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Curcumin-mediated enhancement of lung barrier function in rats with high-altitude-associated acute lung injury via inhibition of inflammatory response

Respiratory Research volume 25, Article number: 354 (2024) Cite this article

Abstract

Background

Exposure to a hypobaric hypoxic environment at high altitudes can lead to lung injury. In this study, we aimed to determine whether curcumin (Cur) could improve lung barrier function and protect against high-altitude-associated acute lung injury.

Methods

Two hundred healthy rats were randomly divided into standard control, high-altitude control (HC), salidroside (40 mg/kg, positive control), and Cur (200 mg/kg) groups. Each group was further divided into five subgroups. Basic vital signs, lung injury histopathology, routine blood parameters, plasma lactate level, and arterial blood gas indicators were evaluated. Protein and inflammatory factor (tumor necrosis factor α (TNF-α), interleukin [IL]-1β, IL-6, and IL-10) concentrations in bronchoalveolar lavage fluid (BALF) were determined using the bicinchoninic acid method and enzyme-linked immunosorbent assay, respectively. Inflammation-related and lung barrier function-related proteins were analyzed using immunoblotting.

Results

Cur improved blood routine indicators such as hemoglobin and hematocrit and reduced the BALF protein content and TNF-α, IL-1β, and IL-6 levels compared with those in the HC group. It increased IL-10 levels and reduced pulmonary capillary congestion, alveolar hemorrhage, and the degree of pulmonary interstitial edema. It increased oxygen partial pressure, oxygen saturation, carbonic acid hydrogen radical, and base excess levels, and the expression of zonula occludens 1, occludin, claudin-4, and reduced carbon dioxide partial pressure, plasma lactic acid, and the expression of phospho-nuclear factor kappa.

Conclusions

Exposure to a high-altitude environment for 48 h resulted in severe lung injury in rats. Cur improved lung barrier function and alleviated acute lung injury in rats at high altitudes.

Highlights

  • • Curcumin (Cur) improves lung barrier function under high-altitude stress in rats

  • • Cur mitigated acute lung injury under high-altitude stress

  • • Cur improved hemoglobin and hematocrit levels under high-altitude stress

  • • Cur reduced bronchoalveolar lavage fluid protein content under high-altitude stress

  • • Cur reduced inflammatory factor TNF-α, IL-α, IL-6 levels under high-altitude stress

AbstractSection Graphical Abstract

Background

As the altitude increases and atmospheric pressure decreases, the atmospheric oxygen partial pressure (PaO2) gradually decreases [1]. Therefore, individuals are prone to acute altitude reactions when they enter a hypobaric and hypoxic environment at an altitude of over 2500 m [2]. In severe cases, high-altitude lung edema and cerebral edema may occur [3, 4]. In recent years, an increasing number of people are traveling to high-altitude areas [5], where the probability of high-altitude lung injury gradually increases. A characteristic of acute lung injury is the acute inflammatory response leading to the destruction of vascular endothelial cells and alveolar epithelial cells [6]. The mechanism of acute high-altitude lung injury is not fully understood. Nevertheless, it is considered to involve factors such as inflammatory responses [7], oxidative stress [8], and high permeability of the pulmonary capillary endothelium [9]. Arterial blood gas (ABG) analysis serves as an intuitive and convenient detection method that can show changes regardless of the type of lung injury [10,11,12]. Increasing altitude can reduce arterial oxygen partial pressure in the human body [13]. ABG can be used as an observational indicator in the prevention and treatment of acute lung injury at high altitudes. Treatments that can improve ABG and maintain lung barrier function may improve high-altitude acute lung injury.

Curcumin (Cur) is a natural lipophilic polyphenol that is safe, well-tolerated, and non-toxic [14]. It exerts various biological activities such as antioxidant-, stress-alleviating-, anti-inflammatory-, and cell apoptosis-inhibiting effects [15]. It can play a protective role in lung injury through various mechanisms, including inhibition of pulmonary interstitial edema, regulation of ABG, and inhibition of inflammatory response [10, 16, 17]. Pregavage of Cur can improve decreased PaO2 and partial pressure of carbon dioxide (PaCO2) in rats exposed to high-altitude-simulated cabins for 6 h and maintain the integrity of the rat lung barrier [18]. Currently, there is a lack of systematic research on the effects of Cur on ABG indicators and lung barrier function in high-altitude environments. Therefore, the primary purpose of this study was to explore the changes in ABG and lung barrier function in rats with high-altitude-associated acute lung injury and determine the protective effect of Cur against acute high-altitude lung injury.

Methods

Animals

Two hundred healthy male Sprague–Dawley (SD) rats weighing 220–260 g were used in the experiment; they were procured from the Experimental Animal Center of Xinjiang Medical University (Urumqi, China; the production license number was SCXK (new) 2016-0001). The rats were adaptively raised in a specific pathogen-free animal laboratory at the Experimental Animal Department of Xinjiang Military Region General Hospital (license number: SYXK (military) 2017-0050). The environmental conditions were as follows: 12/12-h light/dark cycle, 23 °C (± 1 °C), and 55% (± 5%) humidity. The rats were fed under the guidance of professional veterinary laboratory personnel, and sufficient water and feed were provided [SYXK (New) 2016-0003]. All animal procedures were conducted strictly according to the ARRIVE guidelines and the guidelines for the care and use of experimental animals issued by the National Institutes of Health. The procedures were approved by the Animal Ethics Committee of the General Hospital of Xinjiang Military Region, following the 3R principle (Approval number: DWLL20190415).

Experimental methods

Two hundred standard rats were divided into four groups according to the random number table method (50 rats per group): a standard control (NC) group, a high-altitude control (HC) group, a group treated with 40 mg/kg salidroside (Sal) (Sal-40 group) [19], and a group treated with 200 mg/kg Cur (Cur-200 group) [20]. Curcumin and salidroside were diluted with 0.9% physiological saline. Each group was divided into five subgroups according to the analysis time point: 0, 24, 48, 72, and 120 h. The NC group rats were placed in a normal temperature environment [23 °C (± 1 °C), 55% (± 5%) relative humidity]. In contrast, rats were placed in a high-altitude environment in The Simulated Climate Cabin for the Special Environment of Northwest China in the other group (Urumqi, China). The experimental cabin was maintained under the following conditions: 12/12-h light/dark cycle, 15 °C for 12 h during the day, 5 °C for 12 h at night, and 55% (± 5%) humidity. The simulated altitude of the experimental cabin was set to 6000 m with an altitude surge of 10 m/s. The rats in the NC groups were exposed to the plain environment, the rats in the HC, Sal-40, and Cur-200 groups were exposed to the experimental cabin. When the equipment reached the set al.titude, a humidity of 55% (± 5%) was maintained. All rats in the drug intervention group were administered the corresponding drugs and doses via gavage for 3 days before placement in the cabin. The Sal-40 and Cur-200 group rats were gavaged with the corresponding drugs and doses once every 24 h.

The experimental personnel entered the experimental cabin through the transition cabin and quickly anesthetized the rats when the exposure time was reached. The rats from each group were intraperitoneally injected with 2% pentobarbital sodium (2 mL/0.1 kg) to maintain adequate anesthesia to eliminate corneal reflexes and pain reflexes. The anesthetized rats were fixed in the supine position, the right femoral artery was separated, and a 24 G intravenous indwelling needle was inserted. The electrodes were connected to the limbs of the rats; the heart rate (HR) was monitored using an electrocardiogram (ECG) sensor (connected to the electrodes) and a multichannel physiological recorder (Taimeng BIA 20 F, Chengdu, China). The respiratory rate (RR) of rats in the high-altitude environment inside the cabin was monitored by experimental operators by directly observing and recording the fluctuations in the abdomen. The abdominal wall was cut in layers along the center of the abdomen, fully exposing the aorta and extracting arterial blood for blood gas analysis. The right main bronchus was ligated after cutting the chest wall in layers along the middle of the chest, fully exposing the chest. Subsequently, a catheter was inserted into the left main bronchus, and 4 mL of 0.9% normal saline was injected into the left lung through the air tube intubation; the lung was rinsed two to three times repeatedly. Alveolar lavage fluid (3 mL) was collected for the measurement of proteins and inflammatory factors. The right lung was separated, and the middle lobe was fixed with 4% paraformaldehyde for pathological hematoxylin and eosin (H&E) staining.

Arterial blood gas analysis and plasma lactate measurement

An i-STATm gas analyzer (Abbott Laboratories, Princeton, NJ, USA) was used to determine the ABG level immediately after collection.

Routine blood test and plasma lactate

A fully automated blood cell analyzer (BC-2800 Vet; Shenzhen Daily Biomedical Electronics Co. Ltd., Shenzhen, China) was used to examine the routine blood parameters of the arterial blood.

The remaining arterial blood was injected into a heparin sodium tube, centrifuged at 4000 × g for 15 min at 4℃, and the supernatant was collected. The plasma lactate level was measured using a fully automated biochemical analyzer (XA-46000996; Shenzhen Daily Biomedical Electronics Co., Ltd., Shenzhen, China).

Determining protein and inflammatory factor concentrations in bronchoalveolar lavage fluid.

Bronchoalveolar lavage fluid (BALF) samples were centrifuged at 3000 × g for 15 min at 4℃, and the supernatant was collected. A total protein detection kit (Shanghai Aibixin Biological Co. Ltd., Shanghai, China) was used to determine the total protein level in the BALF using the bicinchoninic acid method. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 levels in the BALF were determined using an enzyme-linked immunosorbent assay (ELISA) kit (Shanghai FANKEL Industrial Co. Ltd., Shanghai, China).

Histopathology

The middle lobe of the right lung was fixed in 4% paraformaldehyde for 1 week, dehydrated, embedded, sectioned, and dehydrated with different concentrations of alcohol at 75%, 85%, 95%, and 100%. Then, H&E staining was performed. After staining, the pathological changes in the lungs were observed under an optical microscope, and the degree of lung injury was evaluated using the lung injury scoring method. The films were read under double-blind conditions. The degree of lung tissue damage determined using optical microscopy was based on the following indicators: (1) whether there was edema in the alveoli and interstitium; (2) the degree of neutrophil infiltration; and (3) the degree of bleeding. The severity of lung injury was scored as follows: no injury, 0; 25% of lung field injuries, 1; 50% of lung field injuries, 2; 75% of lung field injuries, 3; changes in the entire lung field, 4 [21].

Western blotting

Lung tissues (0.1 g) were cut with a pair of scissors, ground in RIPA lysis buffer (high) (0.9 mL) using an electric homogenizer, and placed on ice for 2 h. The homogenates were centrifuged at 12,000 × g for 15 min at 4 °C. The homogenate protein concentrations were measured using the Bicinchoninic acid Protein Detection Kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Thereafter, RIPA lysis buffer was used to balance the protein concentration in lung tissue homogenates to the same concentration. All samples were mixed with 4× loading buffer (Solebao Technology Co., Ltd, Beijing, China) and boiled for 10 min. Subsequently, the supernatant was collected and stored at − 80 °C. The frozen sample was centrifuged at 12,000 × g for 3 min at 4℃ and electrophoresed at 50 V for 0.5 h and then at 100 V for 1.5 h; the proteins were transferred onto a polyvinylidene fluoride (PVDF) membrane for 20–40 min (according to the molecular weight of the targeted protein). The PVDF membrane was sealed with 5% skim milk at 25 °C ± 1 °C for 2 h and then incubated with antibodies against phospho-nuclear factor kappa B (P-NF-κB), zonula occludens (ZO-1), claudin-4, and occludin overnight at 4 °C. The membrane was washed five times with Tris-buffered saline with Tween (TBST; 5 min/wash step) and incubated with the corresponding secondary antibodies for 2 h at 25 °C ± 1 °C. Thereafter, the membrane was washed thrice with TBST. Finally, the PVDF membrane was visualized via chemiluminescence (ChemDoc-IT®510 Imager; Ultra-Violet Products Ltd., Cambridge, UK). After scanning, the band intensities were analyzed using Visionworks LS (version 8.1.2; Ultra‑Violet Products Ltd.).

Statistical analysis

Statistical analysis of the data was performed using SPSS version 23.0 (IBM Corp., Armonk, NY, USA). The results of the parameter tests are expressed as the mean ± standard deviation. The data of multiple groups were compared using a one-way analysis of variance followed by post-hoc LSD difference analysis. Results that does not follow a normal distribution shall are expressed as the median (interquartile range), and non parametric Kruskal-Wallis test is used. A statistically significant difference was considered at P < 0.05.

Results

Basic vital sign analysis

Respiratory rate

As shown in Fig. 1A, the RR of rats in the NC group and 0-h group remained relatively stable at approximately 85 beats/min, with no significant changes in the respiratory state. In the other three groups, the RR initially showed an increasing trend and gradually decreased with prolonged high-altitude exposure. The degree of chest undulation in rats changed from shallow to deep, and the exhalation phase gradually extended. The RR of the HC group rats peaked at 24 h and was higher than that at 0 h (P < 0.05). The RR of the HC group was higher than that of the NC group at 24, 48, 72, and 120 h (P < 0.05). Similarly, the RR of the Sal-40 and Cur-200 groups was higher than that of the HC group at 72 and 120 h, but only the difference between the Cur-200 and HC groups was significant (P < 0.05). Moreover, the RR of the Cur-200 group was higher than that of the Sal-40 group at 120 h (P < 0.05).

Heart rate

As shown in Fig. 1B, the HR of the HC group gradually increased with treatment prolongation; the HR at 48 h increased compared with that at 24 h (P < 0.05) and then gradually plateaued. The HR of the HC group was higher than that of the NC group at 48, 72, and 120 h (P < 0.05), whereas the HR of the Sal-40 and Cur-200 groups was lower than that of the HC group (P < 0.05). Moreover, the HR of the Cur-200 group was lower than that of the Sal-40 group at 72 and 120 h (P < 0.05).

Fig. 1
figure 1

Changes in RR and HR in the rats of different groups. (A) respiratory rate (RR) (B) heart rate (HR) (data are presented as means ± standard deviation, N = 10) Note: Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05. RR, respiratory rate; HR, heart rate. Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Routine blood analysis

As shown in Fig. 2A and B, the hemoglobin (HGB) and hematocrit (HCT) levels in the HC group gradually increased; their levels at 48 h were higher than those at 24 h (P < 0.05) and then slowly plateaued. The HGB and HCT levels in the HC group were higher than those in the NC group at 48, 72, and 120 h (P < 0.05), whereas the Sal-40 and Cur-200 groups exhibited lower levels than those in the HC group (P < 0.05), and the Cur-200 group exhibited lower levels than those in the Sal-40 group (P < 0.05).

Fig. 2
figure 2

Changes in HGB and HCT results in the rats of different groups. (A) hemoglobin (HGB) (B) hematocrit (HCT) (data are presented as means ± standard deviation, N = 10). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05. HGB, hemoglobin; HCT, hematocrit; Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Analysis of ABG levels

As shown in Fig. 3A, B, C, D, E, and F, the pH of the HC group rats peaked at 24 h compared with that at 0 h (P < 0.05). The pH decreased to the lowest value at 48 h (P < 0.05 compared with the value at 24 h). The PCO2 of the HC group decreased at 24 h compared with that at 0 h (P < 0.05), followed by an increase at 48 h (P < 0.05). The PaO2, carbonic acid hydrogen radical (HCO3−), base excess (BE), and oxygen saturation (SaO2) levels of the HC group primarily exhibited a downward trend, and the levels of the HC group at 48 h were lower than those at 24 h (P < 0.05). At 72 h, the trend of changes in all ABG indicators tended to plateau, with only the PaO2 of the HC group being significantly lower than that at 48 h (P < 0.05).

At 24 h, the pH increased, and the value of the HC group was significantly higher than that of the NC group (P < 0.05). The PaO2, PCO2, HCO3−, BE, and SaO2 levels of the HC group were significantly lower than those of the NC group (P < 0.05), and the pH of the Cur-200 group was lower than those of the HC group. The PaO2 and PCO2 of the Cur-200 group were higher than those of the HC group (P < 0.05). The PCO2 of the HC group was significantly higher than that of the NC group at 48 h, whereas the PCO2 of the Sal-40 and Cur-200 groups was lower than that of the HC group (P < 0.05), and the level of the Cur-200 group was lower than that of the Sal-40 group (P < 0.05). The pH, PaO2, HCO3−, BE, and SaO2 levels of the HC group were significantly lower than those of the NC group; the values of the Sal-40 and Cur-200 groups were higher than those of the HC group (P < 0.05), and the values of the Cur-200 group were higher than those of the Sal-40 group (P < 0.05).

Fig. 3
figure 3

Changes in arterial blood gas indicators in the rats of different groups. (A) potential of hydrogen (PH) (B) arterial oxygen partial pressure (PaO2) (C) carbon dioxide partial pressure (PCO2) (D) carbonic acid hydrogen radical (HCO3−) (E) arterial oxygen saturation (SaO2) (F) base excess (BE). (data of PH, PaO2, PCO2, HCO3-, and SaO2 are presented as means ± standard deviation, data of BE are presented as median (interquartile range), N = 10). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05. Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Changes in plasma lactate levels

As shown in Fig. 4, the lactate levels in rats exposed to high-altitude environments showed a gradual upward trend, with the HC group showing a peak at 48 h and gradually plateauing thereafter. The lactate level of the HC group was higher than that of the NC group at 48, 72, and 120 h (P < 0.05), whereas the level of the Sal-40 and Cur-200 groups was lower than that of the HC group (P < 0.05). Additionally, the lactate level of the Cur-200 group was lower than that of the Sal-40 group (P < 0.05), and the level of the Cur-200 group was higher than that of the Sal-40 group (P < 0.05).

Fig. 4
figure 4

Changes in the plasma lactate level in the rats of different groups (data are presented as means ± standard deviation, N = 10). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05. Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Protein concentration in BALF

As shown in Fig. 5, the BALF protein level in the HC group gradually increased over time and then stabilized; the peak level at 48 h was significantly higher than that at 24 h (P < 0.05). The protein level of the HC group was higher than that of the NC group at 48, 72, and 120 h (P < 0.05), whereas the protein level of the Sal-40 and Cur-200 groups was lower than that of the HC group (P < 0.05) and the protein level of the Cur-200 group was lower than that of the Sal-40 group (P < 0.05).

Fig. 5
figure 5

Changes in BALF protein level in rats in different groups (data are presented as means ± standard deviation, N = 10). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05. BALF, bronchoalveolar lavage fluid. Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Inflammatory factor levels in BALF

As shown in Fig. 6A, B, C, and D, over time, the TNF-α, IL-1β, and IL-6 levels in the BALF of the HC group gradually increased, peaked at 48 h, and gradually plateaued; their levels were higher at 48 h than those at 24 h (P < 0.05). The HC group exhibited higher levels of TNF-α, IL-1β, and IL-6 than those in the NC group at 48, 72, and 120 h (P < 0.05), whereas the Sal-40 and Cur-200 groups exhibited lower levels of TNF-α, IL-1β, and IL-6 than those in the HC group (P < 0.05). Moreover, there were significant differences between the Sal-40 and Cur-200 groups (P < 0.05). The changes in the IL-10 level were the opposite. In the HC group, the IL-10 levels were lower at 24 h than at 0 h and lower at 48 h than at 24 h (P < 0.05). Moreover, at 24 h, the IL-10 levels in the HC group were lower than those in the NC group, whereas at 48, 72, and 210 h, the IL-10 levels in the HC group were lower than those in the NC group, the Sal-40 and Cur-200 groups were higher than those in the HC group, and the Cur-200 group were higher than those in the Sal-40 group (P < 0.05).

Fig. 6
figure 6

Changes in inflammatory factors in the rats of different groups. (A) tumor necrosis factor (TNF)-α of bronchoalveolar lavage fluid (BALF) (B) interleukin (IL)-1β of BALF (C) IL-6 of BALF (D) IL-10 of BALF (data are presented as means ± standard deviation, N = 10). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05. Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Changes in lung histopathology and injury scores

As shown in Fig. 7 A1, A2, after 48 h of environmental exposure, hematoxylin and eosin staining of rat lung tissue demonstrated that the alveolar structure of the NC groups was intact, with no thickening of the pulmonary septum, no significant edema in the alveolar cavity or interstitial space, and no infiltration of white blood cells or red blood cells in the alveoli and interstitial space. As shown in Fig. 7 B1, B2, the most apparent histopathological damage in the HC group was observed in the lungs of rats at 48 h, characterized by the impaired structural integrity of the alveoli and the fusion and expansion of alveolar cavities, forming large emphysematous alveoli. Local lung tissue consolidation, partial alveolar collapse, partial venous edema, exudation of edema fluid in the alveoli, and infiltration of red blood cells were observed in some alveolar ducts, sacs, and alveoli.

As shown in Fig. 7 C1, C2, the Sal-40 and Cur-200 groups showed a decrease in histopathological changes and degree of injury compared with the HC-48 h group. In particular, as shown in Fig. 7 D1, D2, the Cur-200 group alleviated pulmonary interstitial edema with reduced pulmonary capillary congestion, alveolar hemorrhage, and interstitial edema.

As shown in Fig. 8, the lung injury scores of the HC group gradually increased over time, reaching a peak at 48 h and then gradually plateauing. The lung injury scores of the HC group were higher than those of the NC group at 24, 48, 72, and 120 h (P < 0.05), whereas at 48 h, the lung injury scores of the Cur-200 groups were lower than those of the HC and Sal-40 group (P < 0.05). At 72 h, the scores of the Cur-200 group were lower than those of the HC group (P < 0.05). At 120 h, the scores of the Sal-40, Cur-200 group were lower than those of the HC group (P < 0.05).

Fig. 7
figure 7

Lung histopathology of the rats of different groups (data are presented as means ± standard deviation, N = 10). Note. NC group 48 h (A). HC group 48 h (B). Sal-40 group 48 h (C). Cur-200 group 48 h (D). Sal-40, 40 mg/kg salidroside group; Cur-200, curcumin 200 mg/kg group

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Fig. 8
figure 8

Changes in the lung histopathology scores in the rats of different groups (data are presented as median (interquartile range), N = 10). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; compared to the previous time point in the same group, ※P < 0.05; Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Changes in alveolar epithelial barrier-associated protein expression

As shown in Fig. 9, after 48 h of environmental exposure, P-NF-κB expression was significantly higher in the HC group than in the NC group (P < 0.05). The P-NF-κB level was significantly lower in the Sal-40 and Cur-200 groups than in the HC group (P < 0.05). The P-NF-κB level was significantly lower in the Cur-200 group than that in the Sal-40 group (P < 0.05). However, the expression levels of ZO-1, claudin-4, and occludin in the HC group were significantly lower than those in the NC group (P < 0.05). The levels of claudin-4 in the HC group were significantly lower than those in the Sal-40 group (P < 0.05). Furthermore, the expression of claudin-4, occludin, and ZO-1 in the HC group was significantly lower than that in the Cur-200 group (P < 0.05).

Fig. 9
figure 9

Changes in the alveolar epithelial barrier-associated protein levels in the rats of different groups. (data are presented as means ± standard deviation, N = 3). Note. Comparison with the NC group at the same time point, *P < 0.05; comparison with the HC group at the same time point, #P < 0.05; comparison with the Sal-40 group at the same time point, &P < 0.05; Cur-200, 200 mg/kg curcumin; HC, high-altitude control; NC, standard control; Sal-40, 40 mg/kg salidroside

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Discussion

This study observed the basic vital signs, total protein, and inflammatory factor concentrations in BALF, ABG indicators, and changes in lung tissue histopathology to dynamically evaluate the changes in the ventilation function of rats in a high-altitude environment under the condition of acute lung injury and determined whether Cur protects against lung injury. In high-altitude areas, the relevant physiological responses of the body include an increase in the HR [22, 23], HGB level [24], HCT [25], and ventilation rate [26]. Li et al. showed that acute exposure to a hypobaric hypoxic environment can lead to an increase in HR [27]. We observed similar changes in this study. The HR gradually increased with the prolongation of altitude exposure, mainly owing to acute systemic hypoxia, possibly causing sympathetic nervous system reflex excitation to compensate for the decrease in SaO2 by increasing the HR and cardiac output. Hemoglobin and HCT levels increase in an organism in high-altitude areas [21, 28]; consistently, we observed increased HGB and HCT levels in rats after exposure to a hypobaric hypoxic environment at high altitudes. The primary function of HGB is to transport oxygen and carbon dioxide and maintain blood acid–base balance. An increase in the HGB level can enhance the ability of blood to transport oxygen, enabling better oxygen transport to peripheral tissues [29]. The increase in HCT may be attributed to high altitude dehydration or decreased drinking water and plasma volumes in some rats during hypobaric hypoxic exposure.

As an open organ, the lung is highly susceptible to external environmental influences [30]. Individuals exposed to high-altitude conditions exhibit intense lung tissue damage and respiratory function alterations, which can lead to respiratory failure and death [31]. Blood gas analysis is the gold standard for examining patients with acute respiratory diseases, such as respiratory failure and various acid–base balance disorders [22, 32,33,34,35]. Arterial blood gas parameters are influenced by the respiratory and circulatory systems and the balance among cellular metabolism, renal regulation, and alveolar ventilation [36]. Hypoxia in high-altitude areas can cause hypoxic ventilation responses (HVRs), leading to changes in the ABG parameters [37]. It is difficult to determine the characteristics of various lung diseases and their treatment in high-altitude areas as HVRs vary depending on the duration of hypoxic stimulation [38]. Acute exposure to a hypobaric hypoxic environment at high altitudes decreases oxygen saturation and PaO2 [39, 40]. The HVR is one of the most basic responses of the body to acute hypoxia. In this study, the SaO2 level and PaO2 decreased in rats exposed to a high altitude environment for 24 h. Hypoxemia can stimulate peripheral chemoreceptors, increase RR and minute ventilation, and restore the decrease in PaO2 [41]. The decrease in PaCO2 and increase in pH indicate the occurrence of an excessive ventilation reaction. Overventilation can activate the acid–base-compensatory effect of the kidneys [42]. Thus, a decrease in the BE and HCO3− levels observed in our study indicates compensatory metabolic acidosis, suggesting respiratory alkalosis with mild metabolic acidosis after 24 h of high-altitude exposure. After 48 h of exposure to the high-altitude environment, the levels of SaO2 and PaO2 continued to decrease, whereas the PCO2 gradually increased. PaCO2 is a more sensitive marker of ventilation failure than PaO2 as it is closely related to respiratory depth and frequency [43]. This suggests that the rats transitioned from initial hyperventilation to ventilation failure [44] after 48 h of exposure to a high-altitude environment, owing to decreased sensitivity to hypoxia and respiratory muscle failure, which manifested as a decrease in the RR. The acid–base balance of the internal environment of the body changes from respiratory alkalosis to respiratory acidosis, accompanied by a further decrease in the BE and HCO3− levels, resulting in an acidic state. Here, the rats mainly exhibited respiratory acidosis accompanied by metabolic acidosis after 48 h of high-altitude exposure. Additionally, lactate gradually accumulates in the blood owing to the continuous low-pressure hypoxia in rats [5], leading to a substantial increase in plasma lactate levels and exacerbation of metabolic acidosis. In this study, the pH, PCO2, BE, and HCO3− levels gradually stabilized when rats were exposed to a high altitude for 72 h, although the PaO2 still decreased. Thus, the changes in these indicators were the most significant at 48 h.

Curcumin is a bioactive compound extracted from the Curcuma longa plant, which has various pharmacological properties [17, 45]. In wang et al.‘s study, Cur can increase PaO2, reduce PCO2, inhibit paraquat-induced pulmonary fibrosis, and thus protect against lung injury [46]. Moreover, Cur has a significant protective effect on various types of lung injury [47, 48]. But there is currently no research reporting the regulatory effect of Cur on blood gas analysis indicators in high-altitude acute lung injury. Salidroside is an active ingredient derived from the Rhodiola plant [49], which can improve the abnormal blood gas index, hypoxic symptoms, acid–base balance disorders, inflammatory factor imbalance, and oxidative stress damage caused by hypoxia in rats exposed to acute high-altitude environments [50]. In this study, exposure to the environment for 48 h,

Both Cur and Sal can increase the SaO2 and PaO2 of hypoxic rats, decrease the PCO2, reduce the HGB level in arterial blood. With the improvement of hypoxia and respiratory acidosis, the levels of BE and HCO3− were also relieved, and the increase in lactate caused by hypoxia was inhibited. Subsequently, the pH of the blood returned to the normal range. In addition to its regulatory role in blood gas analysis, Cur also plays an essential role in the process of anti-inflammation [47]. Cur pretreatment can reduce TNF-α, IL-1β, IL-2, and IL-6 levels, control the inflammatory response, and alleviate acute lung injury in the BALF of mice [17]. Our study yielded the same results at all time points except at 0 h. The protein level and TNF-α, IL-1β, and IL-6 levels in the BALF of rats administered Cur and Sal by gavage decreased, whereas the IL-10 level increased compared with those in the model group. The changes in hematological indicators can to some extent reflect the morphological changes in lung tissue. After 48 h of environmental exposure, the histopathological changes in the lung tissue of two groups of rats subjected to the drug interventions showed that the injured part of the lung tissue was improved; the exudate volume in the alveolar cavity was reduced, and pulmonary interstitial edema, capillary congestion, and inflammatory cell infiltration were significantly alleviated. The improvement of lung tissue structure alleviated ventilation disorders in high-altitude rats, and subsequently regulated the acid-base imbalance in the blood. However, based on histopathological scores, Cur showed a significant improvement in lung injury within 48 h, while Sal did not show a significant improvement until 120 h after exposure. This may indicate that compared to Cur, Sal requires a longer administration time to improve lung tissue morphology damage. Therefore, Compared with salidroside, curcumin can better alleviate lung injury in rats at high altitudes. In addition, this difference may be caused by a potential mechanism difference between salidroside and curcumin.

Next, we focused on studying proteins related to the inflammatory response and lung barrier function to explore the potential protective mechanism of Cur. Exposure to high-altitude environments can induce inflammatory responses in rats and increase the expression of P-NF-κB in rat lung tissue, and this finding is consistent with the trend of increased inflammatory factor levels in alveolar lavage fluid. The endothelial cells of pulmonary capillaries are the main target of inflammatory factors [51]. The activation of NF-κB triggers the release of a large number of inflammatory factors that, coupled with hypobaric hypoxia and the cold, can damage the integrity of alveolar epithelium, cause alveolar structure collapse, and disrupt lung barrier function [52]. The maintenance of pulmonary barrier permeability is mainly achieved through tight junctions, and tight junction damage is an important cause of barrier disruption [53]. Occludin is the main transmembrane protein that adheres to cells [54]; ZO-1 is crucial for the formation and organization of tightly connected structures [55]. Occludin and claudin can interact with intracellular ZO-1, playing a crucial role in maintaining the stability and integrity of the blood gas barrier [56]. This study showed that the expression of ZO-1, occludin, and claudin-4 was significantly reduced in the lungs of rats exposed to high-altitude environments. Their downregulation indicates damage to the endothelial cell barrier and increased epithelial permeability. As previously reported, high-altitude exposure can disrupt tight junction integrity by altering the expression of ZO-1, claudin-4, and occludin [25]. In this study, both Cur and Sal can inhibits the inflammatory response by downregulating P-NF-κB expression. But only curcumin significantly upregulated the expression of occludin and ZO-1, thereby improving lung barrier function and alleviating acute lung injury in high-altitude environments. This is consistent with the manifestation of lung tissue pathology. After 48 h of environmental exposure, salidroside showed significant improvement in lung pathological damage and the expression of occludin and ZO-1. This can explain why salidroside can improve acid-base balance disorders and inflammatory cytokine imbalances, but its pathological improvement is not very significant. At 120 h, the pathological damage caused by salidroside was significantly improved. And we found in the literature related to salidroside that salidroside needs to be taken for a certain duration of time to take effect [47, 57,58,59]. So, we can preliminarily believe that curcumin can exert a faster and better protective effect in high-altitude acute lung injury, and its mechanism may be related to curcumin’s ability to repair tight junctions more quickly.

Conclusions

Rapid exposure to a high-altitude, hypobaric, hypoxic environment can lead to lung injury in rats, and the degree of injury is most severe after 48 h of exposure to the high-altitude environment. Compared to salidroside, curcumin can improve lung barrier function related proteins more quickly and comprehensively, thus providing better protection against acute lung injury in rats at high altitudes. However, this study mainly focused on the characteristics and mechanisms of curcumin in alleviating acute lung injury at high altitude, and the action characteristics of salidroside were not the focus of this study, so further mechanism research was not conducted. The results of this study lay a theoretical foundation for Cur utilization and subsequent research on the mechanism of its effect against acute lung injury in rats at high altitudes. But, the protective mechanism of Cur against high-altitude acute lung injury was only explored at the protein level, and there is a lack of direct histological evidence. In the future, more intuitive detection methods such as immunofluorescence and electron microscopy are needed, and genetic testing can be employed to provide more comprehensive evidence from multiple perspectives.

Data availability

Data is provided within the manuscript or supplementary information files.

Abbreviations

ABG:

Arterial blood gas

BE:

Base excess

BALF:

Bronchoalveolar lavage fluid

HCO-3:

Carbonic acid hydrogen radical

Cur:

Curcumin (Cur)

PCO2:

Down regulated carbon dioxide partial pressure

ELISA:

Enzyme-linked immunosorbent assay

HR:

Heart rate

H&E:

Hematoxylin and eosin

HC:

High-altitude control

HVR:

Hypoxic ventilation responses

IL:

Interleukin

NC:

Normal control

SO2:

Oxygen saturation

pao2:

Partial pressure of oxygen

RR:

Respiratory rate

Sal:

Salidroside

TNF-α:

Tumor necrosis factorα

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Acknowledgements

Not applicable.

Funding

This work was supported by the Open Project of Key Laboratory of Xinjiang Uygur Autonomous Region [grant number 2019D04022]. The funder had no specific role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. Xinyue Yang, Jiajia Li and Yan Ma these authors contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Special Environmental Medicine of Xinjiang, General Hospital of Xinjiang Military Command, Urumqi, 830000, China

    Xinyue Yang, Jiajia Li, Xiang Dong, Jinquan Qu, Feixing Liang & Jiangwei Liu

  2. Graduate School , Xinjiang Medical University, Urumqi, 830000, China

    Xinyue Yang

  3. Department of Anesthesiology, Xinjiang Medical University Affiliated First Hospital, Urumqi, 830054, China

    Yan Ma

  4. College of Pharmacy, Xinjiang Medical University, Urumqi, 830000, China

    Jiajia Li

Authors
  1. Xinyue Yang
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  2. Jiajia Li
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  3. Yan Ma
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  4. Xiang Dong
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  5. Jinquan Qu
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  6. Feixing Liang
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  7. Jiangwei Liu
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Contributions

The experimental procedures and vital sign records were conducted by XY, JL, YM, XD, JQ and FL. The routine blood test were conducted by FL. The Elisa teesting were conducted by XY, XD, JQ and FL. The histological examination of the kidney were conducted by XY, JL, YM and XD. The western blotting of the kidney were conducted by XY, JL, YM, XD and JQ. The data processing and statistical analysis were conducted by XY, JL and XD. The Original draft preparation were conducted by XY, JL and YM. The review and editing of manuscripts were conducted by XD, JQ, FL and JL.

Corresponding author

Correspondence to Jiangwei Liu.

Ethics declarations

Ethics approval and consent to participate

The procedures were approved by the Animal Ethics Committee of the General Hospital of Xinjiang Military Region, following the 3R principle (Approval number: DWLL20190415).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Yang, X., Li, J., Ma, Y. et al. Curcumin-mediated enhancement of lung barrier function in rats with high-altitude-associated acute lung injury via inhibition of inflammatory response. Respir Res 25, 354 (2024). https://doi.org/10.1186/s12931-024-02975-z

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  • DOI: https://doi.org/10.1186/s12931-024-02975-z

Keywords

Respiratory Research

ISSN: 1465-993X

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