CN118320101B - Application of iNOS inhibitor in preparation of medicament for treating scleroderma collagen deposition - Google Patents
Application of iNOS inhibitor in preparation of medicament for treating scleroderma collagen deposition Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the technical field of biological medicine. More particularly, to the application of an iNOS inhibitor in preparing medicaments for treating scleroderma collagen deposition. The invention uses bleomycin to build a scleroderma mouse model and uses an iNOS inhibitor (S-methyl isothiourea hemisulphate) to explore the role of iNOS in skin collagen deposition caused by scleroderma. The research shows that the iNOS inhibitor has the functions of relieving skin inflammation, inhibiting collagen deposition and relieving the progress of scleroderma in the pathogenesis of scleroderma, has the advantages of safety, reliability, definite curative effect, definite components, better stability and the like, and can be used as a therapeutic drug for skin collagen deposition caused by scleroderma.
Description
Technical Field
The invention relates to the technical field of biological medicine. More particularly, to the application of an iNOS inhibitor in preparing medicaments for treating scleroderma skin collagen deposition.
Background
The skin is used as the largest organ of a human body, is the first defense line of the body against external injury, and when the skin is affected by severe injury (such as burns and scalds) and autoimmune disorder (increase of serum antinuclear antibodies and the like), various immune cells and skin fibroblasts are often induced to activate, a large amount of collagen is produced, and the collagen is deposited on dermis. Normally, deposition and degradation of body collagen are tightly regulated by a number of factors, which are critical for tissue repair of the skin. However, in the course of serious skin diseases such as extensive burns and scalds, scleroderma, hypertrophic scars, etc., abnormal deposition and degradation of damaged collagen is often accompanied, and tissue fibrosis is caused, so that the normal functions of the collagen are lost.
As is typical of skin fibrosis diseases, scleroderma is an autoimmune disease characterized mainly by extensive inflammation, vasculopathy, interstitial fibrosis. The pathogenesis of the traditional Chinese medicine is complex, and the current means for clinically treating scleroderma still takes immune preparations and glucocorticoids as main substances for inhibiting abnormal inflammation and autoimmune reaction. The occurrence and development of scleroderma not only affect the appearance of a patient, but also are accompanied with symptoms such as pain, itching, scar contracture and the like, and the patient can die when serious. It is therefore particularly necessary to find more effective treatments.
Inducible Nitric Oxide Synthase (iNOS) is an important member of the NOS family, and is expressed under specific stimuli to catalyze the production of Nitric Oxide (NO) from L-arginine. Studies on iNOS knockout mice revealed that iNOS has an important influence in the onset of various diseases, for example, in skin tissues, iNOS can be expressed by almost all cells under certain conditions, and iNOS expression is closely related to inflammatory skin diseases such as psoriasis and atopic dermatitis. However, as the most representative disease of autoimmune mediated skin fibrosis, the relationship between collagen deposition and iNOS inhibitors during the onset of scleroderma has not been reported at present.
Disclosure of Invention
In order to solve the problems in the prior art, the application aims to provide a novel application of an iNOS inhibitor in preparing a medicament for treating scleroderma skin collagen deposition. The research of the application discovers that the iNOS inhibitor can effectively reduce and/or treat the skin collagen deposition caused by scleroderma, thereby providing a new thought for treating the skin collagen deposition caused by scleroderma.
In order to achieve the above purpose, the invention adopts the following technical scheme:
The invention uses bleomycin to build a scleroderma mouse model, and explores the role of iNOS inhibitors (such as S-methyl isothiourea hemisulphate) in skin collagen deposition caused by scleroderma. The research shows that the iNOS inhibitor has the functions of relieving skin inflammation, inhibiting collagen deposition and relieving the progress of scleroderma in the pathogenesis of scleroderma, has the advantages of safety, reliability, definite curative effect, definite components, better stability and the like, and can be used as a therapeutic drug for skin collagen deposition caused by scleroderma.
One of the technical schemes provided by the invention is the application of the iNOS inhibitor in preparing a medicament for treating scleroderma collagen deposition;
further, the application of the iNOS inhibitor in preparing a medicament for treating scleroderma inflammatory infiltration;
further, the application of the iNOS inhibitor in preparing medicines for inhibiting the expression of skin inflammatory factors such as IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha or TLR 4;
Further, the application of the iNOS inhibitor in preparing medicines for inhibiting the expression level of collagen mRNA such as COL6, COL8, COL12 or COL1A1 of skin or MMP9 mRNA;
Further, the application of the iNOS inhibitor in preparing medicines for inhibiting the number of alpha-SMA and PCNA positive cells;
Further, the iNOS inhibitor is at least one selected from S-methyl isothiourea hemisulfate (SMT), N- [3- (aminomethyl) benzyl ] acetamidine dihydrochloride (1400W), aminoguanidine hydrochloride (AG), L-canavanine and the like; preferably, the iNOS inhibitor is S-methyl isothiourea hemisulfate;
Further, the medicament is an external preparation taking the iNOS inhibitor as an active ingredient, and particularly comprises the iNOS inhibitor;
further, the forms of the external preparation include, but are not limited to, ointments, sprays, liniments, patches, and the like;
Further, the external preparation further comprises an auxiliary material, and the auxiliary material can be phosphate buffer solution, ethanol, propylene glycol, glycerol or the like, and has the advantages of stability, safety, convenience in use, easiness in production and the like.
The second technical scheme provided by the invention is a pharmaceutical composition containing an iNOS inhibitor, wherein the composition takes the iNOS inhibitor as an active ingredient; further, the iNOS inhibitor is S-methyl isothiourea hemisulfate.
Advantageous effects
The invention provides a new application of an iNOS inhibitor in preparing a medicament for treating scleroderma skin collagen deposition. It has been found that the iNOS inhibitors can be used to inhibit inflammatory infiltration and reduce the hardness and thickness of the epidermis and dermis of the skin by inhibiting the expression of collagen mRNA and protein levels to treat skin collagen deposition, in particular:
1) Inhibiting the expression level of skin inflammatory factors including IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha and TLR 4;
2) Inhibiting collagen mRNA expression levels and MMP9 mRNA expression levels of skin, including COL6, COL8, COL12, and COL1A 1;
3) Inhibiting the number of alpha-SMA and PCNA positive cells.
The iNOS inhibitor provided by the invention is effective for reducing and/or treating skin collagen deposition caused by scleroderma, has the advantages of safety, reliability, definite curative effect, definite components, good stability, easiness in production and the like, and provides a new thought for treating skin collagen deposition caused by scleroderma.
Drawings
The following describes the embodiments of the present invention in further detail with reference to the drawings.
FIG. 1 is a chart showing statistics of HE staining, masson staining, and epidermis and dermis thickness of skin tissue after SMT using the iNOS inhibitor in example 1; wherein a in fig. 1 is HE staining chart, arrows show dermis thickness; b is an epidermis and dermis thickness statistical graph; c is Masson staining and arrow indicates dermal collagen deposition thickness.
FIG. 2 shows the expression level of collagen mRNA in example 1.
FIG. 3 is an immunohistochemical staining chart for α -SMA in example 1.
FIG. 4 shows the levels of MMP9 mRNA expression in example 1.
FIG. 5 shows the expression level of inflammatory factor mRNA in example 1.
FIG. 6 is an immunohistochemical staining chart for inflammatory factors in example 1.
FIG. 7 shows the HE staining of skin tissue and the statistics of skin thickness after treatment in each group of mice in example 2.
FIG. 8 is a chart showing PCNA staining of skin tissue after treatment in each group of mice in example 2.
FIG. 9 shows the expression levels of collagen mRNA in each group of mice treated in example 2.
FIG. 10 shows the relative expression levels of α -SMA mRNA in skin tissue after treatment in each group of mice in example 2.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments and the accompanying drawings. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
Example 1: research on inhibition of skin collagen deposition by iNOS inhibitor in wild mouse scleroderma model
This example uses bleomycin to establish a mouse model of scleroderma and to investigate the effect of iNOS inhibitors (S-methyl isothiourea hemisulphate) on skin collagen deposition caused by scleroderma.
(1) Preparing the medicine:
Bleomycin (BLM): available from Semerle Feier technologies Inc. (Zeocin TM, R25005) in a specification of 100. 100 mg/ml, 1.25. 1.25 ml. Dilution with Phosphate Buffered Saline (PBS) was performed as follows: mu.l of bleomycin stock solution is sucked and dissolved in 50 mL of 1 XPBS solution to make the final concentration of the bleomycin stock solution be 1mg/mL, and vortex oscillation is carried out for standby.
S-methyl isothiourea hemisulphate (SMT): purchased from MedChemexpress Biotech Inc. (HY-79457) in the United states, 25. 25 mg, dissolved in Phosphate Buffer (PBS) in the following steps: 25 mg SMT was weighed and dissolved in 25 ml of 1 XPBS solution to a final concentration of 1 mg/ml and vortexed for further use.
Control reagent: 1 XPBS, available from Whansai Weibull biotechnology Co., ltd., product number G4202-500ML, 500 ML.
(2) Preparation of a mouse model:
24 wild-type (WT) female mice of 6 weeks of age were prepared and randomly divided into four groups, the first group being a control group (indicated as WT+PBS, 6), the second group being an inhibitor group (indicated as WT+SMT, 6), the third group being a model group (indicated as WT+BLM, 6), and the fourth group being a model plus inhibitor treatment group (indicated as WT+BLM+SMT, 6).
The back hair (area 2cm x 2cm, motion mild to avoid injury to the epidermis) of mice, bare back skin, were removed using a razor, where wild type mice are denoted "WT", phosphate buffer is denoted "PBS", bleomycin is denoted "BLM", S-methyl isothiourea hemisulfate is denoted "SMT", and each group of mice is treated as follows:
Control group (wt+pbs): after shaving, sterile 1 XPBS solution was subcutaneously injected once a day, 200 μl once a day, and mice were sacrificed after 28 days.
Inhibitor group (wt+smt): after shaving, 200-400 μl of 1mg/ml SMT was intraperitoneally injected (maintaining the injection dose at 5 mg/kg), once a day, and after 28 days the mice were sacrificed.
Model group (wt+blm): after shaving, 200 μl of 1mg/ml BLM was subcutaneously injected once daily and the mice were sacrificed after 28 days.
Model plus inhibitor group (wt+blm+smt): after shaving, 200. Mu.l of 1mg/ml BLM was subcutaneously injected once a day, 200. Mu.l to 400. Mu.l of 1mg/ml SMT was intraperitoneally injected one hour later (maintaining the injection dose at 5 mg/kg), and mice were sacrificed once a day after 28 days.
(3) Hematoxylin-eosin (HE) staining
The paraffin sections of the skin (whole skin) of the mice were routinely hydrated and stained according to the procedure of the HE staining kit (G1120, beijing Soy Corp technology Co., ltd.).
(4) Masson staining
The paraffin sections of the skin (whole skin) of the mice were routinely hydrated and stained according to the instructions of the Masson staining kit (G1340, beijing Soy Corp technology Co., ltd.).
(5) Immunohistochemical staining
Conventional hydration of paraffin sections of mouse skin (whole skin) tissue, then antigen retrieval with 1% sodium citrate antigen retrieval solution (C1032, beijing soebao technologies Co., ltd.) after it cooled to room temperature, blocking 10 min with 1% hydrogen peroxide methanol solution, then blocking 1h with 1% BSA (A8020, beijing soebao technologies Co., ltd.) solution, diluting antibodies α -SMA (67735-1-Ig, proteintech, 1:100), IL-1α (16765-1-AP, proteintech, 1:100), IL-1β (ab 254360, abcam, 1:100) and IL-6 (66146-1-Ig, proteintech, 1:100) in the corresponding proportions with antibody dilutions, followed by dropwise addition of the antibodies overnight at 4 ℃; the next day room temperature was warmed 1h, and secondary antibody (HS 101-01, beijing full gold biotechnology Co., ltd., 1:200) was added dropwise in the corresponding proportion, then developed according to DAB color development kit (DA 1010, beijing Soy Bao technology Co., ltd.) and sealed after hematoxylin counterstaining.
(6) Real-time fluorescent quantitative PCR (qRT-PCR) detection of mRNA expression of related genes
The whole-skin RNA of the mice is extracted, the concentration is detected, then reverse transcription is carried out to cDNA by using a reverse transcription kit (#AT 341-03, beijing full-type gold biotechnology Co., ltd.), then the expression of the mRNA level of the related gene is detected by using a SYBR Green kit (G3326-05, wuhansai Weir Biotechnology Co., ltd.) through real-time fluorescence quantitative PCR, and the relative expression quantity of the target gene is calculated by using a 2 -ΔΔCt method.
(7) Analysis of results
As shown in fig. 1, four groups of mice were compared for epidermal and dermal thickening using HE staining (a in fig. 1) after continuous injection of BLM for 4 weeks, and were quantitatively analyzed (B in fig. 1). The results show that:
The dermis of the mice in the model group was significantly thickened and inflammatory cells were heavily infiltrated compared to the control group, indicating that BLM successfully induced the scleroderma phenotype of the mice. The model plus inhibitor group showed that administration of the inhibitor significantly inhibited BLM-induced dermal thickening and inflammatory infiltration, and the model plus inhibitor group had significant differences between epidermis, dermis thickness compared to the model group (< 0.01, < 0.001).
Studies have shown that scleroderma dermis thickening is closely related to a variety of collagen deposition, and thus collagen deposition is further examined. As shown in fig. 1C, the changes in collagen fibers of four mice were compared using Masson staining, and the results showed that dermal collagen deposition was increased after BLM injection and decreased after SMT use, relative to the control. Meanwhile, the real-time fluorescent quantitative PCR was used to detect the mRNA expression level of the related genes, and the results are shown in fig. 2, wherein the BLM significantly increases the collagen mRNA expression levels of COL6A4, COL8A1, COL12A1 after injection, and significantly inhibits the collagen mRNA expression levels of COL6, COL8, COL12 after SMT administration (P <0.001, P <0.01, P < 0.05) relative to the control group.
The disturbance of the balance of collagen synthesis/degradation is a major cause of abnormal collagen deposition in scleroderma, so the expression of alpha-SMA, a key marker of myofibroblasts, which is a key cell for mainly producing collagen, is further examined, and as shown in fig. 3, the expression level of alpha-SMA in dermis is up-regulated after BLM injection, and the number of dermis alpha-SMA positive cells is suppressed after SMT is given. At the same time, the expression level of the collagen degradation related marker MMP9 was detected, and the result is shown in fig. 4, in which the expression level of MMP9 in the skin was up-regulated after BLM injection, and the expression of MMP9 was significantly inhibited after SMT administration (P <0.001, P <0.01, P < 0.05). Upregulation of MMP9 may be associated with compensation caused by abnormal deposition of collagen, and may also be associated with promotion of activation of various inflammatory and growth factors.
Considering that the occurrence and development of scleroderma are closely related to the skin inflammation degree, the expression of various inflammatory factors is further examined, and the results are shown in fig. 5, wherein the BLM injection can up-regulate the expression levels of IL-1α, IL-1β, IL-6, IL-10, TNF- α and TLR4 in skin, and significantly inhibit the expression of these inflammatory factors after SMT administration (P <0.05, P <0.01, P < 0.001). Meanwhile, the expression situation of key inflammatory factors is further verified by utilizing immunohistochemical staining, as shown in fig. 6, the expression of IL-1 alpha, IL-1 beta and IL-6 in skin (in particular in epidermis) is obviously up-regulated after BLM injection, and the expression of the inflammatory factors in skin (in particular in epidermis) is obviously inhibited after SMT is given.
Example 2 action of iNOS inhibitors for improving collagen deposition during wound healing
(1) Preparing the medicine:
S-methyl isothiourea hemisulphate (SMT): purchased from the Biotech company (HY-79457) of U.S. MedChemexpress, 25 mg in size, 25 mg SMT was weighed and dissolved in 25ml of 1 XPBS solution to a final concentration of 1 mg/ml and vortexed for further use.
Control reagent: 1 XPBS, available from Whansai Weibull biotechnology Co., ltd., product number G4202-500ML, 500 ML.
(2) Preparation of a mouse model:
18 6 week old Wild Type (WT) female mice were prepared and divided into three groups, the first group being a control group (denoted control group), the second group being a trauma group (denoted trauma group, 6), the third group being a trauma plus inhibitor group (denoted trauma+smt, 6).
The back hair (4 x 4 cm) of the mice was shaved, and the circular area tissue was excised with an 8mm trephine at approximately the same location on all mice backs, simulating trauma situations. To avoid possible interference between wounds, only one wound was created per mouse. After the wound is healed and the scar is stable (day 14), the scar tissue of the mouse skin is left. Wherein S-methyl isothiourea hemisulfate is denoted by "SMT", each group of mice was treated as follows:
Control group: after shaving, 200 μl of sterile 1×pbs solution was injected intraperitoneally, once daily, and mice were sacrificed after 14 days.
Trauma group: after shaving, the circular area tissue was excised with an 8mm trephine, simulating trauma conditions, while 200 μl of sterile 1×pbs solution was injected intraperitoneally, once a day, and after 14 days, the mice were sacrificed.
Wound plus inhibitor group (wound+smt): after shaving, the circular area tissue was excised with an 8mm trephine, wound conditions were simulated, 200 μl to 400 μl of 1mg/ml SMT was intraperitoneally injected (with the injection dose maintained at 5 mg/kg) once a day, and mice were sacrificed 14 days later.
(3) Hematoxylin-eosin (HE) staining
The paraffin sections of the skin tissue of the mice were routinely hydrated and stained according to the procedure described in the HE staining kit (G1120, beijing Soy Corp technology Co., ltd.).
(4) Masson staining
The paraffin sections of the skin tissue of the mice were routinely hydrated and stained according to the instructions of the Masson staining kit (G1340, beijing Soy Bao technology Co., ltd.).
(5) Immunohistochemical staining
Conventional hydration of paraffin sections of mouse skin tissue, then antigen retrieval with 1% sodium citrate antigen retrieval solution (C1032, beijing soeba technologies Co., ltd.) and after cooling to room temperature, blocking 10 min with 1% hydrogen peroxide methanol solution, then blocking 1 h with 1% BSA (A8020, beijing soeba technologies Co., ltd.) solution, diluting antibody PCNA (10205-2-AP, proteintech, 1:100) with antibody dilution in the corresponding ratio, followed by dropwise addition of antibody at 4℃overnight; the next day room temperature was warmed 1 h, and secondary antibody (HS 101-01, beijing full gold biotechnology Co., ltd., 1:200) was added dropwise in the corresponding proportion, then developed according to DAB color development kit (DA 1010, beijing Soy Bao technology Co., ltd.) and sealed after hematoxylin counterstaining.
(6) Real-time fluorescent quantitative PCR (qRT-PCR) detects the expression of the mRNA of the related gene.
The whole-skin RNA of the mice is extracted, the concentration is detected, then reverse transcription is carried out to cDNA by using a reverse transcription kit (#AT 341-03, beijing full-type gold biotechnology Co., ltd.), then the expression of the mRNA level of the related gene is detected by using a SYBR Green kit (G3326-05, wuhansai Weir Biotechnology Co., ltd.) through real-time fluorescence quantitative PCR, and the relative expression quantity of the target gene is calculated by using a 2 -ΔΔCt method.
(7) Analysis of results
① As shown in fig. 7, after 14 days of SMT continuous injection, we compared the skin dermis thickening condition of three groups of mice using HE staining (a in fig. 7) and performed quantitative analysis (B in fig. 7). The results show that: compared with the wounded group, the epidermis of the mice in the wounded+SMT group is obviously thickened, which shows that the SMT of the iNOS inhibitor can promote the thickening of the epidermis of the wounded mice.
This is in stark contrast to the results shown in example 1, which show a significant reduction in skin thickness in the model set after SMT use.
② In addition, we also examined the expression of cell proliferation nuclear antigen PCNA in skin tissue of each group of mice treated by immunohistochemical staining, as shown in FIG. 8, the expression of both epidermis and dermis PCNA was enhanced in the wounded +SMT group mice compared to the wounded group, indicating that the iNOS inhibitor SMT can promote proliferation of epidermis dermal cells in wounded mice.
③ Studies have shown that dermal thickening is closely related to various collagen deposition during wound recovery, and we also examined the collagen deposition conditions, as shown in fig. 9, and significantly up-regulated the expression levels of collagen mRNA such as COL1, COL3, COL6, COL17 after SMT injection compared to the traumatized mice (P <0.001, P < 0.01).
This is in stark contrast to the results shown in example 1, which showed a significant decrease in the collagenous portion of the model group after SMT use.
④ Furthermore, we examined the expression of α -SMA, a key marker for myofibroblasts, a key cell for collagen production. As shown in fig. 10, expression levels of α -SMA mRNA in dermis were significantly up-regulated after SMT injection (< 0.001).
This is in stark contrast to the results shown in example 1, where SMT usage resulted in reduced expression levels of a-SMA mRNA in the model group.
The above results indicate that SMT can promote dermal thickening and collagen deposition in the epidermis of the wounded mice, suggesting that iNOS inhibitors may not improve collagen deposition in wounded mice.
The above experiments demonstrate that iNOS inhibitors have different effects on collagen deposition at wound sites after trauma and on collagen deposition in scleroderma, possibly related to different mechanisms of collagen deposition during these two diseases.
The onset of scleroderma mainly involves autoimmune dysfunction caused by genetic and environmental factors, and collagen deposition in the onset process is a complex process involving various immune cells, biological small molecules and the like: the abnormal activation of various immune cells of a patient, wherein T cells and macrophages mainly secrete various inflammatory and fibrotic factors to promote the activation of fibroblasts. Meanwhile, B cell activation produces a large amount of autoantibodies, further affecting the functions of vascular endothelium, fibroblasts, keratinocytes, etc., thereby stimulating fibroblast activation and dermal collagen deposition through a plurality of pathways. Furthermore, single cell sequencing in recent years revealed a significant heterogeneity of fibroblasts from normal persons in scleroderma patients, and a high enrichment of various pro-inflammatory-related fibroblast populations in scleroderma patient skin. While for scars caused by wound healing, recent studies have shown a weak correlation between autoimmune factors and scarring, focusing on "responses to periwound tissue parts". Scarring of wound healing is largely due to disorders of macrophage "pro-inflammatory (M1)" and "pro-repair (M2)" function switching; and abnormal communication between macrophage-fibroblasts, keratinocytes-fibroblasts. The above further shows that the mechanisms of scar and scleroderma collagen deposition are not the same, and thus iNOS inhibitors do not have a good inhibitory effect on wound collagen deposition.
It should be understood that the foregoing examples of the present invention are provided merely for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention, and that various other changes and modifications may be made therein by one skilled in the art without departing from the spirit and scope of the present invention as defined by the appended claims.
Claims (3)
1. The application of an iNOS inhibitor in preparing a medicament for treating scleroderma collagen deposition is characterized in that the iNOS inhibitor is S-methyl isothiourea hemisulfate.
2. The use according to claim 1, characterized in that it is the use of iNOS inhibitors for the preparation of a medicament for inhibiting the expression level of COL6, COL8, COL12 collagen mRNA or MMP9 mRNA of the skin.
3. The use according to claim 1, characterized in that it is the use of iNOS inhibitors for the preparation of a medicament for inhibiting the number of α -SMA positive cells.
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| 诱生型一氧化氮合酶在硬皮病皮损中的表达;刘彤等;《2003中国中西医结合皮肤性病学术会议论文汇编》;20031231;127 * |
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