharmacy is the important component part of the magnificent culture of the Chinese nation, is also current China one of the most influential ambit in the world.The theory of the traditional Chinese medical science " preventive treatment of disease " is long-standing, in Plain Questions of Huangdi's Internal Classic first section " the large opinion of regulating life activities according to natural changes in four seasons " " sage's preventing diseases instead for the treatment of diseases; do not control and disorderly control disorderly ... husband's disease become then medicine it; disorderly become and then controlled it; example is still thirsty and wear well; bucket and casting cone, also evening " discussion, started the traditional Chinese medical science to the uniqueness understanding in this field and penetrating opinion." stasis of blood in numbness just " theoretical direction treats early stage adhesion of tendon, namely belongs to " preventing exacerbation after being taken ill " aspect of " preventive treatment of disease ".Meet to " prevention transforms treatment " strategy.Medicine is utilized to prevent nature to become the focus of international evidence-based medicine EBM to carrying out in disease early stage or high-risk group.This is the development trend of global medical health industry.Therefore the intervention of early stage adhesion of tendon is the needs of patient, is also the needs of Development of Health Service.
Adhesion of tendon is complication common after tendon injury, and its control is scientific circles' question of common concern always.How making tendon in damage or occur less after repairing or do not stick together, recover its sliding function as early as possible, the healing simultaneously not affecting again tendon itself is existing technical barrier.
Do not have effective medicine and method thoroughly can solve the problem of adhesion of tendon at present, local injection medication Chinese medicine has the advantage of overall dynamics adjustment and individualized treatment.The advantage scientific evidence of Chinese medicine being proved, is the strategy that Chinese medicine goes to the world.Human body, as a system, regulates and necessarily obtain overall optimum efficiency for this, but not indivedual index optimum efficiency is terminal and object to it.
Therefore the adhesion of tendon of Chinese medicine early prevention is adopted to be current urgent clinical needs.Comply with country, society and individual Man's Demands; Practical interests are brought to patient; Bring long-range economic benefit and social benefit can to country, society, family and individual.
List of references:
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[2]Natsu-umeT,Nakamura N,Shino K,et al.Temporal and spatial expression of transforming growthfactor-beta in the healing patellar ligament of the rat[J].J Orthop Res,1997,15(6):837-843.
[3] Park YingJie, He Huixu, Wang Wei. the regulating and controlling effect [J] that transforming growth factor-beta 1 is bred Tenocyte cell. Chinese hands surgical magazine, 2001,17 (13): 163-165.
[4]Beredjiklian PK,Favata M,Cartmell JS,et al.Regenerative versus reparative healing in tendon:astudy of biomechanical and histologicalproperties in fetal sheep[J].Ann BiomedEng,2003,31(10):1143-1152.
[5]Malmstrom J,Lindberg C,Lindberg H,et al.Transforming growth factor-beta 1specically induceproteins involved in the myobroblast contractile apparatus.Mol Cell Proteomics,2004,3(5):466-477.
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[7] Yang Wei peak, Chen Houchang, Xia Bijun. tanshinone IIA is on the impact [J] of hepatic stellate cell proliferation and extracellular matrix secretion. Chinese journals of practical medicine, 2003,19 (11): 1191-1192.
[8] Sun Xingwang, Cao Ling, Yu Guohua, etc. the impact [J] that Sodium Tanshinone Ⅱ-A sulfonate is expressed fibrosis people renal interstitial Fibroblasts in vitro propagation and cyclin E protein. Third Military Medical University's journal, 2007,29 (7): 585-587.
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[10] Liu Chenghai, Liu Ping, Hu Yiyang, etc. Salvianic acidA and salvianolic acid B salt stimulate the effect [J] of Hepatic Stellate Cell Activation and intracellular signal transduction to transforminggrowthfactor-β1. Chinese Medical Journal, 2002,82 (18): 1267-1272.
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Summary of the invention
The object of the invention is to determine the effect of tanshinone IIA in treatment adhesion of tendon, and then the application of tanshinone IIA in the medicine of preparation treatment adhesion of tendon is provided.
Object of the present invention is achieved through the following technical solutions:
After the present invention makes Tendon Adhesion rat model, heel string local injection sodium tanshinon IIA silate injection (Radix Salviae Miltiorrhizae group) is carried out to it, by comparing Tendon Adhesion situation with blank group, row histological observation and statistical analysis.Result shows, in gross examination of skeletal muscle, Radix Salviae Miltiorrhizae group is fewer than blank group Tendon Adhesion, and P<0.05, has significant difference; In histological observation, the collagen fiber of Radix Salviae Miltiorrhizae group and fibroblast quantity compared with normal heel string tissue increase, and arrangement is rule relatively, and collagen fiber and the fibroblast quantity of blank group obviously increase, irregular arrangement.These results show that tanshinone IIA has and suppress the generation of adhesion of tendon and the effect of progress thereof.Find that Radix Salviae Miltiorrhizae group significantly reduces relative to the expression of blank group TGF-β 1 further by Real-time PCR, show that tanshinone IIA reduces the effect of cell collagen mrna expression by suppressing TGF-β 1 expression realization, the cytokine mechanisms that tanshinone IIA reduces adhesion of tendon is the expression suppressing TGF-β 1.
Suppress the generation of adhesion of tendon and the effect of progress thereof based on tanshinone IIA, tanshinone IIA or sodium tanshinon IIA silate injection can be used for the medicine preparing treatment adhesion of tendon.
Treat a medicine for adhesion of tendon, comprise tanshinone IIA or sodium tanshinon IIA silate injection.
Present invention finds tanshinone IIA and Tendon Adhesion rat model is had to the effect reducing adhesion and occur, it can be used for the medicine preparing treatment adhesion of tendon, thus brings new thinking to clinical prevention adhesion of tendon.
Accompanying drawing explanation
Fig. 1 is Radix Salviae Miltiorrhizae group SD Rat Achilles Tendon HE colored graph (100 ×), collagen fiber and fibroblast increasing number, visible thick collagen, and arrangement is rule relatively, with longitudinal axis, and middle visible a small amount of scar tissue.
Fig. 2 is Radix Salviae Miltiorrhizae group SD Rat Achilles Tendon Masson trichrome stain figure (400 ×), and visible collagen structure is relatively regular, and thickness is homogeneous, arranges with longitudinal axis.
Fig. 3 is blank group SD Rat Achilles Tendon HE colored graph (100 ×), and a large amount of thick fibrous scar structure of visible central authorities, around arrangement of collagen fibers is disorderly.
Fig. 4 is blank group SD Rat Achilles Tendon Masson trichrome stain figure (400 ×), and visible collagen structure is disorderly, and thickness is uneven, random arrangement.
Fig. 5 be Real-time PCR detect tanshinone IIA TGF-β 1 is expressed affect result figure.
Detailed description of the invention
Following examples are used for further illustrating the present invention, but should not be construed as limitation of the present invention.If do not specialize, the conventional means that technological means used in embodiment is well known to those skilled in the art.
The making of embodiment 1 Tendon Adhesion rat model
Laboratory animal: SD rat, male, about 350g, SPF level, is provided by Medical College of Zhejiang Univ.'s Experimental Animal Center.
The making of Tendon Adhesion rat model: lumbar injection phenobarbital (4% phenobarbital, 40mg/kg) anesthetized rat, 0.15cm otch on right rear leg calcaneus, be about 2cm, Rothkopf and Perterson experimental injury method with improvement: get and be about the long heel string of 0.5cm, peel off stndon sheath, with Kocher pincers by far-end proximally clamp 10 times, at every turn by clamp-buckle on earth, continue to unclamp after 1 second, then with sharp knife, longitudinally running through tendon cuts three cuttves, cause extruding to frustrate and split incision, sew up wound after pressurized hemostasis, sterile dressing, right lower extremity diameter 0.8mm Kirschner wire fixation knee sprung degree ankle joint plantar flexion degree toes nature position, steam again and raise.Postoperative continuous intramuscular injection penicillin (80,000 U/kg, q/d) 3d, prevention infection.
The observation of embodiment 2 tanshinone ⅡA control Tendon Adhesion In Rat effect
SD rat after Example 1 modeling 64, be divided into Radix Salviae Miltiorrhizae group and blank group, Radix Salviae Miltiorrhizae group heel string local injection sodium tanshinone IIA sulfate injection (trade name: Nuo Xinkang 2mL/ props up, biochemical pharmaceutical factory, Shanghai first) 0.5mL at once after being treated to modeling, injection is once; Blank group is treated to injection 0.5mL normal saline, and operating procedure is the same.Put to death after 6 weeks, period carries out overview to rat, carries out gross examination of skeletal muscle and histological observation after execution.
(1) overview: the mental status, mobility, fur, body weight, heel string wound healing situation etc. of rat are dynamically observed.Radix Salviae Miltiorrhizae group and blank group rat all survive, and wound primary healing, occurs without situations such as infection and the useless use of hind leg.
(2) gross examination of skeletal muscle: SD rat put to death after otomy district skin and subcutaneous tissue, expose tendon suture place tissue, stndon sheath and tendon respectively, observe the inflammatory reaction of the tendon broken ends of fractured bone, granulation hyperplasia and healing process of tendons and adhesion situation.Standards of grading are: I grade, peri-musculotendinous is without adhesion; II grade, there is a small amount of limitation at tendon suture place, the adhesion of thin film sample, and tendon slides slightly limited; III grade, the loose adhesion of fritter band shape, and tendon surface is easily separated, tendon slipper is limited; IV grade, the medium fine and close adhesion of larger area, has certain mobility, and tendon slides obviously limited; V grade, large-area fine and close adhesion, tendon and sheath pipe, subcutaneous extensive adhesion, sliding extreme difference.
Gross examination of skeletal muscle healing process of tendons situation is excellent with I grade, II grade, and III grade is good, and IV grade, V grade for poor.The results are shown in following table 1, two groups adopt SPSS11.0 to do two independent sample Mann-Whitney rank test, the results are shown in following table, P<0.05, have significant difference.
Table 1
(3) histological observation: 4% paraformaldehyde soaks fixing, dewaters after decalcification process, paraffin embedding, cut into serving pieces; HE staining, Masson trichrome staining are observed: fibroblast, collagen fiber.
The results are shown in Figure 1-4, in the heel string tissue in HE and Masson Radix Salviae Miltiorrhizae group, collagen fiber and fibroblast quantity compared with normal heel string tissue increase, and arrangement is rule (Fig. 1,2) relatively; Collagen fiber in blank group and fibroblast quantity obviously increase, irregular arrangement (Fig. 3,4).
The above results shows, no matter in gross examination of skeletal muscle or histological observation, compares matched group, and Radix Salviae Miltiorrhizae group has and necessarily suppresses the generation of adhesion of tendon and the effect of progress thereof.
(4) Real-time PCR detects the impact that tanshinone IIA is expressed TGF-β 1
Each group of tendon tissue of drawing materials, extracts total serum IgE after grinding.Reverse transcription is carried out according to Reverse Transcriptase kit (TaKaRa, RR036A).According to PCR kit (TaKaRa, RR820A), carry out Real-time PCR gene expression detection (GAPDH is for internal reference) with LightCycler 480System, primer sees the following form 2.
Table 2
| Primer | Sequence |
| TGF-β1-F | CATTGCTGTCCCGTGCAGA |
| TGF-β1-R | AGGTAACGCCAGGAATTGTTGCTA |
| GAPDH-F | CAAGCATCCATGCGGGAAC |
| GAPDH-R | ATGGTGGTGAAGACGCCAGTA |
Real-time PCR the results are shown in Figure 5, and Radix Salviae Miltiorrhizae group significantly reduces relative to the expression of blank group TGF-β 1, P<0.05.This result further demonstrate that tanshinone IIA reduces the effect of cell collagen mrna expression by suppressing TGF-β 1 expression realization, and the cytokine mechanisms that tanshinone IIA reduces adhesion of tendon is the expression suppressing TGF-β 1.
Claims (4)
1. the application of sodium tanshinon IIA silate injection in the medicine of preparation treatment adhesion of tendon.
2. the application of tanshinone IIA in the medicine of preparation treatment adhesion of tendon.
3. treat a medicine for adhesion of tendon, it is characterized in that: comprise sodium tanshinon IIA silate injection.
4. treat a medicine for adhesion of tendon, it is characterized in that: comprise tanshinone IIA.
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| CN111249466A (en) * | 2020-03-14 | 2020-06-09 | 浙江大学医学院附属第一医院 | Application of tanshinone IIA and miR-29b inhibitor in preparation of medicine for treating tendon adhesion |
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Non-Patent Citations (1)
| Title |
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| 卢荟等: "丹参酮ⅡA治疗肌腱粘连的作用机制的研究", 《2014年浙江省医学会手外科暨显微外科学学术年会论文汇编》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111249466A (en) * | 2020-03-14 | 2020-06-09 | 浙江大学医学院附属第一医院 | Application of tanshinone IIA and miR-29b inhibitor in preparation of medicine for treating tendon adhesion |
| CN111249466B (en) * | 2020-03-14 | 2022-04-15 | 浙江大学医学院附属第一医院 | Application of tanshinone IIA and miR-29b inhibitor in preparation of medicine for treating tendon adhesion |
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