Application of S100A8 in preparation of medicine for preventing / treating bladder infection after spinal cord injury

Abstract

The invention belongs to the technical field of biological medicine and molecular biology, and provides application of S100A8 in preparation of a medicine for preventing / treating bladder infection after spinal cord injury. The S100A8 can be used as a prevention target of bladder infection after potential spinal cord injury, and after the S100A8 is perfused into the bladder, the colony count of the bladder tissue is obviously reduced, so that the S100A8 has an infection prevention effect; meanwhile, the damage repair capacity of the bladder epithelium is remarkably improved, the compound can be used as a prevention / treatment target spot for preventing bladder infection after spinal cord injury, and a new thought is provided for clinical prevention and treatment of bladder infection after spinal cord injury.

Description

Technical Field

[0001] This invention belongs to the fields of biomedicine and molecular biology, and relates to the application of S100A8 in the prevention of bladder infection after spinal cord injury. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Spinal cord injury (SCI) often causes lower urinary tract dysfunction, manifesting as storage and voiding symptoms such as obstructed bladder emptying, increased residual urine, and elevated bladder pressure. Urinary retention and bladder hypertension provide a suitable environment for pathogens to multiply, and the bladder epithelial barrier and immune defense mechanisms in SCI patients are often impaired, making it easier for pathogens, especially Escherichia coli, to adhere, colonize, and grow, leading to urinary tract infections (UTIs). Furthermore, SCI patients often require catheterization to assist urination; while catheterization can relieve urinary retention, long-term use also increases the risk of UTIs. Bladder infections not only increase patient suffering and medical burden but can also lead to serious complications such as pyelonephritis and sepsis. Prevention and treatment of UTIs after spinal cord injury mainly rely on antibiotics, which can alleviate infection to some extent, but still have many limitations: long-term or repeated use of antibiotics can easily lead to the development of drug-resistant strains, and the defective bladder epithelial barrier still makes patients susceptible to recurrent infections. Therefore, interventions targeting only the pathogen cannot fundamentally reduce the risk of infection.

[0004] Therefore, there is an urgent need to find new therapeutic targets to provide better treatment options for bladder infections following spinal cord injury. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides the application of S100A8 in the prevention of bladder infection following spinal cord injury. This invention discovers that S100A8 can promote bladder epithelial repair and reconstruction, providing a new approach for the clinical prevention and treatment of bladder infection following spinal cord injury.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, the invention provides the use of S100A8 in the preparation of a medicament for the prevention / treatment of bladder infections following spinal cord injury.

[0007] S100A8 is a calcium-binding protein that often forms a heterodimer with S100A9, enabling it to chelate Zn²⁺. + Mn² +Essential metal ions directly inhibit the growth of bacteria and fungi, blocking their metabolism and reproduction. Simultaneously, S100A8, as a damage-associated molecular pattern (DAMP), can bind to TLR4 and RAGE receptors, activating NF-κB and MAPK signaling pathways, promoting the recruitment and activation of neutrophils and monocytes, and enhancing local inflammatory responses and immune defense. Furthermore, it has been demonstrated that S100A8 improves the reconstruction of damaged endometrial epithelium by promoting tight junction formation and stromal cell transformation, maintaining the structural integrity of the epithelial barrier. In summary, S100A8 can directly inhibit bacteria and indirectly defend against infection by regulating immune responses and protecting the epithelial barrier. Its mechanism involves metal ion chelation, immune activation, and barrier protection, providing a potential novel therapeutic target for bladder infections following spinal cord injury.

[0008] In a second aspect, the invention provides the use of S100A8 in the preparation of a medicament for the prevention / treatment of bladder epithelial damage following spinal cord injury.

[0009] A third aspect of the present invention provides a medicament for preventing bladder infection following spinal cord injury, comprising: S100A8 and a pharmaceutically acceptable pharmaceutical carrier.

[0010] Beneficial effects of the present invention (1) S100A8 can be used as a preventive target for bladder infection after potential spinal cord injury. After bladder instillation of S100A8, the number of bacterial colonies in bladder tissue was significantly reduced, showing the preventive effect of S100A8 on infection. At the same time, it significantly improved the damage repair capacity of bladder epithelium, and can be used as a preventive / therapeutic target for bladder infection after spinal cord injury.

[0011] (2) The method of the present invention is simple, practical and easy to promote. Attached Figure Description

[0012] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. Exemplary embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0013] Figure 1 To identify potential targets for preventing bladder infection following spinal cord injury, the following data were used: A. Expression level of S100A8 in rat bladder tissue 28 days after spinal cord injury; B. Expression level of KRT5 in rat bladder tissue 28 days after spinal cord injury. *** represents P < 0.001, **** represents P < 0.0001. Figure 2 To prevent urinary tract infections after S100A8 bladder instillation therapy, A: bladder tissue colony count after bladder instillation in the control group; B: bladder tissue colony count after bladder instillation in the spinal cord injury group; C: bladder tissue colony count after bladder instillation with S100A8 following spinal cord injury.

[0014] Figure 3 The following are the bladder epithelial findings after S100A8 bladder instillation therapy: A. Normal bladder epithelium; B. Bladder epithelium of the spinal cord injury group; C. Bladder epithelium of the spinal cord injury group after S100A8 instillation. Detailed Implementation

[0015] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. The reagents and raw materials used in this invention are readily available through conventional means, and unless otherwise specified, they are used in accordance with conventional methods in the art or product instructions. Similarly, unless otherwise specified, the test methods of this invention are performed in accordance with conventional methods in the art or industry-standard methods or practices. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0017] Terminology Explanation: S100A8: “S100A8” is a low molecular weight protein belonging to the S100 calcium-binding protein family. It is also known as calcium-binding protein A8 or calgranulin A. It often forms a heterodimer with S100A9 (called calprotectin) and participates in inflammatory responses, immune regulation and barrier function maintenance.

[0018] Bladder infection following spinal cord injury: Bladder infection following spinal cord injury refers to an infection state that occurs after spinal cord injury (SCI) due to factors such as impaired bladder nerve innervation, bladder dysfunction, urinary retention, and decreased epithelial barrier function, which makes the patient's bladder susceptible to bacterial invasion.

[0019] This invention provides the application of S100A8 in the preparation of drugs for the prevention / treatment of bladder infections following spinal cord injury.

[0020] S100A8 can serve as a preventive target for bladder infection following spinal cord injury. Bladder instillation of S100A8 can significantly improve the bladder epithelial repair capacity and can be used as a preventive target for bladder infection following spinal cord injury.

[0021] In some embodiments, the S100A8 is a recombinant S100A8 protein. The recombinant S100A8 protein is a protein produced from the S100A8 gene through genetic engineering technology. It has calcium ion binding function and is widely used in research on immune responses, cytoskeleton regulation, and oxidative stress responses.

[0022] In some embodiments, the present invention uses S100A8 bladder instillation to treat bladder infection following spinal cord injury, and the efficacy includes at least one of the following: a) Decreased bacterial count in bladder tissue; b) Repair of the urothelial tract; c) Bladder epithelial edema is reduced.

[0023] This indicates that after bladder instillation of S100A8, the number of bacterial colonies in the bladder tissue was significantly reduced, demonstrating the infection prevention effect of S100A8. At the same time, it can significantly improve the damage repair capacity of the bladder epithelium.

[0024] Insufficient S100A8 dosage may lead to poor antibacterial or bladder epithelial damage repair effects, while excessive S100A8 dosage may easily cause adverse reactions. Therefore, this invention has studied the dosage of S100A8. In some embodiments, the dosage of S100A8 is 5ug / ml, 200ul / animal, to obtain better therapeutic effects.

[0025] The present invention does not impose any special limitation on the administration method of S100A8. In some embodiments, S100A8 is injected by bladder instillation to obtain better preventive / therapeutic effects.

[0026] This invention provides the application of S100A8 in the preparation of drugs for the prevention / treatment of bladder epithelial damage repair after spinal cord injury.

[0027] This invention can significantly improve the bladder epithelial repair capacity after bladder instillation of S100A8.

[0028] The present invention provides a drug for preventing bladder infection after spinal cord injury, comprising: S100A8 and a pharmaceutically acceptable pharmaceutical carrier.

[0029] This invention does not impose any special limitation on the type of drug carrier. In some embodiments, the drug carrier is selected from one of the following: solution, suspension, emulsion, and gel, to meet the usage requirements of different scenarios or administration methods.

[0030] Drug concentration has a direct impact on efficacy. Too low a concentration may lead to ineffective treatment, while too high a concentration may increase the risk of toxic side effects. It is necessary to maintain it within an appropriate range to achieve the best efficacy and safety. Therefore, this invention has studied the concentration of S100A8. In some embodiments, the concentration of S100A8 is 1-10 ug / ml, preferably 5 ug / ml, to obtain better efficacy.

[0031] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are explanations of the present invention and not limitations thereof.

[0032] Methods for establishing a spinal cord injury (SCI) animal model: Rats were anesthetized and fixed by intraperitoneal injection of urethane. After removing hair from their backs and disinfecting, the skin and subcutaneous tissue were incised at the T10 thoracic vertebra to expose the spinal cord, which was then severed. Upon awakening, the rats exhibited hind limb paralysis, confirming the successful establishment of the SCI model. A control model was used, where only the spinal cord was exposed without severing. In the SCI group, the bladder of the rats was pressed daily to assist urination.

[0033] Example 1: Animal experiments screened S100A8 as a potential target for preventing bladder infection after spinal cord injury. 1) The content of S100A8 and KRT5 proteins in the bladder of rats in the spinal cord injury group and the control group was detected by mass spectrometry.

[0034] 2) A rat model of spinal cord injury was established using 8-week-old SD rats. The rats were treated with S100A8 bladder instillation, and the treatment effect was evaluated by the number of bacterial colonies in the bladder tissue after bladder instillation.

[0035] Depend on Figure 1 As shown in Figure A, the expression level of S100A8 in rat bladder tissue was significantly reduced 28 days after spinal cord injury.

[0036] Depend on Figure 1 As shown in Figure B, the expression level of KRT5 in rat bladder tissue was significantly reduced 28 days after spinal cord injury.

[0037] Depend on Figure 2 As shown in Figure A, the control group had a lower number of bacterial colonies in the bladder tissue after bladder enema. Figure 2 As shown in Figure B, after bladder enema in the spinal cord injury group, the number of bacterial colonies in the bladder tissue significantly increased. Figure 2 As shown in Figure C, after bladder instillation with S100A8 following spinal cord injury, the number of bacterial colonies in the bladder tissue was significantly reduced, demonstrating the infection prevention effect of S100A8.

[0038] Example 2: S100A8 improves bladder epithelial repair and reconstruction after spinal cord injury Rats with spinal cord injury were given bladder instillation with recombinant S100A8 protein, and the repair of urothelial tissue was observed. The control group was injected with the same volume of solvent (200 μL PBS).

[0039] Depend on Figure 3 As shown in Figure A, the bladder epithelium in the normal group showed good mucosal integrity, which was... Figure 3 As shown in Figure B, the spinal cord injury group exhibits bladder epithelial edema, with its integrity disrupted. Figure 3 As shown in Figure C, in the spinal cord injury group, perfusion with S100A8 reduced bladder epithelial edema and improved bladder integrity.

[0040] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. Application of S100A8 in the preparation of drugs for the prevention / treatment of bladder infection after spinal cord injury.

2. The application as described in claim 1, characterized in that, The S100A8 is a recombinant S100A8 protein.

3. The application as described in claim 1, characterized in that, The medicinal effects include at least one of the following: a) Decreased bacterial colony count in bladder tissue; b) Repair of the urothelial tract; c) Bladder epithelial edema is reduced.

4. The application as described in claim 1, characterized in that, The dosage of S100A8 was 200 μL, and the concentration was 5 μg / ml.

5. The application as described in claim 1, characterized in that, The S100A8 was injected using the bladder irrigation method.

6. Application of S100A8 in the preparation of drugs for the prevention / treatment of bladder epithelial damage repair after spinal cord injury.

7. The application as described in claim 6, characterized in that, The S100A8 is the S100A8 recombinant protein; Alternatively, the dosage of S100A8 is 200ul, and the concentration is 5ug / ml; Alternatively, the S100A8 may be injected using the bladder irrigation method.

8. A drug for preventing bladder infection after spinal cord injury, characterized in that, include: S100A8 is a pharmaceutically acceptable carrier.

9. The drug for preventing bladder infection after spinal cord injury as described in claim 8, characterized in that, The pharmaceutical carrier is selected from one of the following: solution, suspension, emulsion, and gel.

10. The drug for preventing bladder infection after spinal cord injury as described in claim 8, characterized in that, The concentration of S100A8 is 5 ug / ml.

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