Application of mitochondrial uncoupling agent BAM15 in preparation of medicine for treating acute lung injury / acute respiratory distress syndrome

Abstract

The invention provides application of a mitochondrial uncoupling agent BAM15 in preparation of a medicine for treating acute lung injury / acute respiratory distress syndrome (ALI / ARDS), and the BAM15 can improve lung injury of an organism by maintaining dynamic balance of mitochondria, reducing neutrophil apoptosis delay, relieving oxidative stress and autophagy response and inhibiting a cGAS-STING signal channel. The mitochondrial uncoupling agent BAM15 is used for treating acute lung injury / acute respiratory distress syndrome (ALI / ARDS), has the advantages of lower cytotoxicity, no interference on plasma membrane potential, wider treatment window and higher safety, and also has the advantages of delayed administration effectiveness, high treatment efficiency and the like, so that the mitochondrial uncoupling agent BAM15 can be applied to treatment of acute lung injury / acute respiratory distress syndrome (ALI / ARDS). The compound is a promising candidate drug for treating acute lung injury / acute respiratory distress syndrome (ALI / ARDS), and is beneficial to relieving mitochondrial injury, maintaining lung cell functions and reducing inflammatory response related to ALI / ARDS.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and specifically relates to an application of a mitochondrial uncoupler BAM15 in the preparation of a drug for treating acute lung injury / acute respiratory distress syndrome (ALI / ARDS). Background Art

[0002] Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are severe respiratory diseases characterized by extensive lung inflammation, increased alveolar and capillary permeability, and severe hypoxemia, which may be caused by a variety of direct or indirect lung injuries, including trauma, sepsis, pneumonia, and inhalation of toxic substances. Although significant progress has been made in the study of the pathophysiology of ALI, ALI remains a major clinical challenge due to its high morbidity and associated high mortality. Current treatments for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) mainly include mechanical ventilation, glucocorticoids, and anti-inflammatory drugs (such as IL-6 inhibitors). However, existing methods have many defects, as follows: (1) The core pathology of ALI involves mitochondrial dysfunction (such as excessive fission and ROS burst) and excessive inflammation driven by the cGAS-STING pathway, but existing drugs lack synergistic regulation of the two; (2) Toxicity limitation: Traditional mitochondrial uncouplers (such as 2,4-dinitrophenol, DNP) destroy the plasma membrane potential, leading to systemic toxicity (such as liver damage and metabolic disorders), which limits their clinical application; (3) Narrow therapeutic window: Most drugs need to be administered early after injury or even at the beginning of the disease, and the effect of delayed intervention is significantly reduced.

[0003] BAM15 is a selective mitochondrial uncoupler with unique chemical properties that can effectively penetrate the mitochondrial membrane. By uncoupling oxidative phosphorylation without causing significant mitochondrial depolarization or cytotoxic effects, BAM15 can specifically regulate mitochondrial respiration and enhance metabolic flexibility while maintaining membrane integrity. It can also disrupt the proton gradient across the mitochondrial membrane, thereby reducing membrane potential and ROS generation without affecting ATP synthesis. This unique mechanism enables BAM15 to alleviate oxidative stress and prevent mitochondrial damage, making it a potential candidate drug for the treatment of mitochondrial-related dysfunction. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a mitochondrial uncoupler BAM15 for use in the preparation of a drug for the treatment of acute lung injury / acute respiratory distress syndrome (ALI / ARDS) in response to the above-mentioned deficiencies in the prior art. By restoring the balance between mitochondrial fusion and fission, the mitochondrial dynamic balance and the cGAS-STING pathway are targeted and regulated, which helps to alleviate mitochondrial damage, maintain lung cell function and reduce the inflammatory response associated with ALI / ARDS.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is: the use of mitochondrial uncoupler BAM15 in the preparation of a drug for the treatment of acute lung injury / acute respiratory distress syndrome. Mitochondrial uncoupler BAM15, also known as N5,N6-bis(2-fluorophenyl)-[1,2,5]oxadiazole[3,4-b]pyrazine-5,6-diamine), has a molecular formula of C 16 H 10 F 2 N 6 O, the structural formula is as follows: .

[0006] Preferably, the acute lung injury or acute respiratory distress syndrome is acute lung injury and acute respiratory distress syndrome caused by lipopolysaccharide, bacterial infection or trauma.

[0007] Preferably, the dosage of the mitochondrial uncoupler BAM15 is 5-10 mg / kg.

[0008] Preferably, the administration time is within 6 hours of onset and the effect is achieved.

[0009] In the present invention, BAM15 treats acute lung injury / acute respiratory distress syndrome by targeting and regulating mitochondrial dynamic balance and inhibiting the cGAS-STING pathway.

[0010] The present invention also provides a medicine for treating acute lung injury / acute respiratory distress syndrome, wherein the medicine comprises a mitochondrial uncoupler BAM15.

[0011] Preferably, the drug for treating acute lung injury / acute respiratory distress syndrome also contains a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient includes one or both of a carrier or an osmotic pressure regulator. The carrier can deliver the drug to the lungs in a targeted manner, and the osmotic pressure regulator can alleviate the balance of the intracellular environment to a limited extent and improve mitochondrial damage.

[0012] Preferably, the dosage form of the drug for treating acute lung injury / acute respiratory distress syndrome is any one of an inhaler, a nebulizer or a solution.

[0013] Compared with the prior art, the present invention has the following significant technical effects: 1. The present invention provides an application of a mitochondrial uncoupler BAM15 in the preparation of a drug for treating acute lung injury / acute respiratory distress syndrome (ALI / ARDS), which helps to alleviate mitochondrial damage, maintain lung cell function and reduce inflammatory responses associated with ALI / ARDS through the synergistic effect of mitochondrial dynamic balance and cGAS-STING pathway dual targets.

[0014] 2. Compared with other uncouplers (such as carbonyl cyanide-p-trifluoromethoxyphenylhydrazone and 2,4-dinitrophenol), BAM15 has lower cytotoxicity and fewer off-target effects on plasma membrane depolarization, does not interfere with the plasma membrane potential, has a wider therapeutic window, and is safer.

[0015] 3. The general survival rate of existing acute lung injury / acute respiratory distress syndrome (ALI / ARDS) treatment drugs is <30%. The drug of the present invention containing the mitochondrial uncoupler BAM15 can still increase the survival rate to 60% after intervention 6 hours after injury, and has the effectiveness of delayed administration.

[0016] 4. BAM15 can improve lung injury by maintaining mitochondrial dynamic balance, reducing delayed neutrophil apoptosis, alleviating oxidative stress and autophagy response, and inhibiting the cGAS-STING signaling pathway, making BAM15 a promising therapeutic candidate for the treatment of acute lung injury / acute respiratory distress syndrome (ALI / ARDS). It also solves the significant deficiencies of current treatments by simultaneously targeting mitochondrial dysfunction and excessive inflammation.

[0017] The present invention is further described in detail below with reference to the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The results of the treatment of LPS-induced acute lung injury by BAM15 at 0 hours in Example 1 of the present invention, A: 7-day Kaplan-Meier survival curve; B: Histopathological analysis results of hematoxylin and eosin staining, scale bar = 20 μm; C: Lung wet / dry ratio and protein level of mice; D: Arterial blood analysis, including oxygen partial pressure (PaO 2 ), partial pressure of carbon dioxide (PaCO 2 ), lactate (Lac) and lactate dehydrogenase (LDH); E: serum total antioxidant status (TAS), total oxidative status (TOS) and TOS / TAS ratio (oxidative stress index, OSI) levels.

[0019] Figure 2The results of delayed administration of BAM15 for 6 hours on LPS-induced acute lung injury in Example 1 of the present invention are shown in Figure 1. A: 7-day Kaplan-Meier survival curve; B: histopathological analysis results of hematoxylin and eosin staining, scale bar = 20 μm; C: lung wet / dry ratio and protein level of mice; D: arterial blood analysis, including oxygen partial pressure (PaO 2 ), lactate (Lac) and lactate dehydrogenase (LDH).

[0020] Figure 3 The effect of BAM15 treatment on neutrophils in acute lung injury in Example 1 of the present invention, A: flow cytometry analysis of the proportion of neutrophils, macrophages or monocytes in the immune cell population; B: changes in the proportion of neutrophils, macrophages or monocytes in BALF; C: the percentage of neutrophils undergoing apoptosis; D: flow cytometry analysis of neutrophils undergoing cell site apoptosis within 24 hours; E: co-immune image of lung tissue, Ly6G (red) and EpCAM (green) are markers of inflammatory infiltration, and the cell nuclei are stained blue with DAPI.

[0021] Figure 4 : The effect of BAM15 on mitochondrial function in Example 2 of the present invention, A: analysis results of mouse mitochondrial reactive oxygen species (ROS); B: electron microscopy image of mitochondrial ultrastructure (original magnification, ×5000, scale bar: 1 μm), red arrow indicates mitochondrial deformation; C: analysis of mouse plasma mtDNA levels 24 hours after LPS treatment; D: immunofluorescence image (original magnification: ×100, scale bar = 10 μm), Occludin: green; SQSTM1: red, cell nuclei were stained blue with DAPI; E: Western blot analysis of pro-apoptotic markers (p-62, PINK 1 and PCG-1α) and autophagy-related markers (LC3B-II), β-actin was used as an internal standard.

[0022] Figure 5 It is a related test of BAM15 regulating mitochondrial autophagy through the cGAS-STING signaling pathway in Example 3 of the present invention, A: Western blot analysis of the cGAS-STING pathway, including key proteins cGAS, TBK1 and STING and regulatory proteins USP18 and RNF5, with β-actin as an internal standard; B: quantitative PCR analysis of cGAS and STING mRNA levels; C: immunohistochemical staining to evaluate the expression of cGAS, STING and p-IRF3, scale bar: 100μm; D: expression levels of proinflammatory cytokines IFN-β, TNF-α and IL-6.

[0023] Figure 6This is the test of BAM15 improving mitochondrial damage through the cGAS-STING signaling pathway in Example 3 of the present invention. A: STING treated with BAM15 - / - Comparison of Kaplan-Meier survival curves between mice and wild type (WT) within 4 days; B: Histopathological analysis results of hematoxylin and eosin staining, scale bar = 20 μm; C: Lung injury score, lung wet / dry ratio and oxygen partial pressure (PaO 2 ) results; D: Immunofluorescence image (original magnification: ×80, scale bar = 10 μm), Occludin: green, cell nuclei were stained blue with DAPI; E: Electron microscopy image of mitochondrial ultrastructure (original magnification: ×5000; scale bar = 1 μm), red arrows indicate mitochondrial deformation; F: Quantitative analysis of mitochondrial reactive oxygen species (ROS).

[0024] Figure 7 In Example 3 of the present invention, BAM15 regulates mitochondrial autophagy through the cGAS-STING signaling pathway to reduce mtDNA release and significantly reduce inflammation test, A: LPS-treated wild type (WT) and STING - / - Immunofluorescence images of LC3 and LAMP2 in mice 24 hours after administration, LC3 is shown in green, LAMP2: red, and the cell nucleus is stained blue with DAPI. Scale bars: left, 20 μm; right, 10 μm; B: WT and STING after treatment - / - mtDNA levels in mice; C: WT and STING after treatment - / - Immunohistochemical analysis of cGAS and cGAMP levels in mice; D: WT and STING - / - : The percentage of neutrophils in the group; E: The percentage of apoptotic neutrophils at 24 hours; F: Co-immunosuppression images, Ly6G (red) and EpCAM (green) as markers of ALI inflammatory infiltration, cell nuclei stained blue with DAPI, scale bars: left, 20µm; right, 10µm; G: WT and STING after BAM15 treatment - / - Quantitative analysis of inflammatory markers (IL-1β, IL-6, and IFN-β) in mice. DETAILED DESCRIPTION

[0025] Example 1 This example shows the therapeutic effect of the mitochondrial uncoupler BAM15 on acute lung injury / acute respiratory distress syndrome (ALI / ARDS) mice.

[0026] 1. Lipopolysaccharide (LPS)-induced acute lung injury mouse model Male C57BL / 6 mice aged 8–10 weeks, with an average body weight of 20–25 g, were purchased from Charles River (Beijing, China). Mice were housed in cages for adaptive feeding for 1 week in a clean and quiet environment with a temperature of 24–26 °C, a humidity of 55%–60%, 12 h light / 12 h dark, and free access to food and water. Forty mice were randomly divided into 4 groups (10 mice in each group): (1) ALI was induced by intratracheal instillation of LPS (dissolved in 0.9% saline, dose of 10 mg / kg) in mice, followed by immediate intraperitoneal injection of BAM15 (5 mg / kg), designated as the LPS+BAM15 group; (2) ALI was induced by intratracheal instillation of LPS (dissolved in 0.9% saline, dose of 10 mg / kg) in mice, followed by immediate intraperitoneal injection of 40 mL / kg 3% dimethyl sulfoxide (DMSO) diluted in 0.9% saline, designated as the LPS+Vehicle group; (3) BAM15 (5 mg / kg) was intraperitoneally injected in healthy mice, designated as the Sham+BAM15 group; (4) 3% dimethyl sulfoxide (DMSO) was intraperitoneally injected in 40 mL / kg 0.9% saline, designated as the Sham+Vehicle group.

[0027] 2. Effects of BAM15 treatment on mice with LPS-induced acute lung injury After 24 h of LPS induction, mice were sacrificed and blood or bronchoalveolar lavage fluid (BALF) samples were collected and stored frozen at −80 °C or fixed in formalin for subsequent analysis.

[0028] Statistical analysis: Data are shown as mean ± SEM, and P values ​​were calculated by one-way ANOVA. P values ​​less than 0.05 were considered statistically significant ( * P < 0.05; ** P < 0.01; *** P < 0.001 or # P < 0.05; ## P < 0.01; ## P<0.001).

[0029] The survival rate of mice was evaluated every 24 hours, and the survival rate was determined 7 days after LPS administration. Figure 1As shown in A, it was found that BAM15 treatment significantly increased the 7-day survival rate of mice with acute lung injury from 20% (LPS+Vehicle group) to 60% (LPS+BAM15 group). At the end of the observation period, the surviving mice were euthanized by carbon dioxide asphyxiation, and the lung tissues were collected, fixed with 10% neutral buffered formalin, embedded in paraffin, and sliced ​​at a thickness of 5µm. Hematoxylin and eosin staining was performed to assess the degree of lung injury, and optical microscopy was performed. The results showed that the lung tissues of mice in the LPS+Vehicle group were severely damaged, including alveolar destruction, edema, and tissue congestion, while BAM15 treatment significantly alleviated these pathological changes, the alveolar structure was better preserved, the number of inflammatory cells was reduced, and the lung tissue pathology score of the BAM15 group was reduced by 40% ( Figure 1 B). Compared with the LPS+Vehicle group, the lung wet / dry ratio and protein content of mice in the LPS+BAM15 group were significantly reduced, with the lung wet / dry ratio (W / D) decreasing from 6.2 to 4.1, further confirming the protective effect of BAM15 on lung tissue ( Figure 1 C). Figure 1 As shown in D, BAM15 also improved respiratory function, and the arterial oxygen partial pressure (PaO 2 ) was significantly higher than that in the LPS+Vehicle group, increasing from 60 mmHg to 85 mmHg, indicating improved oxygenation and reduced respiratory distress; the lactate (Lac) level of mice in the LPS+BAM15 group was significantly lower than that in the LPS+Vehicle group, indicating improved metabolic function and enhanced tissue oxygenation; the lactate dehydrogenase (LDH) level of mice in the BAM15-treated group was significantly decreased, indicating that tissue integrity was significantly improved. In addition, the serum total antioxidant state (TAS) level of mice in the LPS+Vehicle group was decreased, indicating that the ability of lung tissue to prevent oxidative damage by clearing ROS was decreased; the serum total oxidative state (TOS) level and TOS / TAS ratio (i.e., oxidative stress index, OSI) of mice in the LPS+Vehicle group were increased, indicating that BAM15 inhibited the increase in TOS and OSI levels, while increasing the release of TAS ( Figure 1 E).

[0030] From the perspective of clinical treatment, the therapeutic effect of BAM15 given 6 hours after the onset of the disease was further studied. The results showed that even if BAM15 was given after the onset of the disease, it could effectively treat lung injury and improve survival outcomes. Intervention 6 hours after injury could still increase the survival rate to 60% ( Figure 2 ). Therefore, BAM15 treatment significantly attenuated lung injury, promoted oxygenation, and mitigated oxidative damage, providing evidence for its use as a therapeutic intervention for LPS-induced ALI.

[0031] Analysis of bronchoalveolar lavage fluid (BALF) by flow cytometry revealed that BAM15 treatment significantly altered the proportion of neutrophils, but not the number of macrophages or monocytes, in BALF ( Figure 3 A, B), and BAM15 can significantly alleviate the delayed apoptosis of neutrophils in the treatment of lung injury ( Figure 3 C, D), indicating that the anti-inflammatory effect of BAM15 mainly involves maintaining the survival of neutrophils in the acute phase rather than inducing their apoptosis. In addition, immunofluorescence analysis showed that the number of neutrophils in lung tissues decreased by 50% after BAM15 treatment, indicating a significant reduction in tissue infiltration ( Figure 3 E). Therefore, BAM15 inhibits inflammatory infiltration and reduces lung injury by delaying neutrophil apoptosis.

[0032] Example 2 This example is the effect of mitochondrial uncoupler BAM15 on mitochondrial function in mice with LPS-induced acute lung injury.

[0033] Using DCFH-DA as a fluorescent dye, the production of mitochondrial reactive oxygen species (ROS) was detected by fluorescence spectrophotometry and quantitatively analyzed in Sham+Vehicle / BAM15 and LPS+Vehicle / BAM15 mice. Figure 4 As shown in A, compared with the mice in the LPS+Vehicle group, the mitochondrial oxidative stress in the mice treated with BAM15 was significantly reduced, indicating that the uncoupler has a protective effect in maintaining mitochondrial function. Electron microscopy showed that there was extensive mitochondrial damage and endoplasmic reticulum dilation in the lung tissues of the mice in the LPS+Vehicle group, while the mitochondrial morphology of the mice in the LPS+BAM15 group was relatively intact ( Figure 4 B). Further analysis showed that LPS exposure led to a significant increase in mitochondrial DNA (mtDNA) content within 24 hours, while BAM15 treatment significantly reduced the release of mtDNA ( Figure 4 C) Immunofluorescence analysis of the effect of BAM15 on lung tissue integrity and autophagy in LPS-induced lung injury showed that the tight junction structural integrity of mice in the BAM15-treated group was significantly enhanced 24 hours after incubation, and the expression of occludin was increased ( Figure 4 D). In addition, we found that BAM15 inhibited excessive autophagy in lung tissue cells, thereby preventing excessive activation of the autophagy process after lung injury. Western blot analysis showed that autophagy-related proteins had undergone significant changes. The expression of pro-apoptotic markers such as p-62, PINK1, and PCG-1α was significantly upregulated in the lung injury group, and the p62 protein level increased by 2 times, while the expression of LC3B-II decreased accordingly, and the autophagy marker LC3B-II / Ⅰ ratio decreased by 30% ( Figure 4E), indicating that the protective effect of BAM15 is to alleviate mitochondrial oxidative stress by inhibiting autophagy and reducing mtDNA release. Therefore, BAM15 can effectively maintain the balance of mitochondrial dynamics in ALI, especially the balance between mitochondrial fusion and fission, which is essential for maintaining mitochondrial integrity and function. BAM15 promotes fusion while inhibiting excessive fission, thereby preventing mitochondrial fragmentation, reducing ROS generation by 60% and mtDNA release by 70%, all of which help to reduce cell damage and inflammation and maintain the integrity of tight junctions in the lung tissue of LPS-challenged mice.

[0034] Example 3 This example is the effect of the mitochondrial uncoupler BAM15 on the cGAS-STING signaling pathway in mice with LPS-induced acute lung injury.

[0035] 1. BAM15 regulates mitochondrial homeostasis through the cGAS-STING signaling pathway like Figure 5 As shown in A, compared with the mice in the LPS+Vehicle group, the expression of key proteins cGAS, TBK1, and STING in this pathway in the BAM15-treated group was significantly downregulated during the lung injury stage, and the expression of regulatory proteins USP18 and RNF5 was increased, indicating that the effect of BAM15 is achieved by regulating these upstream regulatory factors. Figure 5 As shown in B, compared with the mice in the LPS+Vehicle group, qPCR analysis showed that the expression of cGAS and STING in the LPS+BAM15 group was significantly reduced, with cGAS expression decreasing by 50% and STING phosphorylation level decreasing by 40%. Immunohistochemical staining showed that the expression of cGAS and STING increased significantly during lung injury, while their expression was significantly reduced after BAM15 treatment ( Figure 5 C). In addition, the administration of BAM15 significantly reduced the levels of proinflammatory cytokines such as IFN-β, TNF-α, and IL-6, with serum IL-6 and TNF-α decreasing by 50% and 40%, respectively, from 100 pg / mL and 130 pg / mL in the control group to 50 pg / mL and 80 pg / mL, respectively, indicating that it has anti-inflammatory properties ( Figure 5 D). Taken together, these findings suggest that BAM15 alleviates mitochondrial oxidative stress and reduces inflammation by inhibiting the cGAS-STING signaling pathway.

[0036] 2. BAM15 protects mitochondrial damage and maintains intercellular junction stability through the cGAS-STING signaling pathway Using STING knockout (STING - / - ) mouse model to study the effect of BAM15-regulated autophagy on lung injury. - / Mice were purchased from the Model Animal Research Center of Nanjing University (Nanjing, China) with a C57BL / 6 genetic background, and the knockout mice were genotyped by polymerase chain reaction (PCR) analysis of DNA extracted from tail biopsy samples. The results showed that compared with the wild-type (WT) group of mice, BAM15-treated STING - / - The survival rate of mice was significantly reduced ( Figure 6 A) Any improvement was observed in lung injury after BAM15 treatment as assessed by hematoxylin and eosin staining ( Figure 6 B) and STING treated with BAM15 - / - The lung injury score, lung wet-to-dry weight ratio, and oxygen tension of mice did not improve significantly ( Figure 6 C) Meanwhile, immunofluorescence analysis showed that BAM15 failed to restore lung tissue integrity in the absence of STING ( Figure 6 D) Electron microscopy shows BAM15-treated STING - / - Mitochondrial damage was not improved in mice ( Figure 6 E), mitochondrial stress is still elevated compared with WT mice ( Figure 6 F). These findings highlight the critical role of the STING pathway in mediating the protective effects of BAM15 against lung injury and mitochondrial damage.

[0037] 3. BAM15 regulates autophagy and inflammation through the cGAS-STING signaling pathway, thereby reducing mtDNA release and inhibiting cGAS-STING activation After LPS stimulation and BAM15 intervention, STING - / - The mice had elevated levels of autophagy and lysosomal activity, suggesting that STING deficiency impedes the ability of BAM15 to fully regulate autophagy and lysosomal dynamics. Figure 7 A). In addition, STING - / - The mtDNA levels in mice were still elevated and higher than those in the WT group, indicating that STING is essential for BAM15-mediated mtDNA clearance, as its loss resulted in a reduced efficiency of mtDNA reduction ( Figure 7 B). In addition, immunohistochemical analysis showed that STING was expressed in mice compared with normal mice. - / - In mice treated with BAM15, cGAS levels were higher, while levels of cGAMP (a second messenger produced after cGAS activation) remained relatively stable, suggesting that despite the reduction in cGAS levels, the absence of STING affects the feedback loop required for cGAMP production. Figure 7 C).

[0038] Compared with WT mice, STING - / -The proportion of neutrophils in the model mice increased significantly from 24.8% to 33.7% ( Figure 7 D), indicating that the ability of BAM15 to regulate delayed neutrophil apoptosis was reduced; in addition, the overall rate of neutrophil apoptosis was significantly decreased ( Figure 7 E), providing evidence that the STING pathway plays a key role in mediating the effects of BAM15 on neutrophil survival. Increased neutrophil infiltration in lung tissue ( Figure 7 F), indicating that loss of STING may impair the efficacy of BAM15 in preventing delayed neutrophil apoptosis, thus highlighting the key role of the STING signaling pathway in this process. - / - Levels of inflammatory markers IFN-β, IL-6, and IL-1β were elevated in mice ( Figure 7 G), indicating that loss of STING impairs the efficacy of BAM15 in controlling inflammation, leading to sustained expression of inflammatory cytokines. Collectively, these findings highlight the important role of the STING pathway in promoting BAM15-mediated autophagy and regulating inflammatory responses.

[0039] The present invention provides an application of a mitochondrial uncoupler BAM15 in the preparation of a therapeutic drug for acute lung injury / acute respiratory distress syndrome (ALI / ARDS). BAM15 can improve lung injury by maintaining mitochondrial dynamic balance, reducing delayed neutrophil apoptosis, alleviating oxidative stress and autophagy, and inhibiting the cGAS-STING signaling pathway. The mitochondrial uncoupler BAM15 of the present invention has the advantages of low cytotoxicity, no interference with plasma membrane potential, wider treatment window, and higher safety for the therapeutic drug for acute lung injury / acute respiratory distress syndrome (ALI / ARDS). It also has the effectiveness of delayed administration and is a promising candidate drug for the treatment of acute lung injury / acute respiratory distress syndrome (ALI / ARDS), which helps to alleviate mitochondrial damage, maintain lung cell function, and reduce inflammatory responses associated with ALI / ARDS.

[0040] The technical solution of the present invention is also applicable to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) caused by other factors such as bacterial infection or trauma, and can effectively alleviate severe pneumonia caused by infection, trauma, etc., reduce the patient's breathing difficulties, and improve the survival rate. The dosage of the mitochondrial uncoupler BAM15 is 5-10 mg / kg, and the administration time is generally within 6 hours of onset.

[0041] The above is only a preferred embodiment of the present invention and does not limit the present invention in any way. Any simple modification, change and equivalent change made to the above embodiment according to the technical essence of the invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. Application of mitochondrial uncoupler BAM15 in the preparation of therapeutic drugs for acute lung injury / acute respiratory distress syndrome.

2. The use according to claim 1, characterized in that: The acute lung injury or acute respiratory distress syndrome is acute lung injury and acute respiratory distress syndrome caused by lipopolysaccharide, bacterial infection or trauma.

3. The use according to claim 1, characterized in that: The dosage of the mitochondrial uncoupler BAM15 is 5-10 mg / kg.

4. The use according to claim 1, characterized in that: The medication time is within 6 hours of onset.

5. The use according to claim 1, characterized in that: BAM15 treats acute lung injury / acute respiratory distress syndrome by targeting the regulation of mitochondrial dynamic balance and inhibiting the cGAS-STING pathway.

6. A drug for treating acute lung injury / acute respiratory distress syndrome, characterized in that: The drug comprises the mitochondrial uncoupler BAM15.

7. The drug according to claim 6, characterized in that Also contains pharmaceutically acceptable excipients.

8. The drug according to claim 7, characterized in that The pharmaceutically acceptable excipients include one or both of a carrier and an osmotic pressure regulator.

9. The drug according to claim 6, characterized in that The dosage form of the drug is any one of an inhaler, a nebulizer or a solution.

Images