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Application of CXC chemokine receptor 3 as cough drug target

A chemokine receptor and chemokine technology, which is applied in the screening of compounds, drug combinations, and determination/examination of microorganisms, etc., can solve the problems of unknown mechanism and no specific drugs yet

Pending Publication Date: 2021-11-23
THE FIRST AFFILIATED HOSPITAL OF GUANGZHOU MEDICAL UNIV (GUANGZHOU RESPIRATORY CENT)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the unknown mechanism, no specific drug for CHS has been found yet

Method used

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  • Application of CXC chemokine receptor 3 as cough drug target
  • Application of CXC chemokine receptor 3 as cough drug target
  • Application of CXC chemokine receptor 3 as cough drug target

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Effects of IFN-γ pretreatment on lymphocytes in peripheral blood and bronchoalveolar lavage fluid (Bronchoalveolar lavage fluid, BALF) of mice.

[0084] 1. Experimental animal grouping and drug administration method

[0085] Twenty mice were randomly divided into two groups, and the mice were pretreated with different solutions: normal saline control group and IFN-γ group (25 μg / ml, using mouse-derived IFN-γ).

[0086] Mice were anesthetized with chloral hydrate, and each mouse was given 50 μl of normal saline containing the above-mentioned modeling agent by intranasal drops; once a day, for five consecutive days, and then sacrificed by acute bloodletting after deep anesthesia with 1% pentobarbital sodium , so as to obtain peripheral blood and BALF specimens.

[0087] 2. Differential counting method of peripheral blood and BALF cells

[0088] The peripheral blood and BALF specimens were made into smears, and the cell smears were stained with hematoxylin-eosin, so as t...

Embodiment 2

[0092] The effect of IFN-γ intranasal drops on CD3 in mouse peripheral blood and lung tissue was analyzed by flow cytometry + IFN-γ + The influence of the proportion of T lymphocytes, the grouping of experimental animals and the way of administration are the same as before.

[0093] 1. Preparation of peripheral blood mononuclear cells (PBMC)

[0094]Take the left lung tissue of each mouse, add 0.6ml of digestive juice, fully grind and cut into pieces, lyse in a water bath at 37°C for 40 minutes, blow and beat until no lung tissue is visible to the naked eye, filter through a filter, and centrifuge (800g, 5 minutes, 4 ℃), placed in a 4 ℃ refrigerator for later use. Use the lymphocyte separation medium Ficoll to carry out gradient centrifugation on the peripheral blood and lung tissue suspension (800g, 25 minutes, 4°C, rising speed: 7, falling speed: 0), take the middle clear cell layer after gradient centrifugation, split red (1X Lysis red solution, 1ml, protected from light...

Embodiment 3

[0100] Effects of IFN-γ pretreatment on the expression of CXC chemokine IP-10 in the lungs of mice.

[0101] 1. Specimen Preparation and Immunofluorescence Staining Method

[0102] The middle lobe of the right lung of the mice was taken to make lung tissue frozen sections, which were stored in a -80°C refrigerator. Take out the slice and let it dry at room temperature for 30 minutes, then wash with PBS 3 times, 5 minutes each time, to remove OCT; circle the tissue to be stained with a histochemical oil pen, in order to minimize the scope of subsequent antibody incubation , so that the antibody can be effectively incubated; 0.3% PBST permeabilized for 15 minutes; PBS washed 3 times, 5 minutes each; 5% donkey serum blocked for 30 minutes; then incubated with IP-10 antibody, placed in a 4 ° C refrigerator overnight; remove the slice After rewarming at room temperature for 30 minutes, wash with PBS 3 times, 5 minutes each time; incubate the corresponding secondary antibody at roo...

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Abstract

The invention provides application of a CXC chemokine receptor 3 (CXCR3) as a drug target in screening a drug for treating cough. The earlier-stage research finds that IFN-gamma (Interferon-gamma) can directly cause cough. According to the invention, IFN-gamma nasal drop modelling on a mouse is carried out; it is found that the IFN-gamma can cause enrichment of peripheral blood and lymphocytes in BALF (Bronchoalveolar Lavage Fluid); it is found that the IFN-gamma can cause increase of a CXC chemotactic factor IP-10, and the IP-10 has the ability of chemotactic lymphocytes; the IFN-gamma is found to increase the proportion of CD3+IFN-gamma+T lymphocytes, so that the release of the IFN-gamma is increased; and, through intraperitoneal injection of a CXCR3 antagonist AMG487, it is found that the proportion of IFN-gamma intranasal mouse peripheral blood and BALF lymphocytes can be reduced by inhibiting a CXCR3 target, the proportion of the CD3+IFN-gamma+T lymphocytes can be reduced, and the content of the IFN-gamma in mouse lung tissue homogenate is obviously reduced. These results show that antagonism of the CXCR3 can reduce the proportion of the CD3+IFN-gamma+T lymphocytes, so that the IFN-gamma released by the lymphocytes is reduced, cough is inhibited, and the CXCR3 or the gene thereof can be used as a potential drug target to be applied to screening or preparation of drugs for treating cough.

Description

technical field [0001] The present invention relates to the field of protein function and application, in particular, relates to the use of CXC chemokine receptor 3 as a cough drug target. Background technique [0002] Chronic cough refers to those who have cough as the only symptom or the main symptom for more than 8 weeks and have no obvious abnormalities in chest X-ray examination. Common known causes of chronic cough in China include cough variant asthma, upper airway cough syndrome, eosinophilic bronchitis, allergic cough, and gastroesophageal reflux cough 1 . The receptors of the cough reflex are mainly located in the mucous membrane of the respiratory tract. The mechanism of chronic cough may be that the cough receptors are increased by chemical and physical stimuli, or the cough sensitivity is increased. Cough sensitivity refers to the difficulty of coughing when the body receives external stimuli (including chemical, mechanical, and heat). Cough hypersensitivity...

Claims

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Application Information

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IPC IPC(8): C12Q1/02G01N33/68G01N33/58A61K45/06A61P11/00
CPCG01N33/505G01N33/6863G01N33/6854G01N33/582A61K45/06A61P11/00G01N2333/7158G01N2500/10G01N2333/57
Inventor 邓政赖克方丁文斌
Owner THE FIRST AFFILIATED HOSPITAL OF GUANGZHOU MEDICAL UNIV (GUANGZHOU RESPIRATORY CENT)
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