Application of Activin A in preparation of NEC diagnostic reagent and therapeutic drug

Abstract

The invention belongs to the technical field of biological medicines, and particularly discloses an application of Activin A (ACV-A) as a biomarker and a treatment target spot in neonatal necrotizing enterocolitis (NEC), and a preparation method of the ACV-A, the ACV-A and the neonatal necrotizing enterocolitis (NEC) of the neonatal enterocolitis (NEC) of the neonatal enterocolitis (NEC) of the neonatal enterocolitis. On one hand, the invention provides application of Activin A as a biomarker in preparation of an NEC diagnostic reagent, a prognosis reagent or a curative effect evaluation reagent; in another aspect, the invention provides the use of an Activin A neutralizing antibody and / or other potential inhibitors and / or blockers of Activin A in the preparation of a medicament for ameliorating and / or treating NEC. The invention can provide a new strategy for the clinical diagnosis and treatment of NEC, and has potential clinical application value for the clinical diagnosis and treatment of NEC.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to use of Activin A in preparing diagnostic reagents and therapeutic drugs for neonatal necrotizing enterocolitis. Background Art

[0002] Neonatal necrotizing enterocolitis (NEC) is a common and extremely serious gastrointestinal emergency in the neonatal period. It is mainly seen in premature infants and low birth weight newborns. It is a disease unique to newborns, characterized by intestinal damage ranging from mucosal damage to full-thickness necrosis, perforation and other degrees of damage. According to statistics, the incidence of NEC in infants with a gestational age of ≤33 weeks or a birth weight of ≤2500g is as high as 13%, and the mortality rate of NEC is about 20% to 30%; the mortality rate of children undergoing surgery is as high as 50%. At present, the clinical diagnosis and treatment of NEC still face many difficulties. In terms of diagnosis, it is currently mainly based on clinical manifestations and imaging examinations. Due to the non-specific clinical manifestations and the limitations of the medical level of medical staff, missed diagnosis or misdiagnosis is prone to occur; imaging tests can more accurately detect combined intestinal perforation and large-area intestinal necrosis, but it is difficult to make early diagnosis. There are currently no serological markers for the diagnosis of NEC. When intestinal lesions occur at the molecular, cellular, or local tissue levels, imaging cannot distinguish them, but some serological biomarkers will change significantly. By detecting biomarkers in blood or body fluids, early diagnosis and early treatment can be achieved. At present, the clinical treatment of NEC is still mainly based on conservative medical treatment, because children who undergo surgical treatment often have many complications after surgery, such as short bowel syndrome, cholestasis, significant growth impairment, and neurodevelopmental disorders. In addition, these infants require long-term care, and the treatment is complex and expensive. Therefore, surgical treatment is only required when intestinal perforation is combined or conservative medical treatment is ineffective or the disease progresses. It is currently recognized that early and timely treatment is still the best way to improve the survival rate of children with NEC. Therefore, the discovery of new markers for the early diagnosis of NEC and new immune therapies is of great significance to the clinical treatment of NEC.

[0003] Activin is a multifunctional cytokine that belongs to the transforming growth factor-β (TGF-β) superfamily. Other members of the family include inhibin, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), etc. Among them, Activin A is a dimeric protein composed of two βA subunits. Studies have shown that activin is involved in a variety of physiological and pathological processes in the body, including inflammation, metabolism, homeostasis, repair, cell protection, immune response and endocrine regulation. As the most abundant member of the activin family, increased expression of Activin A is associated with the progression of a variety of inflammatory and autoimmune diseases, including inflammatory bowel disease, meningitis, rheumatoid arthritis, etc. However, the role of Activin A in NEC remains unclear. The inventors of this application have recently found that during NEC, the expression level of Activin A in diseased intestinal tissue increases, and it is a potential diagnostic marker. Animal experiments and cell experiments have further revealed that Activin A promotes intestinal tissue damage by inducing apoptosis of small intestinal epithelial cells, and blocking Activin A can effectively treat NEC-mediated intestinal damage, suggesting that it is a new therapeutic target for NEC. Based on this, we propose that Activin A, as a new marker for NEC, has important clinical significance in the diagnosis and treatment of NEC. Summary of the invention

[0004] In view of the shortcomings of the prior art described above, the purpose of the present invention is to provide the use of Activin A in the preparation of NEC diagnostic reagents and therapeutic drugs, and to explore the role of Activin A in NEC and study the intervention effect of Activin A neutralizing antibodies on NEC, so as to provide a new target and new strategy with potential and good application value for the diagnosis, prognosis, efficacy evaluation and treatment of NEC in clinical practice.

[0005] To achieve the above-mentioned object and other related objects, the present invention provides, in a first aspect, the use of Activin A as a biomarker in the preparation of NEC diagnostic reagents, prognostic reagents or efficacy evaluation reagents.

[0006] In some embodiments, the reagent is used to measure the concentration of Activin A in a blood, body fluid sample and / or a tissue sample.

[0007] In some embodiments, the method for detecting Activin A concentration by the reagent includes but is not limited to enzyme linked immunosorbent assay (ELISA), chemiluminescence, immunoturbidimetry, immunofluorescence, colloidal gold method, mass spectrometry, microfluidic chip method, etc.

[0008] In some embodiments, the concentration of Activin A in the body fluid sample and / or tissue sample is positively correlated with the severity of NEC.

[0009] In some embodiments, the blood sample includes but is not limited to serum, plasma, whole blood, etc.

[0010] In some embodiments, the body fluid sample includes but is not limited to urine, cerebrospinal fluid, pleural effusion, ascites, etc.

[0011] In some embodiments, the tissue sample includes but is not limited to intestinal tissue, etc.

[0012] In some embodiments, the agent is used to diagnose or monitor the presence and / or course and / or severity and / or prognosis of NEC.

[0013] The second aspect of the present invention provides use of Activin A neutralizing antibodies and / or other potential inhibitors and / or blockers of Activin A in the preparation of a medicament for improving and / or treating NEC.

[0014] In some embodiments, the active ingredient of the drug includes at least one of the following components: Activin A neutralizing antibody, a substance other than Activin A neutralizing antibody for inhibiting and / or blocking the expression or activity of Activin A, a derivative obtained by chemical modification of the Activin A neutralizing antibody, and a derivative obtained by chemical modification of a substance other than Activin A neutralizing antibody for inhibiting and / or blocking the expression or activity of Activin A. The chemical modification will change the structure of the protein, thereby affecting the stability, biological activity and function of the protein, but will not affect the main function of the protein. At the same time, the purpose of the chemical modification is to further effectively control and improve the quality and safety of the drug, for example, oxidation modification, glycosylation, phosphorylation, acetylation, etc.

[0015] In some embodiments, the drug has at least one of the following effects (I) to (III):

[0016] (Ⅰ) Inhibit the expression and release of inflammatory factors mediated by NEC;

[0017] (Ⅱ) Reduce NEC-induced intestinal epithelial cell apoptosis;

[0018] (III) Reduce intestinal damage.

[0019] In some embodiments, the NEC-mediated inflammatory factors include but are not limited to interleukin-6 (IL-6), interleukin-1β (IL-1β), and the like.

[0020] In some embodiments, the drug reduces intestinal epithelial cell apoptosis by down-regulating the expression and / or activation level of pro-apoptotic factors and / or up-regulating the expression and / or activation level of anti-apoptotic factors, wherein the pro-apoptotic factors include but are not limited to BAX, Cleaved-caspase 9, etc., and the anti-apoptotic factors include but are not limited to BCL-2, etc.

[0021] In some embodiments, when the drug is used, the effective dosage of the active ingredient is not less than 50 μg / kg body weight.

[0022] In some embodiments, the drug may be a single-component substance or a compound preparation.

[0023] In some embodiments, the drug further comprises a pharmaceutically acceptable carrier and / or excipient.

[0024] In some embodiments, the form of the drug is not particularly limited and can be in various forms such as solid, liquid, gel, semi-fluid, aerosol, etc.

[0025] In some embodiments, the drug is mainly targeted at mammals, and the mammals are preferably rodents, even-toed ungulates, perissodactyls, lagomorphs, primates, etc., and the primates are preferably monkeys, apes or humans.

[0026] In some embodiments, the drug can be administered in a variety of forms, such as enteral administration or parenteral administration. It is generally recommended to administer the drug by known routes for each chemical drug, such as intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, etc. In animal experiments, intraperitoneal injection or tail vein injection is usually used, and intraperitoneal injection is simple to operate; while for the treatment of human NEC, intravenous injection or other methods are usually used.

[0027] As described above, the use of Activin A of the present invention in the preparation of NEC diagnostic reagents and therapeutic drugs has the following beneficial effects:

[0028] The present invention discovered for the first time that the expression level of Activin A increases during NEC and promotes the occurrence and development of NEC. Based on this, the present invention further studied and explored the therapeutic effect of Activin A neutralizing antibodies on NEC, and found that Activin A neutralizing antibodies can significantly inhibit the expression and release of NEC-mediated inflammatory factors, effectively reduce the apoptosis of intestinal epithelial cells, and significantly improve NEC intestinal damage. Therefore, the present invention proposes the use of Activin A as a biomarker and therapeutic target in NEC, provides a basis for the research and development and preparation of diagnostic reagents for NEC and original new drugs for the treatment of NEC, and provides a new strategy for the clinical internal medicine treatment of NEC, which is of great significance for the treatment of NEC. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The bar graph shows the expression level of Activin A in the intestinal tissue of the NEC model mice and the intestinal tissue of the control group in Example 1 of the present invention.

[0030] Figure 2 The immunohistochemical images show the expression levels of Activin A in the intestinal tissues of NEC model mice and the control group in Example 1 of the present invention.

[0031] Figure 3 Shown are weight curves of the NEC model mice in Example 2 of the present invention, the NEC model mice intraperitoneally injected with recombinant Activin A protein (recombinant Activin A, rActivin A), and the NEC model mice intraperitoneally injected with Activin A neutralizing antibody (anti-Activin A).

[0032] Figure 4 Shown is a graph of the survival rates of the NEC model mice in Example 2 of the present invention, the NEC model mice intraperitoneally injected with rActivin A, and the NEC model mice intraperitoneally injected with anti-Activin A.

[0033] Figure 5 Shown are intestinal appearance and HE staining images of the NEC model mice in Example 2 of the present invention, the NEC model mice injected with rActivin A intraperitoneally, the NEC model mice injected with anti-Activin A intraperitoneally, and the control group.

[0034] Figure 6 Shown are graphs showing intestinal injury scores of the NEC model mice in Example 2 of the present invention, the NEC model mice intraperitoneally injected with rActivin A, the NEC model mice intraperitoneally injected with anti-Activin A, and the control group.

[0035] Figure 7The bar graph shows the expression levels of IL-6 and IL-1β in the intestinal tissues of the NEC model mice in Example 2 of the present invention, the NEC model mice injected with rActivin A intraperitoneally, the NEC model mice injected with anti-Activin A intraperitoneally, and the control group.

[0036] Figure 8 Shown are TUNEL (TdT-mediated dUTP Nick-End Labeling) fluorescence images of intestinal tissue sections of NEC model mice in Example 3 of the present invention, NEC model mice injected with rActivin A intraperitoneally, NEC model mice injected with anti-Activin A intraperitoneally, and a control group.

[0037] Fig. 9 Shown are immunoblot analysis graphs of the expression levels of intestinal apoptosis proteins BAX, BCL-2, and Cleaved-caspase 9 in the NEC model mice in Example 3 of the present invention, the NEC model mice injected with rActivin A intraperitoneally, the NEC model mice injected with anti-Activin A intraperitoneally, and the control group. DETAILED DESCRIPTION

[0038] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0039] The present invention aims to treat NEC by studying the use of Activin A neutralizing antibodies in preparing NEC therapeutic drugs.

[0040] The present invention aims to provide a new strategy for the clinical diagnosis and treatment of NEC. The present invention finds through animal experiments that Activin A is a key harmful internal factor in the occurrence and development of NEC, and clarifies the important role of blocking Activin A in the treatment of NEC.

[0041] Based on this, the present invention proposes the use of Activin A as a biomarker and therapeutic target in NEC.

[0042] The following specific examples are given to illustrate the present invention in detail. It should also be understood that the following examples are only used to specifically illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention. The specific process parameters and the like in the following examples are also only examples within a suitable range, that is, those skilled in the art can make a selection within a suitable range according to the description herein, and are not limited to the specific values ​​​​exemplified below.

[0043] In the following examples, mouse rActivin A and mouse anti-Activin A were purchased from R&D Systems, USA.

[0044] Example 1

[0045] Expression of Activin A in NEC model mice

[0046] 1. Materials and Methods

[0047] 1.1. Construction of mouse NEC model

[0048] Newborn C57BL / 6 mice (male and female) aged 7 to 10 days were randomly divided into two groups. The mice in the NEC group were gavaged with 20 to 30 μl / g of hypertonic formula milk every 4 hours for a total of 5 times. The formula milk contained Similac 60 / 40 (Abbott Laboratories, Saint Laurent, Canada) and Esbilac (PetAg, Hampshire, Illinois). In addition, the mice were exposed to cold stimulation (4°C, 10 minutes) and hypoxia (100% N 2 , 90 seconds) and fed with lipopolysaccharide (LPS, SigmaAldrich, St.Louis) 5μg / g / d. The pups in the control group were fed with breast milk. Mice that were improperly fed or died within 24 hours after NEC induction were excluded. All surviving pups were euthanized 96 hours after NEC induction.

[0049] 1.2. Activin A detection in mouse intestinal tissue

[0050] The small intestinal tissue of mice was obtained, homogenized, centrifuged and the supernatant was collected. The level of Activin A was detected by ELISA according to the instructions of the kit and detected by an enzyme marker.

[0051] 1.3 Immunohistochemistry

[0052] Antigen retrieval was performed according to the instructions of the primary antibody. An appropriate amount of endogenous peroxidase blocker was added to the sample, incubated at room temperature for 10 minutes, and then washed with phosphate buffered saline (PBS). Goat anti-mouse Activin A antibody (AF338 SP) was dropped on the specimen and incubated at 37°C for 60 minutes. The tissue was stained using the Anti Goat HRP DAB Cell and Tissue Staining Kit (brown; R&D, CTS008) and counterstained with hematoxylin (blue).

[0053] 1.4 Statistical methods

[0054] GraphPad Prism 7 (GraphPad Software, La Jolla, CA) was used for all statistical analyses and data. Continuous data were expressed as mean ± standard deviation, and ordinal data were expressed using median and interquartile range (IQR). Unpaired t-test or analysis of variance was performed for comparisons between two or more groups. p < 0.05 was considered statistically significant.

[0055] 2. Results

[0056] 2.1, such as Figure 1 As shown, the expression level of Activin A in the intestinal tissue of NEC model mice was significantly higher than that in the intestinal tissue of the control group.

[0057] 2.2, such as Figure 2 As shown, the expression level of Activin A (brown-yellow) in the intestinal tissue sections of NEC model mice was significantly higher than that in the intestinal tissue sections of the control group.

[0058] 3. Conclusion

[0059] The expression level of Activin A in the intestinal tissue of mice was detected by ELISA and immunohistochemistry. The results showed that the expression of Activin A in the model mice was significantly increased, suggesting that Activin A may be related to the occurrence and development of NEC.

[0060] Example 2

[0061] This example found that Activin A is a key harmful internal factor in the development of NEC, and blocking Activin A with anti-Activin A can significantly reduce intestinal damage in NEC model mice. The specific implementation process is as follows:

[0062] 1. Materials and Methods

[0063] 1.1 Modeling and intervention

[0064] The modeling method is the same as 1.1 in Example 1. NEC+rActivin A group: During NEC modeling, rActivin A 83.33 μg / kg was intraperitoneally injected every day for 4 consecutive days; NEC+anti-Activin A group: During NEC modeling, anti-Activin A 83.33 μg / kg was intraperitoneally injected every day for 4 consecutive days. Control group: The mice were kept in the same cage as the mother mice, fed with mouse milk and fed freely. Mice that were improperly fed or died within 24 hours after NEC induction were excluded. All surviving pups were euthanized 96 hours after NEC induction.

[0065] 1.2. NEC intestinal tissue injury score

[0066] The mouse small intestine tissue was fixed by soaking in 4% paraformaldehyde, dehydrated with gradient alcohol concentrations from 70% to 100%, and then transparentized with 100% xylene. After transparency, the tissue was immersed in wax, embedded in paraffin, and sectioned. After H&E staining of the sections, pathological changes were observed under a microscope and intestinal injury scores were performed. Intestinal injury scores ≥ 2 points were judged as NEC.

[0067] 1.3. Detection of inflammatory factors in mouse intestinal tissue

[0068] The small intestinal tissue of mice was obtained, homogenized, centrifuged and the supernatant was collected. The inflammatory factors IL-6 and IL-1β were detected by ELISA according to the instructions of the kit and detected by an enzyme marker.

[0069] 1.4 Statistical methods

[0070] GraphPad Prism 7 (GraphPad Software, La Jolla, CA) was used for all statistical analyses and data. Continuous data are expressed as mean ± SD, and ordinal data are expressed as median and IQR. Unpaired t-test or analysis of variance was performed for comparisons between two or more groups. P < 0.05 was considered statistically significant.

[0071] 2. Results

[0072] The experiment in this example found that the body weight of NEC mice injected with rActivin A ( Figure 3 ) and survival rate ( Figure 4 ) was significantly reduced, and changes such as intestinal flatulence, bleeding, and necrosis were visible to the naked eye. HE staining showed that intestinal damage was aggravated ( Figure 5 However, in NEC mice injected with anti-Activin A, intestinal tissue damage was significantly reduced ( Figure 6 ).

[0073] Uncontrolled inflammation is another important feature of NEC and one of the causes of intestinal damage during NEC. Therefore, this experiment evaluated intestinal inflammation by detecting the expression of intestinal inflammatory factors. After NEC induction, proinflammatory cytokines such as IL-6 and IL-1β in intestinal tissues increased significantly, while anti-Activin A significantly inhibited the expression and release of IL-6, IL-1β and other inflammatory factors mediated by NEC ( Figure 7 ).

[0074] 3. Conclusion

[0075] Through the detection and analysis of the survival rate curve, weight change curve, HE staining and inflammatory factors, the results showed that Activin A plays a promoting role in the pathogenesis of NEC. Activin A is a key harmful internal factor in the occurrence and development of NEC. rActivin A can aggravate intestinal damage. Anti-Activin A can reduce intestinal damage to NEC and play a protective role on the intestine.

[0076] Example 3

[0077] This example found that rActivin A aggravated the apoptosis of intestinal epithelial cells, while blocking Activin A by anti-Activin A could effectively reduce the apoptosis of intestinal epithelial cells. The specific implementation process is as follows:

[0078] 1. Materials and Methods

[0079] 1.1 Modeling and intervention

[0080] The modeling method is the same as 1.1 in Example 1. NEC+rActivin A group: During NEC modeling, rActivin A 83.33 μg / kg was intraperitoneally injected every day for 4 consecutive days; NEC+anti-Activin A group: During NEC modeling, anti-Activin A 83.33 μg / kg was intraperitoneally injected every day for 4 consecutive days. Control group: The mice were kept in the same cage as the mother mice, fed with mouse milk and fed freely. Mice that were improperly fed or died within 24 hours after NEC induction were excluded. All surviving pups were euthanized 96 hours after NEC induction.

[0081] 1.2 TUNEL staining

[0082] Apoptosis in ileum sample sections was assessed by a commercially available TUNEL staining kit (Roche Diagnostics, Indianapolis, IN) according to the manufacturer's instructions.

[0083] 1.3 Western Blot Analysis

[0084] Mouse ileum tissue was added with RIPA buffer, ground with a homogenizer, and centrifuged at 12,000r / min for 10min. The supernatant was used as tissue lysate. After preparing SDS polyacrylamide gel electrophoresis to separate proteins, the proteins were transferred into polyvinylidene fluoride (PVDF) membranes. After sealing with 5% skim milk at room temperature for 2 hours, the membranes were washed three times with TBST, and BAX (1:1000), BCL-2 (1:1000), Cleaved-caspase 9 (1:1000), and β-actin (1:5000) were added. The membranes containing primary antibodies were then incubated at 4°C overnight, and then horseradish peroxidase-labeled goat anti-rabbit IgG antibody (1:10000) was added and incubated at room temperature for 1h. After washing the membranes, the PVDF membranes were developed using an ultrasensitive ECL chemiluminescence kit and quantitatively analyzed using ImageJ (National Institutes of Health, Bethesda, MD). The following antibodies were used in this example: anti-BAX (ab32503) and anti-BCL-2 (ab182858) from Abcam, and anti-Cleaved-caspase 9 (9509T) from Cell Signaling Technology.

[0085] 1.4 Statistical methods

[0086] GraphPad Prism 7 (GraphPad Software, La Jolla, CA) was used for all statistical analyses and data. Continuous data are expressed as mean ± SD, and ordinal data are expressed as median and IQR. Unpaired t-test or analysis of variance was performed for comparisons between two or more groups. P < 0.05 was considered statistically significant.

[0087] 2. Results

[0088] 2.1, such as Figure 8 As shown, the proportion of apoptotic cells in the NEC group was significantly greater than that in the control group. rActivin A treatment aggravated NEC-induced cell apoptosis, while anti-Activin A treatment almost completely eliminated NEC-induced cell apoptosis.

[0089] 2.2, such as Fig. 9As shown in Figure 2, changes in apoptosis-related factors reflect the severity of enterocyte apoptosis in NEC. Therefore, the expression of BAX, BCL-2, and Cleaved-caspase 9 in the intestine was also evaluated in ileal tissue samples collected after NEC. Compared with the control group, the expression of pro-apoptotic factors BAX and Cleaved-caspase 9 was upregulated in the NEC group, while the expression of anti-apoptotic factor BCL-2 was downregulated. The upregulation and downregulation of the two proteins were more significant after treatment with Activin A recombinant protein. Anti-ActivinA significantly reversed the upregulation and downregulation of the two proteins to levels similar to those in the control and NEC groups.

[0090] 3. Conclusion

[0091] TUNEL fluorescence and immunoblotting results showed that Activin A plays a key role in the course of NEC by affecting intestinal epithelial cell apoptosis, and Activin A recombinant protein can aggravate intestinal epithelial cell apoptosis. Activin A neutralizing antibody plays a protective role against NEC and can reduce intestinal epithelial cell apoptosis.

[0092] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. Use of Activin A as a biomarker in the preparation of diagnostic reagents, prognostic reagents or efficacy evaluation reagents for neonatal necrotizing enterocolitis.

2. The use according to claim 1, characterized in that: The reagent is used for determining the expression level of Activin A in a blood sample and / or a body fluid sample and / or a tissue sample.

3. The use according to claim 2, characterized in that: The method for detecting the expression level of Activin A by the reagent is selected from at least one of enzyme-linked immunosorbent assay, chemiluminescence, immunoturbidimetry, immunofluorescence, colloidal gold method, mass spectrometry, microfluidic chip method and the like.

4. The use according to claim 2, characterized in that: The expression level of Activin A in the body fluid sample and / or tissue sample is positively correlated with the severity of neonatal necrotizing enterocolitis.

5. The use according to claim 2, characterized in that: The blood sample is selected from at least one of serum, plasma and whole blood; and / or, the body fluid sample is selected from at least one of urine, cerebrospinal fluid, pleural effusion, and ascites; And / or, the tissue sample is selected from small intestine tissue.

6. Use of Activin A neutralizing antibodies and / or other potential inhibitors and / or blockers of Activin A in the preparation of drugs for improving and / or treating neonatal necrotizing enterocolitis.

7. The use according to claim 6, characterized in that: The active ingredient of the drug includes at least one of the following components: Activin A neutralizing antibody, a substance other than Activin A neutralizing antibody for inhibiting and / or blocking the expression or activity of Activin A, a derivative obtained by chemically modifying the Activin A neutralizing antibody, and a derivative obtained by chemically modifying a substance other than Activin A neutralizing antibody for inhibiting and / or blocking the expression or activity of Activin A.

8. The use according to claim 6, characterized in that: The drug has at least one of the following effects (I) to (III): (Ⅰ) Inhibit the expression and release of inflammatory factors mediated by neonatal necrotizing enterocolitis; (II) Reduce neonatal necrotizing enterocolitis-induced intestinal epithelial cell apoptosis; (III) Reduce intestinal damage.

9. The use according to claim 6, characterized in that: The medicine further comprises a pharmaceutically acceptable carrier and / or excipient.

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