Research ArticleExperimental Studies
Open Access

Ischemic Postconditioning Mitigates Lipopolysaccharide-induced Acute Lung Injury in Rats

BİLKAY SEREZ KAYA, SELEN YILDIZ, ONUR ERSOY, ÜMMÜHAN ERGE, EBRU TAŞTEKİN, ÖZGÜR GÜNDÜZ and OKTAY KAYA
In Vivo November 2024, 38 (6) 2705-2711; DOI: https://doi.org/10.21873/invivo.13748

Abstract

Background/Aim: Acute lung injury (ALI) is a syndrome characterized by the disruption of alveolar endothelial and epithelial barriers, neutrophilic infiltration in pulmonary regions, and non-cardiogenic edema, associated with high mortality and morbidity. Despite intensive research efforts, there is currently no approved specific treatment for the condition. The aim of this study was to investigate the potential beneficial effect of ischemic post-conditioning in lipopolysaccharide (LPS)-induced lung injury and its possible association with inflammatory and apoptotic processes. Materials and Methods: Lung injury was induced in rats by a single intraperitoneal administration of 10 mg/kg LPS. Under anesthesia, latex tourniquets were wrapped around both hind limbs of the animals in a region close to the body to achieve complete ischemia. The ischemic conditioning procedure consisted of four cycles of 10 min of ischemia followed by 10 min of reperfusion. Inflammation, and apoptosis levels were measured using ELISA. Hematoxylin and eosin staining was used for histopathological evaluation, while TUNEL staining was employed for apoptotic cell counting. One-way analysis of variance (ANOVA) with post hoc Tukey test was used for comparisons between groups. Results: Intraperitoneal LPS administration induced neutrophil infiltration and apoptotic cell death in lung tissue. These effects were prevented by remote ischemic postconditioning (RIPostC) application. Additionally, the beneficial effects of ischemic conditioning can be transferred via serum. Conclusion: RIPostC can ameliorate LPS-induced ALI. The mechanism of the protective effects of RIPostC may lie in the suppression of apoptosis and neutrophil infiltration.

Key Words:

Acute lung injury (ALI) is a syndrome caused by factors, such as sepsis, shock, trauma, pneumonia, aspiration, and massive transfusion. They are associated with high rates of morbidity and mortality. It has been reported that 25 to 50 percent of sepsis patients develop acute lung injury (ALI), with a mortality rate of 40% (1, 2). Worldwide, 150,000 to 200,000 patients die each year due to ALI caused because of sepsis. It has been reported that the mortality rate of ALI patients with sepsis in intensive care units is higher than that of those without sepsis (3, 4).

The mechanisms initiating and promoting lung injury remain unclear despite intensive research. However, inflammation, cytokine imbalances, oxidative stress, and apoptosis are emerging as key mechanisms. Lipopolysaccharide (LPS), the principal component of the cell wall of gram-negative bacteria, serves as the primary stimulus for the release of inflammatory mediators. Inflammation and oxidative damage collectively contribute to heightened capillary permeability, tissue edema, and exacerbation of tissue damage. Oxidative stress can directly damage the lung parenchyma as well as affect the capillary basement membrane (5, 6). Another important pathogenic mechanism is apoptosis, and therapeutic interventions targeting alveolar epithelial apoptosis have been reported to be important in sepsis-induced ALI (1).

Murry et al. demonstrated that brief episodes of ischemia provide protection against subsequent injury, a phenomenon they termed ischemic preconditioning (7). The ability of ischemic conditioning in a distant organ to protect another organ is called remote ischemic preconditioning (RIPC). RIPC has been shown to have anti-inflammatory effects in various models of acute inflammation (8). In our previous study, we showed that flap viability in rats treated with a random pattern skin flap model was increased by ischemic preconditioning. We also showed that the positive effect could be transferred between rats via serum (9). Despite its positive effects, the clinical use of RIPC is limited because it must be generated before damage occurs. For this reason, the effects of remote ischemic postconditioning (RIPostC) against acute injury have come to the forefront as a field of study. RIPostC has been shown to have protective effects by preventing inflammation, oxidative stress and apoptosis (10, 11).

Despite intensive efforts, there are no clinically approved drugs that can effectively reduce mortality in patients with ALI. Although interventions such as nitric oxide inhalation, intratracheal surfactant instillation, prone ventilation, and extracorporeal membrane oxygenation improve oxygenation in ALI patients, the mortality rate remains high (12). In this study, a lipopolysaccharide (LPS)-induced lung injury rat model was employed, and its effects were observed using biochemical and histological methods. It was hypothesized that RIPostC exerts its beneficial effects by suppressing the inflammatory response and oxidative stress in the LPS-induced lung injury model.

Materials and Methods

A total of 40 male Sprague-Dawley rat in five groups (n=8 for each) were used. Additionally, two rats were used to obtain ischemic conditioned serum. Animals were kept under laboratory conditions of 12/12 light/dark cycle, 22±2°C, 40% humidity. All groups were fed ad libitum with standard pellet feed. Adequate measures were taken to minimize discomfort, and “Animal Research Ethics Committee” of Trakya University approved all experimental protocols of this study (TUHADYEK -2022.02.08).

Animal groups. While physiological saline was administered intraperitoneally to the control and RIPostC groups, a dosage of 10 mg/kg lipopolysaccharide (Escherichia coli LPS, O55:B5) was administered to the ALI, ALI+ RIPostC, and ALI+ RIPostCs groups. RIPostC and ALI+ RIPostC groups underwent ischemic postconditioning 4 h after intraperitoneal injections. Rats in the ALI+ RIPostCs Group received 100 microliters per 50 grams of body weight of serum obtained from animals subjected to ischemic postconditioning, administered via the tail vein 4 h after intraperitoneal injection. At 12 h after intraperitoneal administration of LPS or physiological serum, blood samples were collected from the rats, and their lungs were excised under anesthesia induced using 10 mg/kg rompun and 50 mg/kg ketamine. After blood collection, the samples were centrifuged, and the serum was stored at −80°C until further laboratory studies. The right lungs were preserved at −80°C for use in ELISA studies, while the left lungs were immersed in neutral buffered formalin for histopathological evaluation.

Ischemic conditioning procedure. Following anesthesia with ketamine and xylazine, a latex tourniquet was applied around both hind legs of the animals near the body, inducing ischemia for 10 min, followed by 10 min of reperfusion. This cycle was repeated four times.

Acquiring ischemic conditioned serum. Two rats were euthanized 24 h after ischemic conditioning, and blood was collected intracardially from each rat. The collected blood was then centrifuged at 1,467 g for 10 min. Subsequently, the serum remaining at the top of the tube after centrifugation was collected.

Evaluation of inflammation, and apoptosis. Interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), myeloperoxidase (MPO), Bcl-2-associated X protein (BAX), B-cell lymphoma gene-2 (Bcl-2) and caspase 3 levels in lung tissues were measured with commercial ELISA kits (Bioassay Technology Laboratory, Shanghai, PR China; E0135Ra, E0764Ra, E0574Ra, E0037Ra, E1869Ra, and E1648Ra, respectively).

Histopathology and TUNEL staining. The collected tissues were fixed with Neutral buffered Formalin for 24 h, followed by embedding in paraffin for routine dehydration treatment, and preparation of 5-μm slices. After dewaxing and staining with hematoxylin & eosin, pathological changes in lung tissue were observed under an optical microscope. The damage score was computed based on the presence of neutrophils in the alveolar space, neutrophils in the interstitial space, hyaline membranes, proteinaceous debris filling the air spaces, and alveolar septal thickening (13).

The apoptosis of lung tissue was detected in strict accordance with the procedure of TUNEL staining. The staining of lung tissue was observed under a light microscope, in which the positive apoptotic cells showed yellow staining in the nuclei. With the selection of over 10 fields of vision (high magnification of ×400), the number of apoptotic cells and the total number of apoptotic cells in lung tissues were calculated using Image-Pro Plus 6.0 software (Media Cybernetics, Rockville, MD, USA).

Statistical analysis. Means and standard deviations were used for descriptive analysis. One-way analysis of variance (ANOVA) together with post hoc Tukey’s test was used for inter-group comparisons using GraphPad Prism software (GraphPad Inc., La Jolla, CA, USA). Statistical significance was adjusted to a p-value lower than 0.05.

Results

Markers of inflammation. When compared with the Control (17.37±1.25) and RIPostC (17.98±1.14) groups, the MPO levels were higher in the ALI group (21.38±2.04). MPO levels were lower in ALI+ RIPostC group (17.28±2.89), and ALI+ RIPostCs group (17.26±3.24) than in ALI group. MPO levels were comparable in the other groups. TNFα levels were lower in ALI+ RIPostCs group (137±22.59) than in other groups; Control (184.3±8.45), RIPostC (177.2±12.79), ALI (169.7±13.93), ALI+ RIPostC (174.4±8.45), and ALI+ RIPostCs. Interleukin 6 levels were comparable in all study groups. Markers of inflammation in the lung tissue samples are shown in Figure 1.

Figure 1.
Figure 1.

Markers of inflammation. Results are expressed as mean±SD, n=8, and statistical analysis was performed using one-way analysis of variance (ANOVA) and post hoc Tukey test. *Compared to Control group p<0.05; #Compared to remote ischemic preconditioning (RIPostC) group p<0.05; αCompared to acute lung injury group (ALI) group p<0.05.

Apoptosis markers. BAX levels were higher in the ALI group (1,249±97.61) than in the control group (1,048±120.5). BAX levels were lower in the ALI+ RIPostC group (893.4±67.37) than in the ALI group. BAX levels were higher in the ALI+ RIPostCs group (1,120±94.88) than in the ALI+ RIPostC group. Bcl-2 levels were comparable in all groups. The levels of caspase 3 were higher in all groups treated with LPS compared to the control and RIPostC groups. The apoptosis markers of the groups are shown in Figure 2.

Figure 2.
Figure 2.

Apoptosis markers in lung tissue samples. Results are expressed as mean±SD, n=8, and statistical analysis was performed using one-way analysis of variance (ANOVA) and post hoc Tukey test. *Compared to Control group p<0.05; #Compared to remote ischemic postconditioning (RIPostC) group p<0.05; αCompared to acute lung injury group (ALI) group p<0.05; βCompared to ALI+RIPostC group p<0.05.

Histopathological findings and TUNEL staining. Normal histological structure was observed in the lung tissue samples of the Control and RIPostC groups. High lung parenchymal damage was observed in the ALI, ALI+ RIPostC and ALI+ RIPostCs groups compared with the control group. The damage score was lower in the ALI+ RIPostC and ALI+ RIPostCs groups than in the ALI group. H&E-stained sections and morphological analysis score of the groups are shown in Figure 3.

Figure 3.
Figure 3.

The figure shows the lung histopathology and morphological analysis score of all groups. Results are expressed as mean±SD, n=8, and statistical analysis was performed using one-way analysis of variance (ANOVA) and post hoc Tukey test. *Compared to Control group p<0.05; #Compared to remote ischemic postconditioning (RIPostC) group p<0.05; αCompared to acute lung injury group (ALI) group p<0.05; red arrow: bronchial wall; blue arrow: inflammatory cells; blue asterisk: alveolar space.

TUNEL-positive cells were remarkably rare in the lung tissues of the control and RIPostC groups (Figure 4A and B). However, LPS application resulted in a significant increase in the number of apoptotic cells (Figure 4C and D). In comparison, the number of TUNEL-positive cells in the lung sections of the ALI+ RIPostC and ALI+ RIPostCs groups was lower than in the ALI group. The percentage of apoptotic cells in each group is shown in Figure 4E.

Figure 4.
Figure 4.

TUNEL staining of sections of paraffin-embedded lung tissue and percentage of apoptotic cells. Results are expressed as mean±SD, n=8, and statistical analysis was performed using one-way analysis of variance (ANOVA) and post hoc Tukey test. *Compared to Control group p<0.05; #Compared to remote ischemic postconditioning (RIPostC) group p<0.05; αCompared to acute lung injury (ALI) group p<0.05; red arrow: apoptotic cell.

Discussion

In our study, we tested the hypothesis that remote ischemic postconditioning would show positive effects by suppressing inflammatory response, and apoptosis in LPS-induced lung injury in rats. The major discovery of our study is that intraperitoneal LPS administration causes lung tissue damage, and this damage is prevented by remote ischemic postconditioning. Here, we further demonstrated that serum from rats subjected to ischemic conditioning also had a similar beneficial effect. To our knowledge, our study is the first to examine the effects of ischemic postconditioning in the LPS-induced lung injury model.

ALI is a life-threatening disease with high morbidity and mortality for which there are currently no approved treatments. Sepsis is the most common cause of ALI (6-42%) and is associated with a higher mortality rate compared to other causes of ALI (14). Previous studies suggest that inflammation and cell apoptosis are the main causes of ALI (15).

Infiltration and activation of neutrophils in lung tissue plays an important role in potentiating the inflammatory response in ALI (16). MPO, found in intracellular granules, is a marker of neutrophil migration (13). A study examining the effects of oxytocin on LPS-induced acute lung injury in mice showed that MPO activity increased in the LPS-treated group compared to the control group (5). Similarly, another study examining the effects of fortunellin, a flavonoid, in LPS-induced acute lung model, showed that MPO activity was higher in the lung tissues of the LPS-treated group compared to the control group (17). In our study, LPS administration caused a significant increase in MPO activity compared to the control group. This is consistent with the aforementioned studies. Furthermore, this increase was significantly inhibited in the RIPostC group.

In the study conducted by Liu et al. in mice, intratracheal administration of 5 mg/kg LPS caused an increase in TNF-alpha and IL-6 levels (17). In a recent study conducted by Kim et al. in mice, the intratracheal administration of LPS during neutropenia recovery led to an increase in IL-1β and TNF-α levels in BAL fluid (18). In our study, there was no significant difference between the groups in the levels of TNFα and IL-6, which are accepted as indicators of the inflammatory process. The type of animal used, the dose of LPS, the route of administration (intratracheal, intravenous, intraperitoneal), the timing of euthanasia of the animals, and the method of measurement may affect laboratory findings in animal models of acute lung injury (13, 19, 20). There are studies showing that TNF-alpha levels peak within the first few hours after intravenous administration of LPS and return to basal levels within 12-24 h (21, 22). These findings can be interpreted as time-dependent changes in LPS-induced pathophysiological pathways and signaling molecules are differentially activated during disease progression. This may account for the difference between our study and previous studies.

LPS-induced cellular damage appears to be associated with apoptosis. Endothelial cell apoptosis develops rapidly after LPS administration and precedes other tissue damage (13). Wang et al. showed that the intrinsic apoptotic pathway is necessary for LPS-induced endothelial cell death and is independent of reactive oxygen species generation (23). In the study conducted by Liu and colleagues, cellular apoptosis increased in lung tissue following LPS stimulation. Moreover, after LPS stimulation, the expression of cleaved caspase-3 and Bax increased, while the levels of Bcl-2 decreased (17). In the study by Li and colleagues on acute lung injury induced by myocardial ischemia-reperfusion in mice, RIPostC reduced apoptotic death of lung cells (14). Consistent with the mentioned studies, in our study, the increased TUNEL-positive cell count induced by LPS application was lower in both the RIPostC and RIPostCs groups compared to the ALI group. Additionally, while BAX and caspase-3 levels increased with LPS application, ischemic post-conditioning led to a decrease in BAX levels. Caspase-3 levels remained elevated even after ischemic post-conditioning applications in the LPS-treated groups. Despite partial inconsistencies in the study findings, we can say that apoptotic cell death induced by LPS application was mitigated by ischemic post-conditioning interventions. As in our previous study, we found that the beneficial effects of ischemic conditioning could be transferred via serum (9, 24).

In a recent study by Kwon and colleagues, similar to our findings, intratracheal LPS administration resulted in significant histological damage characterized by intense inflammatory cell infiltration in the lungs (25). One of the significant findings of our study is that the lung injury induced by LPS administration is mitigated through the application of ischemic conditioning.

Due to the complex pathophysiological processes of acute lung injury, caution should be exercised when extrapolating our study findings to acute lung injury associated with sepsis in humans. In our study, euthanasia of the animals was performed at 24 h, and it should be noted that earlier or later euthanasia may alter the data.

Conclusion

We report that RIPostC can ameliorate LPS-induced ALI. The mechanism of the protective effects of RIPostC may lie in the suppression of apoptosis and neutrophil infiltration. Further detailed studies will be useful to determine the molecular mechanisms and cellular pathways of remote ischemic postconditioning. Therefore, RIPostC may be a novel therapeutic option for the treatment of sepsis-associated ALI.

Acknowledgements

The Authors thank Muhammed Ali Aydın and Canberk Topuz for their technical assistance.

Footnotes

  • Authors’ Contributions

    B.S.K.: Concepts, design, definition of intellectual content, data analysis, statistical analysis, manuscript preparation; S.Y.: Concepts, design, definition of intellectual content, experimental studies, manuscript preparation; O.E.: Concepts, design, definition of intellectual content, experimental studies, manuscript preparation; Ü.E.: Concepts, design, definition of intellectual content, experimental studies, manuscript preparation; E.T.: Concepts, design, definition of intellectual content, experimental studies, manuscript preparation; Ö.G.: Concepts, design, definition of intellectual content, experimental studies, manuscript preparation.

  • Funding

    This study was supported by Trakya University scientific research projects unit (TÜBAP 2022/197).

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Received July 29, 2024.
  • Revision received August 27, 2024.
  • Accepted August 28, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Ischemic Postconditioning Mitigates Lipopolysaccharide-induced Acute Lung Injury in Rats
BİLKAY SEREZ KAYA, SELEN YILDIZ, ONUR ERSOY, ÜMMÜHAN ERGE, EBRU TAŞTEKİN, ÖZGÜR GÜNDÜZ, OKTAY KAYA
In Vivo Nov 2024, 38 (6) 2705-2711; DOI: 10.21873/invivo.13748
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