CN115089713B - Application of lysosomal inhibitor in preparation of medicine for preventing, treating and/or relieving acute lung injury/acute respiratory distress syndrome - Google Patents
Application of lysosomal inhibitor in preparation of medicine for preventing, treating and/or relieving acute lung injury/acute respiratory distress syndrome Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention provides application of a lysosomal inhibitor in preparing a medicament for preventing, treating and/or relieving acute lung injury/acute respiratory distress syndrome, wherein the lysosomal inhibitor can prevent, treat or relieve acute lung injury/acute respiratory distress syndrome by targeted inhibition of lysosomal activity, especially targeted inhibition of cathepsin L activity in lysosomes. The invention discovers the phenomenon of airway epithelial cell/macrophage lysosome activation in acute lung injury/acute respiratory distress syndrome for the first time. The lysosome inhibitor is found to inhibit the activity of lysosomes and can relieve lipopolysaccharide-induced airway inflammation in vitro; by constructing animal models, lysosomal inhibitors were found to significantly alleviate acute lung injury/acute respiratory distress syndrome in mice. The invention provides a new thought and a new target for clinically developing novel medicines for treating acute lung injury/acute respiratory distress syndrome in the future.
Description
Technical Field
The invention relates to the field of respiratory disease treatment, and provides a small molecular compound for targeted inhibition of lysosomal activity, which can effectively prevent, treat and/or relieve acute lung injury/acute respiratory distress syndrome.
Background
Acute lung injury (acute lung injury, ALI) and more severe acute respiratory distress syndrome (acute respiratory distress syndrome, ARDS) refers to alveolar epithelial and capillary endothelial cell injury caused by various direct and indirect injury factors, resulting in diffuse pulmonary interstitial and non-cardiac pulmonary oedema and severe hypoxia. ALI/ARDS has a number of etiologies, such as severe infections, shock, trauma and burns, among which severe infections are the most common and the incidence of pulmonary infections is the first of infectious diseases. Lipopolysaccharide (LPS) is a structural component of the outer membrane of gram-negative bacteria and can induce the body to produce severe pneumonia and septicemia. When LPS invades the human body, it first activates the cellular pattern recognition receptor Toll-like receptor 4 (TLR 4), and then signals through the adaptor MyD88 and TRIF, activating NF-. Kappa.B and IRF3 mediated gene transcription encoding molecules of the immune system. The number of cases of acute lung injury/acute respiratory distress syndrome in western countries is between 25-70/10 ten thousand per year. Even if surviving, patients with acute lung injury/acute respiratory distress syndrome have a severe impact on their quality of life over a long period of time, even for life due to severe impairment of lung function. Therefore, the acute lung injury/acute respiratory distress syndrome is critical and refractory respiratory diseases which seriously endanger the health and life of people, further explores the pathogenesis of the acute lung injury/acute respiratory distress syndrome and searches for a new intervention target, and has important significance for clinical prevention and treatment of the acute lung injury/acute respiratory distress syndrome.
Lysosomes (lysoames) are a membranous organelle that is present in cells of all protozoa and multicellular animals. All animal cells except mature erythrocytes contain lysosomes. Lysosomes are intracellular active metabolic sites containing more than 60 acid hydrolases, the major organelles that break down and recover various biological macromolecules. In addition, lysosomes are involved in a variety of life processes, including gene regulation, signal transduction, energy metabolism, immunity, etc., and are the centers of complex regulatory networks that regulate the stabilization of the cell and organism's internal environment. The related proteins currently studied to represent lysosomal function are mainly P62, LAMP1, LAMP2, cathepsin B, cathepsin S, etc. Current studies indicate that lysosomal dysfunction is involved in the development of a variety of diseases, including Lysosomal Storage Diseases (LSDs), neurodegenerative diseases, metabolic disorders, and cancers. LSDs and neurodegenerative diseases are often congenital genetic diseases in which the genes encoding lysosomal proteins or non-lysosomal proteins involved in lysosomal function are mutated, resulting in lysosomal mediated degradation and impaired recycling processes, resulting in accumulation of specific types of substrates, which in turn cause impaired cellular and tissue metabolism, leading to disease occurrence. Metabolically, prolonged lipid overload can disrupt the protective effects of lysosomes and autophagy on metabolic homeostasis, resulting in impaired lysosomal function. In terms of tumors, recent studies indicate that rapidly proliferating cancer cells rely on high synthesis rates of new proteins, membrane lipids, DNA and RNA, and lysosomal catabolism is of great importance in the feed of raw materials for tumor growth when cancer cells are unable to obtain ready external nutrients.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and providing application of a lysosomal inhibitor in preparing medicines for preventing, treating and/or relieving acute lung injury/acute respiratory distress syndrome.
The invention aims at realizing the following technical scheme:
use of a lysosomal inhibitor for the development of a medicament for the treatment or alleviation of acute lung injury/acute respiratory distress syndrome, wherein the lysosomal inhibitor effects the treatment or alleviation of acute lung injury/acute respiratory distress syndrome by targeted inhibition of lysosomal activity.
Further, the lysosomal inhibitor is one or more of cathepsin L inhibitor (SID 26681509), novel small molecule inhibitor 4-indole-2-arylamino pyrimidine (IAAP).
The beneficial effects of the invention are as follows: according to the invention, the inhibition of the lysosome activity in macrophages and animal models can effectively reduce the inflammatory response induced by lipopolysaccharide LPS, so that the lysosome inhibitor can effectively relieve acute lung injury/acute respiratory distress syndrome, and can provide a new direction for the treatment of future acute lung injury/acute respiratory distress syndrome or the research and development of medicines.
Drawings
FIG. 1 is a graph showing the expression of inflammatory factors involved in alleviating LPS-induced in vitro cell production following lysosomal inhibitor intervention;
FIG. 2 is a graph of BALF cell class counts in mice after lysosomal inhibitor application;
FIG. 3 is a graph showing H & E staining pathology of mouse lung tissue after lysosomal inhibitor application;
FIG. 4 is a graph showing the detection of related inflammatory factor expression in mouse BALF using ELISA kit after lysosomal inhibitor application;
FIG. 5 is a graph showing the survival rate of mice after application of lysosomal inhibitor SID 26681509;
FIG. 6 is a graph showing the survival rate of mice after application of the lysosomal inhibitor IAAP;
FIG. 7 is a schematic representation of novel small molecule IAAP inhibiting lysosomal function.
Detailed Description
The invention provides application of a lysosomal inhibitor in medicines for treating or relieving acute lung injury/acute respiratory distress syndrome in the future, wherein the lysosomal inhibitor realizes treatment or relief of acute lung injury/acute respiratory distress syndrome by targeted inhibition of lysosomal activity.
The invention is further described below with reference to the drawings and examples; wherein, 4-indole-2-arylamino pyrimidine (IAAP) is a novel small molecule inhibitor, and the structure is shown as follows:
example 1: in vitro experiments prove that the lysosome inhibitor can effectively relieve the expression of main inflammatory factors of airway epithelial cells and macrophages induced by LPS.
After culturing the macrophage cell line THP1, the macrophage cell line THP1 is used for interfering with LPS (100 ng/ml) and simultaneously interfering with LPS (100 ng/ml) and lysosomal inhibitor (SID 26681509/IAAP,100 mu M/20 mu M) for 24 hours, the condition of expressing inflammatory factors is shown in figures 1A and B, and it can be seen that the lysosomal inhibitor can alleviate the production of inflammatory factors induced by LPS in vitro.
After culturing the epithelial cell line HBE, and interfering with LPS (100 mug/ml) and simultaneously interfering with LPS (100 mug/ml) and lysosomal inhibitor (SID 26681509/IAAP,500nM/10 mug) in airway epithelial cell HBE solution for 24 hours, the conditions of expressing inflammatory factors are shown in FIGS. 1C and D, and it can be seen that lysosomal inhibitor can alleviate LPS-induced inflammatory factor production in vitro.
Example 2: classical acute lung injury/acute respiratory distress syndrome was constructed using wild-type mice, and the regulation of acute lung injury/acute respiratory distress syndrome in mice was observed by intraperitoneal administration of lysosomal inhibitors.
After 1 hour of intraperitoneal injection of wild-type mice with SID 26681509 (20 mg/kg animal body weight) or IAAP (20 mg/kg animal body weight) dissolved in dimethyl sulfoxide DMSO, airway instillation of LPS constructed a classical acute lung injury/acute respiratory distress syndrome mouse model, 24 hour post-treatment model. The right lung of the mouse was ligated and lavaged for the left lung, 0.4mL x 3 times, and the bronchoalveolar lavage fluid BALF was finally collected about 1 mL. 50. Mu.L of BALF cell suspension was added to 50. Mu.L of white blood cell count solution, and after mixing, 10. Mu.L was added to a blood cell count plate (modified Neubauer count plate) and the total white blood cells were counted under an optical microscope. The above BALF was centrifuged (4 ℃,6000rpm,10 min) and the resulting cell pellet was resuspended in balanced salt solution PBS and thoroughly mixed. The cell suspension was spun down (700 rpm,2 min) on a glass slide and the percentage of each cell counted after staining with Rayleigh-Giemsa. As shown in fig. 2, the differential cell count of the mouse alveolar lavage fluid showed that intraperitoneal administration of the lysosomal inhibitor significantly reduced the absolute value and percentage of neutrophils, and reduced acute lung injury/acute respiratory distress syndrome.
After lavage of the left lung, the left lung was inflated (internal fixation) by pouring 4% formaldehyde 0.4mL through the tracheal cannula, the trachea was ligated, the left lung was cut off by the ophthalmology and poured into 4% formaldehyde (external fixation) for 24-48 hours. Fixed lung tissue was embedded, sectioned, and H & E stained. Inflammation of the airway (complete airway with diameter between 300 μm and 100 μm and ratio of long diameter to short diameter not less than 0.6) in the section is observed under an optical microscope of a pathological imaging analysis system (Olympus), and photographing is carried out under the same condition. The score was 0-3 based on the degree of inflammatory cell infiltration around the airways, and the score criteria were as follows: 0 minutes, there is no inflammatory cell infiltration around the airway; 1 minute, a small amount of inflammatory cells infiltrate around the airway; 2 minutes, 1-5 layers of inflammatory cells infiltrate around most airways; 3 minutes, most airways are surrounded by >5 layers of inflammatory cell infiltrates. The inflammation scores were done independently by two observers using a double blind method, and the scores for each sample were averaged. As shown in fig. 3, H & E staining showed that lysosomal inhibitors significantly reduced inflammatory cell infiltration around the airways and blood vessels of mice lung tissue.
The supernatant was centrifuged (4 ℃ C., 6000rpm,10 min) at BALF of the mouse, and the expression of inflammatory factors related to lung tissues of the mouse was detected by ELISA kit. As shown in fig. 4, lysosomal inhibitors significantly down-regulate the expression of the mouse BALF inflammatory factors IL-6, CXCL1 and CXCL2, protecting airway inflammation in mice for acute lung injury/acute respiratory distress syndrome.
Detecting survival of mice, (1) wild-type mice were divided into two groups: LPS group, lps+sid 26681509 group, each mouse numbered and the two groups of mice were injected intraperitoneally with DMSO or SID 26681509,1 hours, respectively, followed by airway instillation of LPS, after which the mice survived and weight changes were recorded for 8 consecutive days, mice weight loss of 20% over initial weight were treated as death, (2) wild type mice were divided into two groups: LPS group, LPS+IAAP group, each mouse was numbered and weighed, two groups of mice were respectively intraperitoneally injected with DMSO and IAAP, LPS was instilled into the airway after 1 hour, and survival and weight change of the mice were recorded for 8 consecutive days, and weight loss of the mice more than 20% of the initial weight was treated as death. As shown in fig. 5 and 6, the lysosomal inhibitor can significantly increase the survival rate of mice, and the lysosomal inhibitor can alleviate acute lung injury/acute respiratory distress syndrome of mice.
FIG. 7 is data for IAAP inhibiting lysosomal activity, as shown in panel A, IAAP inhibits lysosomal degradation function; panel B shows that IAAP inhibits activation of cathepsin B and cathepsin L in lysosomes, demonstrating that lysosomal inhibitors achieve prevention, treatment or alleviation of acute lung injury/acute respiratory distress syndrome by targeted inhibition of lysosomal activity.
The above examples illustrate that lysosomal inhibitors are effective in alleviating airway inflammation in acute lung injury/acute respiratory distress syndrome and can be used in the treatment or alleviation of acute lung injury/acute respiratory distress syndrome. The above embodiments are intended to illustrate the present invention, not to limit it, and any modifications and changes made to the present invention within the spirit of the present invention and the scope of the appended claims fall within the scope of the present invention.
Claims (1)
1. Use of a lysosomal inhibitor, said lysosomal inhibitor being cathepsin L inhibitor SID 26681509, for the manufacture of a medicament for the prevention, treatment and/or alleviation of acute lung injury/acute respiratory distress syndrome caused by bacterial infection.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105820996A (en) * | 2016-04-18 | 2016-08-03 | 浙江大学 | Human primary airway epithelial cell culture method |
| CN111057073A (en) * | 2019-12-26 | 2020-04-24 | 浙江工业大学 | 4-indole-2-arylamino pyrimidine compound and application thereof in inflammation treatment |
| CN113563310A (en) * | 2021-06-25 | 2021-10-29 | 浙江工业大学 | 4- (1-methylindol-3-yl) pyrimidine derivative and application thereof |
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| US20110207726A1 (en) * | 2008-04-17 | 2011-08-25 | The Trustees Of The University Of Pennsylvania | Inhibitors of Human Cathepsin L, Cathepsin B, and Cathepsin S |
| CA2729780A1 (en) * | 2008-07-03 | 2010-01-07 | University Of Massachusetts | Methods and compositions for reducing inflammation and treating inflammatory disorders |
| WO2016205641A2 (en) * | 2015-06-17 | 2016-12-22 | Research Institute At Nationwide Children's Hospital | Respiratory syncytial virus having cleavage-resistant g protein and related materials and methods |
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