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CN-122005804-A - Application of CCR5 inhibitor in promoting tissue repair of severe acute pancreatitis

CN122005804ACN 122005804 ACN122005804 ACN 122005804ACN-122005804-A

Abstract

The present application relates to the use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor for the prevention or treatment of Severe Acute Pancreatitis (SAP).

Inventors

  • WEN LI
  • ZHANG XIULI
  • LIU SONG
  • Peng Kaixin
  • LU WANYI

Assignees

  • 中国医学科学院北京协和医院

Dates

Publication Date
20260512
Application Date
20260211
Priority Date
20250805

Claims (10)

  1. 1. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor for the prevention or treatment of Severe Acute Pancreatitis (SAP) or sepsis.
  2. 2. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for the prevention or treatment of Severe Acute Pancreatitis (SAP) or sepsis.
  3. 3. The use of claim 2, wherein the prevention or treatment of Severe Acute Pancreatitis (SAP) comprises the prevention or treatment of tissue injury, repair and post-operative periods of Severe Acute Pancreatitis (SAP).
  4. 4. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for promoting repair of pancreatic tissue damage.
  5. 5. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for promoting regeneration after damage to pancreatic acinar cells.
  6. 6. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for the treatment or alleviation of pancreatic inflammation.
  7. 7. A pharmaceutical composition comprising any one or more of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor, preferably the pharmaceutical composition is for the prevention or treatment of Severe Acute Pancreatitis (SAP), or preferably the pharmaceutical composition is for promoting repair of pancreatic tissue damage, or preferably the pharmaceutical composition is for promoting regeneration of damaged pancreatic acinar cells, or preferably the pharmaceutical composition is for alleviating or treating pancreatic inflammation, or preferably the pharmaceutical composition is for the prevention or treatment of sepsis.
  8. 8. A method of preventing or treating Severe Acute Pancreatitis (SAP), comprising administering to a subject an effective dose of any one or more of an Axl agonist, mertk agonist, CCR5 inhibitor, or CD22 inhibitor.
  9. 9. Use of M2 type macrophages in the prevention or treatment of Severe Acute Pancreatitis (SAP) or sepsis.
  10. 10. Use of M2 type macrophages in the manufacture of a medicament or cell preparation for the prevention or treatment of Severe Acute Pancreatitis (SAP) or sepsis.

Description

Application of CCR5 inhibitor in promoting tissue repair of severe acute pancreatitis Technical Field The invention relates to the technical field of biology and medicines, in particular to application of a CCR5 inhibitor in prevention and treatment of severe acute pancreatitis. Background Severe Acute Pancreatitis (SAP) is associated with systemic inflammatory response syndrome and multiple organ failure with mortality rates up to 30% and there is currently no specific drug therapy. SAP patients often develop local complications during recovery, resulting in significantly prolonged recovery time and increased hospitalization period. The progression and prognosis of the disease are closely related to the extent of tissue damage and repair capacity. Previous studies have shown that SAP is characterized by rapid and massive cell death. Studies have also found that almost all known cell death pathway patterns are clearly linked to SAP severity, including classical apoptotic and necrotic pathways, as well as newly discovered pathways for necrotic apoptosis, pyro-death, and iron death. Most studies focused on key regulatory factors in pancreatic acinar or ductal cells, revealing a strict regulatory mechanism of death pathway activation in these cells, providing a potential target for early treatment of SAP. However, the narrow therapeutic window time of SAP requires the exploration of a drug to limit tissue damage and promote later tissue repair of this fatal disease. A large feature of pancreatitis is infiltration of large numbers of immune cells (e.g., neutrophils, macrophages, dendritic cells or T/B cells). During Acute Pancreatitis (AP), infiltration of inflammatory cells may act directly on pancreatic acinar cells to participate in the tissue injury and repair process by releasing inflammatory cytokines. Recent studies have shown that macrophage phenotype changes dynamically during the injury and repair phases of Acute Pancreatitis (AP). In the repair stage, the transformation of macrophages to the M2 polarization state can promote the regeneration of pancreatic tissues, and activated macrophages can also build a specific immune microenvironment for tissue repair after pancreatic injury, thereby assisting the regeneration of damaged acinar cells. Manohar et al further found that macrophages play a key role in mediating post-SAP pancreatitis severity and tissue repair. However, in the microenvironment, the regulatory factors or sensors expressed in these immune cells remain largely unknown. How they coordinate the signals of activation of the cell death pathway, particularly those related to apoptotic cells, to sense and address tissue damage and repair, still requires further investigation for practical use. Disclosure of Invention To achieve the above object, the present inventors have found that TAM receptor tyrosine kinase capable of being expressed in macrophages or neutrophils consists of three cognate receptor tyrosine kinases, TYRO3, AXL and MERTK. Among them, AXL and MERTK (but not the receptor sensing apoptosis signal such as Tyro 3) can be selectively expressed in pancreatic macrophages, and the expression level of AXL and MERTK in pancreatic macrophages is related to the degree of SAP tissue damage and repair. Whereas single cell transcriptome analysis showed enhanced ligand-receptor interactions between cxcr2+ neutrophils and cd163+ macrophages via the CCL4-CCR5 axis. Inhibition of CCR5 would likely promote pancreatic tissue repair following SAP treatment, a strategy that provides broader therapeutic prospects and potential drugs for SAP treatment. Specifically, the application provides the following technical scheme: 1. use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor for the prevention or treatment of Severe Acute Pancreatitis (SAP) or sepsis. 2. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for the prevention or treatment of Severe Acute Pancreatitis (SAP) or sepsis. 3. The use according to item 2, wherein the prevention or treatment of Severe Acute Pancreatitis (SAP) comprises prevention or treatment of tissue injury, repair and post-operative periods of Severe Acute Pancreatitis (SAP). 4. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for promoting repair of pancreatic tissue damage. 5. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for promoting regeneration after damage to pancreatic acinar cells. 6. Use of an Axl agonist, mertk agonist, CCR5 inhibitor or CD22 inhibitor in the manufacture of a medicament or formulation for the treatment or alleviation of pancreatic inflammation. 7. The use according to any one of claims 4 to 6, wherein the pancreatic tissue injury or pancreatic acinar cell injury or pancreatic inflammation is caused by Severe Acute