Search

CN-122005818-A - Application of miR-144 inhibitor in preparation of medicine for enhancing curative effect of glucocorticoid on ARDS and composition thereof

CN122005818ACN 122005818 ACN122005818 ACN 122005818ACN-122005818-A

Abstract

The invention belongs to the technical field of biological medicines, relates to application of miRNA targeting regulation in acute respiratory distress syndrome treatment, and in particular relates to application of a miR-144 inhibitor in preparation of a medicament for improving glucocorticoid treatment sensitivity of ARDS patients. According to the invention, through the research of an ARDS rat model induced by lipopolysaccharide, miR-144 participates in regulation and control of glucocorticoid receptor beta (GRbeta) and NF- κB signal paths in the ARDS inflammatory reaction process, and by using miR-144 inhibitor combined glucocorticoid treatment, the neutrophil number and IL-6, TNF-alpha and other inflammatory factors in alveolar lavage fluid can be obviously reduced, the wet-dry ratio and pathological damage score of lung tissues are reduced, and GRbeta and NF- κB expression is inhibited, so that the anti-inflammatory effect of the glucocorticoid is obviously enhanced. The invention provides a treatment strategy for improving glucocorticoid resistance of ARDS patients by taking miR-144 as a target spot for the first time, and provides a new drug target spot and a technical scheme for ARDS accurate treatment.

Inventors

  • HONG SHUKUN
  • WANG HONGYE
  • LIU YANLING
  • QIAO LUJUN

Assignees

  • 胜利油田中心医院

Dates

Publication Date
20260512
Application Date
20260323

Claims (10)

  1. Application of miR-144 inhibitor in preparation of medicine for enhancing curative effect of glucocorticoid on acute respiratory distress syndrome.
  2. 2. The use according to claim 1, wherein the glucocorticoid is one or more of methylprednisolone sodium succinate, dexamethasone or hydrocortisone.
  3. 3. The use of claim 1, wherein the miR-144 inhibitor comprises one or more of a nucleic acid inhibitor or a small molecule inhibitor that specifically inhibits miR-144 expression.
  4. 4. The use of claim 3, wherein the nucleic acid inhibitor is one or more of an antisense oligonucleotide to miR-144, a siRNA, shRNA, microRNA inhibitor, a nucleic acid aptamer.
  5. 5. The use according to claim 1, wherein the medicament is a composition of a miR-144 inhibitor and a glucocorticoid, and the medicament is one or more of an injection, a suspension, a lyophilized powder injection or a liposome preparation.
  6. 6. The use of claim 5, wherein the composition comprises a miR-144 inhibitor administered in an amount of 20-30 nmol/kg and a glucocorticoid administered in an amount of 1.5-2.5 mg/kg.
  7. 7. The use of claim 6, wherein the miR-144 inhibitor is administered at a dose of 25 nmol/kg and the glucocorticoid is methylprednisolone sodium succinate at a dose of 2 mg/kg.
  8. 8. The use according to any one of claims 1 to 7, wherein the medicament exerts a sensitization by down-regulating GR β and NF- κb expression, inhibiting inflammatory responses in the lung, alleviating pulmonary oedema.
  9. 9. A pharmaceutical composition for enhancing the efficacy of a glucocorticoid in treating acute respiratory distress syndrome, the pharmaceutical composition comprising an effective amount of a miR-144 inhibitor and a pharmaceutically-acceptable carrier.
  10. 10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition further comprises a glucocorticoid.

Description

Application of miR-144 inhibitor in preparation of medicine for enhancing curative effect of glucocorticoid on ARDS and composition thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of miRNA targeting regulation technology in acute respiratory distress syndrome treatment, in particular to application of a miR-144 inhibitor as a glucocorticoid sensitizer in preparation of an ARDS (acute respiratory syndrome) treatment drug. Background Acute Respiratory Distress Syndrome (ARDS) is a common type of acute respiratory failure in the clinical critical medical field, characterized by progressive hypoxia, diffuse alveolar damage and uncontrolled intrapulmonary inflammation. How to optimize the treatment regimen of ARDS is a medical challenge to be solved. The pathophysiological core of ARDS is non-cardiogenic pulmonary edema caused by alveolar epithelium and capillary endothelial permeability increase, the essence of the ARDS is that inflammatory cascade reaction in the lung is out of control, and neutrophil infiltration and massive release of pro-inflammatory factors (such as IL-6 and TNF-alpha) are key links for exacerbating lung injury. Glucocorticoid (GC) is used as a classical powerful anti-inflammatory drug, and can reduce lung injury by reducing vascular permeability, inhibiting inflammatory factor release and other mechanisms, but has obvious heterogeneity in clinical application effects, and part of patients show obvious GC resistance, so that the therapeutic value of the glucocorticoid is severely limited. The anti-inflammatory effect of GC is achieved primarily by binding to the glucocorticoid receptor alpha (grα), while the glucocorticoid receptor beta (grβ) competitively antagonizes grα function, a core molecule that leads to GC resistance. Studies have demonstrated significant increases in grβ expression in GC resistant patients, but the regulatory mechanisms of grβ expression in ARDS have not been elucidated. MicroRNA (miRNA), on the other hand, is a class of small non-coding RNAs that act as post-transcriptional regulatory molecules to regulate gene expression by targeting to the 3' untranslated region (UTR) of a target gene. Research shows that miR-144 can target and regulate expression of GR beta gene 3' UTR. Existing researches show that miR-144 can be involved in the regulation and control process of various diseases. For example, chinese patent CN104548134a discloses application of miR-144 and inhibitors thereof in myocardial oxidative stress injury diseases, and discloses that miR-144 can inhibit Nrf2 gene expression and promote myocardial oxidative stress. In bladder cancer cells, blocking the binding of miR-144 to GRbeta 3' UTR using the peptide nucleic acid molecule "Sweet-P" can inhibit cancer cell migration. However, the action and mechanism of miR-144 in ARDS GC resistance have not been reported, a targeted intervention strategy is lacked, and the application of miR-144 inhibitor in enhancing ARDS GC treatment effect is not described or suggested in the prior art. Therefore, an intervention means taking miR-144 as a target spot is developed, the GC treatment sensitivity of ARDS patients is improved, and the method has important clinical significance and application value. Disclosure of Invention The invention aims to provide an application of miR-144 inhibitor as glucocorticoid sensitizer in preparation of ARDS (acute respiratory syndrome) treatment drugs, and aims to define the regulation and control effect and molecular mechanism of miR-144 on glucocorticoid treatment sensitivity of ARDS patients, provide a GC sensitization strategy taking miR-144 as a target spot, and provide a new drug target spot and technical support for clinically improving ARDS GC resistance and optimizing treatment schemes. In one aspect, the invention provides an application of a miR-144 inhibitor in preparing a medicament for enhancing a glucocorticoid curative effect on treating acute respiratory distress syndrome. Preferably, the glucocorticoid is one or more of methylprednisolone sodium succinate, dexamethasone or hydrocortisone. Preferably, the miR-144 inhibitor comprises one or more of a nucleic acid inhibitor or a small molecule inhibitor that specifically inhibits miR-144 expression. Preferably, the nucleic acid inhibitor is one or more of antisense oligonucleotide, siRNA, shRNA, microRNA inhibitor, nucleic acid aptamer of miR-144. Preferably, the medicament is a composition of miR-144 inhibitor and glucocorticoid, and the medicament dosage form is one or more of injection, suspension, freeze-dried powder injection or liposome preparation. Preferably, the miR-144 inhibitor is administered in the composition at a dosage of 20-30 nmol/kg and the glucocorticoid is administered at a dosage of 1.5-2.5 mg/kg. Preferably, the miR-144 inhibitor is administered at a dose of 25 nmol/kg, and the glucocorticoid is methylprednisolone