Application of pyroptosis pathway inhibitor in protection of plateau brain impact lung injury

Abstract

The invention discloses an application of a pyroptosis pathway inhibitor in protection of plateau brain impact lung injury, the pyroptosis pathway inhibitor is applied to preparation of a medicine for preventing and / or treating lung injury caused by plateau brain impact injury, the pyroptosis pathway inhibitor acts on a Caspase-1 / GSDMD signal pathway, the inhibitor comprises a Caspase-1 inhibitor, an ASC inhibitor or a GSDMD-D inhibitor, and the inhibitor comprises a Caspase-1 inhibitor, an ASC inhibitor or a GSDMD-D inhibitor. The medicine is used for improving lung function impairment caused by plateau brain impact injury. The lung function indexes comprise at least one of the maximum inspiration flow rate, the maximum expiration flow rate, the respiratory rate and the accumulated volume, and the medicine is used for relieving lung tissue pathological injury caused by the plateau brain impact injury; the pathological injury comprises at least one of pulmonary alveolar wall thickening, inflammatory cell infiltration, pulmonary alveolar cavity internal hemorrhage and pulmonary alveolar rupture and fusion into pulmonary bulla. The invention provides a new target spot and strategy for clinical prevention and treatment of the secondary lung injury of the plateau craniocerebral impact injury.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and more particularly to the application of pyroptosis pathway inhibitors in the protection against lung injury caused by high-altitude brain impact. Background Technology

[0002] High-altitude regions are characterized by high altitude, low oxygen levels, low air pressure, and large temperature differences. Low oxygen levels are a major factor endangering human health, significantly impacting brain and lung function. Acute altitude sickness primarily targets the brain and lungs, causing pathological features such as cerebral edema, cognitive impairment, and pulmonary vascular leakage. Blast-induced traumatic brain injury (bTBI), a common type of traumatic brain injury (TBI), accounts for approximately 60% of cases and can lead to secondary pulmonary infections (incidence in 50%), resulting in acute respiratory distress syndrome (ARDS) or neurogenic pulmonary edema (NPE). High-altitude bTBI has become a serious medical challenge, but the mechanisms by which high-altitude hypoxia exacerbates TBI and distal lung injury remain unclear.

[0003] Recent studies have shown that pyroptosis, as a core mechanism of inflammatory programmed cell death, activates inflammatory factors such as IL-1β and IL-18 through a Caspase-1-dependent pathway (involving ASC and GSDM-D proteins), participating in the inflammatory cascade. Following a traumatic brain injury, brain-related injury pattern molecules (DAMPs) enter the bloodstream, activating the NLRP3 inflammasome in lung tissue via the circulatory system, which in turn activates the Caspase-1 pathway, leading to lung dysfunction and forming a vicious cycle of "brain injury-systemic inflammation-lung injury." High-altitude hypoxia can exacerbate this process, but the dynamic mechanisms underlying it remain unknown.

[0004] Therefore, this invention proposes the application of pyroptosis pathway inhibitors in the protection against lung injury caused by high-altitude brain impact. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies and propose the application of pyroptosis pathway inhibitors in the protection of lung injury from high-altitude brain impact.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: The application of pyroptosis pathway inhibitors in the protection of lung injury caused by high-altitude brain impact, and the application of said pyroptosis pathway inhibitors in the preparation of medicaments for the prevention and / or treatment of lung injury caused by high-altitude brain impact.

[0007] Preferably, the pyroptosis pathway inhibitor acts on the Caspase-1 / GSDMD signaling pathway, and the inhibitor includes a Caspase-1 inhibitor, an ASC inhibitor, or a GSDM-D inhibitor.

[0008] Preferably, the pyroptosis pathway inhibitor is a Caspase-1 inhibitor.

[0009] Preferably, the drug is used to improve lung function impairment caused by high-altitude brain trauma; the lung function indicators include at least one of the following: maximum inspiratory flow rate, maximum expiratory flow rate, respiratory rate, and cumulative volume.

[0010] Preferably, the drug is used to alleviate pathological damage to lung tissue caused by high-altitude brain trauma; the pathological damage includes at least one of the following: alveolar wall thickening, inflammatory cell infiltration, alveolar hemorrhage, and alveolar rupture and fusion into bullae.

[0011] Preferably, the drug is used to reduce the levels of inflammatory factors generated by activation of the pyroptosis pathway in lung tissue and / or serum; the inflammatory factors include at least one of interleukin-1β and interleukin-18.

[0012] Preferably, the drug is administered within 24 hours of the occurrence of the brain injury.

[0013] Preferably, the drug is administered via intravenous injection, intraperitoneal injection, or inhalation.

[0014] Preferably, the drug contains a pharmaceutically acceptable carrier.

[0015] A pharmaceutical composition for the prevention and / or treatment of lung injury caused by high-altitude brain trauma, characterized in that it comprises a therapeutically effective amount of a pyroptosis pathway inhibitor and a pharmaceutically acceptable carrier.

[0016] The beneficial effects of this invention are as follows: Inhibiting this pathway (such as by using Caspase-1 inhibitors) can significantly improve lung function, reduce pulmonary edema and pathological damage, providing a new approach for the prevention and treatment of secondary lung injury following high-altitude traumatic brain injury. Attached Figure Description

[0017] Figure 1 This is a schematic diagram illustrating changes in lung function according to the present invention; Figure 2 This is a schematic diagram of lung tissue pathological changes according to the present invention; Figure 3 This is a schematic diagram of pyroptosis-related protein expression in lung tissue according to the present invention; Figure 4 This is a schematic diagram showing the serum and lung tissue IL-1β and IL-18 content of the present invention. Detailed Implementation

[0018] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0019] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," "linking," and "setting" should be interpreted broadly. For example, they can refer to a fixed connection or setting, a detachable connection or setting, or an integral connection or setting. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0020] Example 1: I. Experimental Method 1. Model Building An acute high-altitude exposure model (hypobaric chamber) and a brain trauma model (BST-I type bio-shock tube) were prepared. 2. Testing time points and sampling methods Non-invasive lung function tests were performed on mice at 24, 48, and 72 hours after injury. After the tests, the mice were anesthetized, blood was collected from the mice, and serum was obtained by centrifugation. The mice were then sacrificed and lung tissue was immediately collected for appropriate processing.

[0021] 3. Lung function test Lung function in mice was assessed at 24, 48, and 72 hours post-injury using a whole-body volume plethysmography (WBP) system. The assessment included general indicators such as inspiratory time (Ti) and expiratory time (Te); conductance indicators such as peak inspiratory flow (PIF) and peak expiratory flow (PEF); airway obstruction indicators such as enhanced pause (Penh) and relaxation time (Tr); and ventilation indicators such as respiratory rate (F) and accumulated volume (Av).

[0022] 4. Lung histopathology Lung tissue was stained with hematoxylin and eosin (HE) and semi-quantitatively scored (0-3 points): 0 points = no damage; 1 point = mild (affected area <20%); 2 points = moderate (20%-50% affected); 3 points = severe (>50% affected). Assessment indicators included alveolar wall thickening, inflammatory cell infiltration, and alveolar hemorrhage.

[0023] 5. Wet-to-dry weight ratio of lung tissue The wet-to-dry weight ratio of the lungs of mice was measured at 24, 48, and 72 h post-injury to assess the degree of pulmonary edema.

[0024] 6. Expression of lung tissue-related proteins The expression of pyroptosis-related proteins in lung tissue was detected by Western blot at 24, 48, and 72 hours post-injury.

[0025] 7. Serum and lung tissue IL-1β and IL-18 levels The levels of IL-1β and IL-18 in serum and lung tissue were detected by ELISA at 24, 48, and 72 hours post-injury.

[0026] 8. Statistical Analysis Quantitative data are expressed as mean ± standard deviation (x ± s). Statistical analysis was performed using SPSS 23.0, and visualization was done using GraphPad 9.0. Two-way ANOVA was performed for comparisons between groups at each time point, and p < 0.05 was considered statistically significant.

[0027] II. Results 1. Changes in lung function Compared with group C, at 24 hours post-injury, group H showed a decrease in PIF, PEF, and Av, with mild bronchoconstriction. At 24 hours post-injury, group B showed a decrease in PIF, PEF, F, and Av compared to group C (P < 0.01), with prolonged Ti and Te (P < 0.01). At 48 hours post-injury, PIF, PEF, F, and Av increased (P < 0.01), Ti and Te also prolonged, with increased bronchoconstriction and further prolonged Tr. At 72 hours, PIF, PEF, F, and Av continued to increase (PIF: P < 0.05), with reduced bronchoconstriction. At 24 hours post-injury, group HB showed a significant decrease in PIF, PEF, F, and Av (P < 0.01), with prolonged Ti and Te, increased bronchoconstriction, and prolonged Tr. At 48 hours post-injury, the decrease was less severe than at 24 hours, with further prolonged inspiratory and expiratory times and increased bronchoconstriction.

[0028] 2. Pathological changes in lung tissue In Group H, 24 hours post-injury, alveolar cavities showed mild dilation, mild thickening of alveolar walls with occasional rupture, mild congestion, and a small amount of inflammatory cell infiltration; at 48 hours, some alveolar walls ruptured and fused into bullae, with a small amount of inflammatory cell infiltration. In Group B, 24 hours post-injury, alveolar walls thickened, alveolar cells detached, cavities narrowed, with more inflammatory cell infiltration and severe hemorrhage; at 48 hours, inflammatory cells increased, alveolar walls thickened, and erythrocyte exudation decreased. In Group HB, 24 hours post-injury, alveolar wall thickening was more significant than in Group B, with increased erythrocyte exudation and inflammatory cell infiltration in the alveolar cavities, numerous alveoli fused into bullae, and multiple obvious inflammatory foci were observed in the pulmonary interstitium and around the alveoli; at 48 hours, alveolar wall thickening and hemorrhage remained significant, some alveoli collapsed, bullae increased, and a small amount of inflammatory cell infiltration remained; at 72 hours, alveolar wall thickening and erythrocyte exudation decreased.

[0029] 3. Results of wet-to-dry weight ratio of lung tissue The wet-to-dry weight ratio of lung tissue in each experimental group (H group, B group, HB group) was significantly higher than that in group C at all time points, with the most significant change in group HB. At 24 h post-injury, group HB was significantly higher than group C (P<0.01) and group B (P<0.01).

[0030]

[0031] 4. Expression of pyroptosis-related proteins in lung tissue Following injury, the expression levels of Caspase-1, ASC, and GSDM-D in the lung tissues of groups H, B, and HB were all higher than those in group C. The ASC expression level in group H was significantly higher than that in group C (P<0.05), but significantly lower than that in group HB (P<0.01). Caspase-1 and GSDM-D were significantly higher than those in group C only at 24 and 48 h (P<0.05, P<0.001), and significantly lower than those in group HB (P<0.05). The ASC expression in group B was significantly higher than that in group C (P<0.001), and showed a significant difference from group HB at 24 h (P<0.05). Caspase-1 was significantly higher than that in group C at both 24 and 48 h (P<0.01, P<0.001), but significantly lower than that in group HB at 48 h (P<0.05). GSDM-D was higher than that in group C at 24 h post-injury (P<0.05), and significantly different from group HB at 48 h post-injury (P<0.05).

[0032] 5. Serum and lung tissue IL-1β and IL-18 levels Compared to group B, serum IL-1β levels in group HB were significantly different only at 24 hours (P < 0.01). Serum IL-18 levels in group HB were also significantly different from those in group C (P < 0.001), peaking at 48 hours post-injury; IL-1β levels in group HB were also significantly different from those in group B at 24 hours (P < 0.01). Lung tissue IL-1β levels in groups H and B were significantly higher than those in group C, with differences at both 24 and 48 hours (P < 0.001), and the differences between groups HB and B were statistically significant (P < 0.05, P < 0.01). Lung tissue IL-18 levels in groups H and B were significantly higher than those in group C, with significant differences at all time points (group H at 48 hours, P < 0.01).

[0033] This invention constructs a model of brain injury following acute high-altitude hypoxia exposure, elucidating how brain injury following acute high-altitude hypoxia exposure exacerbates lung injury by activating the Caspase-1 / GSDMD pyroptosis pathway. This provides new evidence for the precise prevention and treatment of secondary lung injury after high-altitude traumatic brain injury and for the protection of lung function based on organ-to-organ interactions.

[0034] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. Use of a pyroptosis pathway inhibitor for the protection against high altitude cerebral pulmonary injury, characterized in that, Use of the pyroptosis pathway inhibitor in the preparation of a drug for preventing and / or treating lung injury caused by high-altitude brain impact injury.

2. The use of a pyroptosis pathway inhibitor according to claim 1 for the protection against high altitude cerebral impact lung injury, characterized in that, The pyroptosis pathway inhibitor acts on the Caspase-1 / GSDMD signal pathway, and the inhibitor includes a Caspase-1 inhibitor, an ASC inhibitor or a GSDM-D inhibitor.

3. The use of a pyroptosis pathway inhibitor according to claim 2 for the protection against high altitude cerebral impact lung injury, characterized in that, The pyroptosis pathway inhibitor is a Caspase-1 inhibitor.

4. The pyroptosis pathway inhibitor for use in the protection against high altitude cerebral impact lung injury according to any one of claims 1 to 3, characterized in that, The drug is used for improving lung function damage caused by high-altitude brain impact injury; the lung function indicators include at least one of maximum inspiratory flow rate, maximum expiratory flow rate, respiratory rate and cumulative volume.

5. The pyroptosis pathway inhibitor for use in the protection against high altitude cerebral impact lung injury according to any one of claims 1 to 3, characterized in that, The drug is used for reducing lung tissue pathological damage caused by high-altitude brain impact injury; the pathological damage includes at least one of alveolar wall thickening, inflammatory cell infiltration, intra-alveolar cavity hemorrhage and alveolar rupture and fusion into pulmonary bulla.

6. The pyroptosis pathway inhibitor for use in the protection against high altitude cerebral impact lung injury according to any one of claims 1 to 3, characterized in that, The drug is used for reducing the lung tissue wet / dry weight ratio caused by high-altitude brain impact injury, so as to reduce the degree of pulmonary edema.

7. The pyroptosis pathway inhibitor for use in the protection against high altitude cerebral impact lung injury according to any one of claims 1 to 3, characterized in that, The drug is used for reducing the level of inflammatory factors in lung tissue and / or serum caused by activation of the pyroptosis pathway; the inflammatory factors include at least one of interleukin-1β and interleukin-18.

8. The pyroptosis pathway inhibitor for use in the protection against high altitude cerebral impact lung injury according to any one of claims 1 to 3, characterized in that, The drug is administered within 24 hours after the brain impact injury occurs.

9. The pyroptosis pathway inhibitor for use in the protection against high altitude cerebral impact lung injury according to any one of claims 1 to 3, characterized in that, The drug is administered by intravenous injection, intraperitoneal injection or inhalation.

10. A pharmaceutical composition for preventing and / or treating lung injury caused by high-altitude brain impact injury, characterized by, The drug comprises a therapeutically effective amount of the pyroptosis pathway inhibitor of claim 2 or 3 and a pharmaceutically acceptable carrier.

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