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Hindawi Journal of Healthcare Engineering Volume 2022, Article ID 4185195, 7 pages https://doi.org/10.1155/2022/4185195 ResearchArticle Dexmedetomidine Attenuates LPS-Induced Acute Lung Injury in Rats by Activating the Nrf2/ARE Pathway 1,2 2 Yuandong Qiu and Zhiwei Tang Department of Anesthesiology, Koiqeung Memorial Hospital, Guangzhou, Guangdong, China e Fifth Aﬃliated Hospital of Southern Medical University, Guangzhou, Guangdong 510900, China Correspondence should be addressed to Zhiwei Tang; firstname.lastname@example.org Received 11 January 2022; Revised 16 March 2022; Accepted 23 March 2022; Published 11 April 2022 Academic Editor: Bhagyaveni M.A Copyright © 2022 Yuandong Qiu and Zhiwei Tang. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. To investigate the eﬀect of dexmedetomidine (Dex) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and its mechanism. Methods. Eighteen SD rats were randomly divided into 3 groups (6 rats in each group): control group (intratracheal instillation of saline), ALI group (intratracheal instillation of 5 mg/kg LPS), and ALI-Dex group (tail vein injection of 50μg/kg/h Dex + intratracheal instillation of LPS). Subsequently, the water content of lung tissues was assessed using the wet- dry (W/D) ratio and the histopathological changes of lung tissues using H&E staining. Further activities of ROS, SOD, and GSH- Px in lung tissues of rats were measured by an automatic biochemistry analyzer. ELISA was performed to detect TNF-α, IL-1β, and IL-6 expression in alveolar lavage ﬂuid (BALF) and Western blot to detect the expression of Nrf2/ARE pathway-related proteins. Results. After Dex treatment, a reduction in water content in lung tissue and an improvement of lung injury were found in the ALI rats. Compared with the ALI group, rats in the ALI-Dex group had decreased ROS activity and increased activities of SOD and GSH-Px in lung tissues. Dex-treated rats were also associated with a decrease in TNF-α, IL-1β, and IL-6 expression in alveolar lavage ﬂuid (BALF). Additionally, increased expression levels of HO-1 and NQO1 in lung tissues and elevated expression of Nrf2 in the nucleus were shown in the ALI-Dex group compared with the ALI group.Conclusion. Dex alleviates LPS-induced ALI by activating the Nrf2/ARE signaling pathway. have been reported to accelerate the regression of alveolar 1. Introduction edema by reducing inﬂammation and upregulating alveolar Acute lung injury (ALI) and acute respiratory distress to transport salt and water . Despite encouraging early syndrome (ARDS) are common and severe complications in preclinical evidence for these drugs, phase III clinical trials critically ill patients and are prevalent in intensive care units have shown unsatisfactory results . To date, signiﬁcant . ARDS aﬀects at least 10% of patients in the intensive care advances have been made in the treatment strategies of ALI unit, with a mortality rate of about 40% . ALI is an acute and understanding of related respiratory physiology, but the annual mortality rate of ALI remains at 40%. -erefore, the inﬂammatory disease caused by disruption of the pulmonary endothelial and epithelial barriers . Its pathological fea- search for new drugs and the development of appropriate tures include loss of alveolar-capillary membrane integrity, therapeutic strategies are of great urgency. uncontrolled migration of neutrophils, and uncontrolled Dexmedetomidine (Dex) is a highly eﬀective and se- release of proinﬂammatory factors . Given the patho- lective alpha-2 adrenergic receptor agonist with sedative and genesis, most clinical treatments are aimed at improving the analgesic properties. It is widely used in the anesthesia of respiratory status of patients, such as using 3-hydroxy-3- critically ill patients and can also improve amnesia and methylglutaryl coenzyme A (HMG-CoA) reductase inhib- sympathetic nervous system . Further studies on the itors (statins) and β-2 agonists. In addition, glucocorticoids function of Dex have found that Dex can improve 2 Journal of Healthcare Engineering postoperative recovery in a variety of diseases . Dex can lungs and weighed; the result was recorded as wet weight. reduce mortality as well as ventilator use in patients with -en, the lung tissue was placed in a constant temperature sepsis . Dex can decrease the levels of inﬂammatory incubator at 80 C for more than 48 h until the weight no mediators (e.g., cytokines and interleukins) and immuno- longer changed; this weight was the dry weight. Finally, the suppression, thus improving the prognosis of the systemic W/D ratio was calculated. inﬂammatory response syndrome that is often triggered by surgical resection of tumors [9, 10]. In addition, Gu et al. 2.3. H&E Staining. Lung tissues of the same site of rats in found that in ALI induced by renal ischemia-reperfusion, each group were perfused with 4% paraformaldehyde and Dex improved pulmonary microvascular hyperpermeability then ﬁxed with 4% paraformaldehyde for another 12 h. After to protect the lung tissue . -ese studies suggest that ﬁxation, the tissue samples were embedded in paraﬃn and Dex, in addition to its highly eﬀective anesthetic eﬀect with sectioned (5μm). -e sections were rinsed 3 times with PBS low side eﬀects, also has the ability to slow down the de- and stained with hematoxylin at room temperature for velopment of diseases caused by immune dysregulation. In 5 min, followed by diﬀerentiation using hydrochloric acid recent years, it has been found that Dex has a positive eﬀect alcohol and bluing with 1% v/v ammonia. Subsequently, the on lipopolysaccharide (LPS)-induced ALI through the high samples were stained with eosin for 30 s after rinsing with mobility group protein B1 (HMGB1)-mediated TLR4/NF- tap water. Finally, the sections were dehydrated with alcohol, κB and PI3K/Akt/mTOR pathways . LPS can combine treated with xylene, and sealed. -e histopathological with the TLR4 group on the surface of cell membrane to changes in the lung tissues were observed under an inverted transfer the signal to the interior of immune cells. Activate microscope. myeloid diﬀerentiation factor 88 (MyD88)-dependent sig- naling pathway and TLR domain adaptor protein (TRIF)- dependent signaling pathway, activate mitogen activated 2.4. ROS, SOD, and GSH-Px Activities in Lung Tissue. protein kinase (MAPK), and activate NF-κB. To activate the First, 50 mg of lung tissue from each group was collected and MAPK/NF-κB signal pathway, activated NF-κB enters the placed in a homogenization tube, followed by addition of nucleus and acts with the promoter of related genes, so as to 1 mL of precooled PBS buﬀer into the tube. -en, a low- promote the release of inﬂammatory factors or chemokines temperature homogenizer was used to break down the and cause inﬂammatory response . -e Nrf2/ARE sig- tissues. -e cell suspension was collected, centrifuged, and naling pathway has been proved to be one of the mecha- the supernatant was transferred to a new centrifuge tube. nisms of ALI or ARDS . However, there is no study on -e activities of ROS, SOD, and GSH-Px in the lung tissues the mechanism that Dex regulates ALI through the Nrf2/ of each group were measured by an automatic biochemistry ARE signaling pathway. -erefore, in this study, we attempt analyzer (Olympus, Japan). to elucidate the eﬀect of Dex on LPS-induced ALI and its mechanism by constructing an ALI rat model. 2.5.ELISAAssay. After 6 h of LPS or saline administration, the lungs were lavaged 3 times with 500μl of sterile PBS 2. Materials and Methods (total volume 1.5 ml) to collect BALF. -en, 1 mL of BALF was taken from each group in a 1.5 mL centrifuge tube and 2.1. Construction of Rat Models of Acute Lung Injury. centrifuged at 4 C and 12000 g for 10 min. -e cell debris was Eighteen male SD rats of 6–8 weeks of age, weighing removed, and the supernatant was collected in a new cen- 180 g–220 g, were randomly divided into three groups (6 rats trifuge tube. Subsequently, the levels of TNF-α, IL-1β, and in each group): control group, ALI group, and ALI-Dex IL-6 in BALF were measured according to the instructions of group. -e ALI group received intratracheal instillation of the ELISA kits (Nanjing Jiancheng Bioengineering Institute, 8 mg/kg LPS . -e ALI-Dex group was ﬁrst given tail China). vein injection of 50μg/kg/h Dex for 90 min (50μg/kg/h, total dose≤75μg/kg), and 30 min after the injection, received the 2.6.WesternBlot. Nrf2 was extracted from the lung tissues same procedure as the ALI group. -e control group had using the nuclear protein extraction kit, and HO-1 and intratracheal instillation of an equal volume of saline. All rats NQO1 proteins were extracted using RIPA buﬀer. -e were killed 6 h after LPS induction to obtain lung tissues and protein concentrations were then determined by BCA alveolar lavage ﬂuid (BALF) and store them at −80 C. Lung protein assay (-ermo Fisher, USA). Equal amounts of tissues for H&E staining were ﬁxed and stored in 4% proteins were extracted and separated by 10% SDS-PAGE. paraformaldehyde. All research protocols involving animals -e target proteins were then transferred to PVDF mem- in this study after adaptive feeding were approved by the branes. -e membranes were blocked with 5% skim milk for Institutional Animal Ethics Committee of the Guangdong 1 h and incubated with primary antibodies at 4 C overnight. Provincial Medical Laboratory Animal Center (C202201-2) -e next day, the membranes were incubated with the and carried out according to the approved guidelines. corresponding secondary antibodies at room temperature for 1 h, followed by rinsing step with TBST. -e membranes 2.2. Lung Wet-to-Dry Weight (W/D) Ratio. -e water con- were placed in a gel imaging and analysis system with ECL tent of rat lung tissue was measured by wet/dry (W/D) ratio. chemiluminescent substrate, and images were acquired TM -e right lung tissue was separated from the obtained rat using Image Lab software to analyze the grayscale values Journal of Healthcare Engineering 3 of the bands. β-actin was used as an internal reference for inﬂammatory inﬁltration, and erythrocyte extravasation in whole-cell proteins, while Lamin B was for nuclear proteins. ALI rats. After DEX treatment, the activity of ROS in the lung tissue of the rats in the ALI-Dex group decreased, the activities of SOD and GSH-Px increased, and the expressions 2.7. Statistics Analysis. SPSS 26.0 software was used for of TNF-α, IL-1β, and IL-6 in BALF were also decreased. -is statistical analysis. -e experimental data were expressed as indicates that DEX can attenuate oxidative stress and in- mean± standard deviation (SD). One-way analysis of vari- ﬂammatory response in ALI rats. In addition, compared ance compared the diﬀerence between groups. P< 0.05 with the ALI group, the expression levels of HO-1 and suggested a statistically signiﬁcant diﬀerence. NQO1 in the lung tissue of the ALI-Dex group increased, and the expression of Nrf2 in the nucleus increased, indi- 3. Results cating DEX able to activate the Nrf2/ARE pathway. ALI is a progressive and destructive disease. Various 3.1.DexmedetomidineRelievesAcuteLungInjuryCausedby direct and indirect factors result in lung injury and subse- LPS. -e results of the W/D ratio showed that LPS caused a quent ALI, with endotoxemia being a common causation signiﬁcant increase in the water content of lung tissues, while . It is reported that systemic diseases caused by various Dex treatment signiﬁcantly reduced the water content pathogenic factors inside and outside the lung are the root (Figure 1(a)). H&E staining showed no apparent patho- causes of pediatric ALI/ARDS. In addition, the incidence logical damage in the control group, with normal alveolar rate of ALI/ARDS in sepsis patients is 25–50%, causing structure and intact alveolar wall. By contrast, in the ALI serious complications and death [16, 17]. Moreover, a large group, the alveolar structure was destroyed, and the alveolar number of clinical transfusions, multiple trauma, and as- wall was thickened and edematous. Also, ALI rats had a large piration can also lead to ALI/ARDS, with an incidence rate number of inﬂammatory cell inﬁltrates and erythrocyte of 40%, 11–25%, and 9%, respectively [18, 19]. Although a exudates observed in the alveolar wall and alveolar cavity. variety of drug options have been developed for ALI, treating After Dex treatment, the thickening and edema of the al- the primary aﬀection is the ﬁrst principle in the treatment of veolar, the inﬂammatory inﬁltration, and erythrocyte exu- ALI because ALI is only a terminal pathological process of dation mentioned in ALI rats were improved (Figure 1(b)). many conditions. -e promising eﬃcacy of Dex has been demonstrated in the treatment of multiple diseases. -is 3.2. Dexmedetomidine Attenuates Oxidative Stress in Rats highly selective α2-adrenergic receptor inhibitor with anti- withAcuteLungInjury. -e results of biochemical assays of inﬂammatory eﬀects is often used as a sedative for critically lung tissue lysates showed that LPS-induced ALI and sig- ill patients . Sun et al. showed that Dex could protect niﬁcantly increased ROS content in lung tissues while de- glial cells by reducing apoptosis and protecting neurons, creasing SOD and GSH-Px activities. In contrast, the ROS thus preserving brain function and ultimately improving the content was decreased and SOD and GSH-Px activities prognosis of sepsis . Zheng et al. found that Dex reduced became higher in the lung tissues after Dex treatment HIF-1alpha expression and upregulated miR-155 expression (Figures 2(a)–2(c)). in ovarian cancer cells, thereby inhibiting cell proliferation, migration, and invasion and promoting apoptosis . Kong et al. reported that Dex attenuated LPS-induced 3.3.DexmedetomidineAttenuatesInﬂammationinRatswith myocardial injury in mice with septic cardiomyopathy, AcuteLungInjury. -e ELISA results showed (Figures 3(a)– suggesting that Dex has some protective functions against 3(c)) that the levels of inﬂammatory factors TNF-α, IL-1β, LPS . According to the results of our study, Dex can and IL-6 were signiﬁcantly higher in the BALF of rats in the eﬀectively alleviate LPS-caused ALI. -is means that the ALI group compared with the control group (P< 0.05). clinical use of Dex has been extended. -eir expression levels in BALF, however, were decreased Many studies have also pointed out that Dex can inhibit after Dex treatment (P< 0.05). body damage caused by excessive oxidative stress. Chen et al. found that Dex reduced oxidative stress and apoptosis by inhibiting the ROS/JNK pathway, preventing acute stress 3.4.DexmedetomidineActivatestheNrf2/AREPathwayinthe kidney injury in rats . Cai et al. revealed that Dex Lung Tissue of Rats with Acute Lung Injury. Western blot downregulated PKC-α to inhibit the NOX2/ROS signaling showed (Figures 4(a)–4(d)) that compared with the control pathway, decreased VLA-4 and LFA-1 expression, and ul- group, Nrf2 expression in the nucleus and cellular HO-1 and timately led to a decrease in monocyte-endothelial adher- NQO1 protein expression were signiﬁcantly lower in the ence . In our study, we found that after DEX treatment, lung tissue in the ALI group (P< 0.05). In comparison with the concentrations of TNF-α, IL-1β, and IL-6 in the BALF of the ALI group, the expression of such 3 proteins was all rats were decreased, the activity of ROS in the lung tissue was signiﬁcantly upregulated after Dex treatment (P< 0.05). decreased, and the activities of SOD and GSH-Px were increased. -ese ﬁndings suggest that Dex can counteract 4. Discussion dysregulated oxidative stress in the organism, and we got In this study, we found that in the LPS-induced rat ALI consistent results that Dex attenuates oxidative stress and excessive inﬂammatory response in ALI rats. It is known that model, DEX could reduce the water content of the lung tissue and improve the alveolar thickening, edema, dysregulation of inﬂammatory response and oxidative stress 4 Journal of Healthcare Engineering ** ## Control ALI ALI-Dex (a) Control ALI ALI-Dex (b) Figure 1: Dexmedetomidine alleviates acute lung injury caused by LPS. (a) Wet-to-dry ratio for assessing the water content of lung tissues. ∗∗ ## (b) H&E staining to observe the pathological changes of lung tissues. N � 6. P< 0.01 vs. the control group; P< 0.01 vs. the ALI group. 60 120 50 ** ## ## ## ** 40 80 ** 20 40 0 0 0 Control ALI ALI-Dex Control ALI ALI-Dex Control ALI ALI-Dex (a) (b) (c) Figure 2: Dexmedetomidine attenuates oxidative stress in rats with acute lung injury. -e ROS (a) content and SOD (b) and GSH-Px ## ∗∗ activities (c) in the lung tissue of rats measured by an automatic biochemistry analyzer.N � 6. P< 0.01 vs. the control group; P< 0.01 vs. the ALI group. is a crucial factor leading to ALI. -us, it can be endogenous antioxidant response elements (AREs) and concluded that mechanistically, Dex attenuates LPS-caused enables the expression of many antioxidant genes and ALI by regulating the inﬂammatory response and oxidative proteins to maintain cellular redox homeostasis and normal stress. metabolism . Conversely, dysregulation of the Nrf2/ARE -e Nrf2/ARE pathway plays a critical role in developing pathway can develop many inﬂammatory diseases, including many diseases and is essential for natural antioxidant reg- cancer, Alzheimer’s disease, Parkinson’s disease, and dia- ulation in cells. Many antioxidant drugs function through betes . -erefore, this signaling pathway is considered a the Nrf2/ARE pathway. Nrf2, once activated, binds to regulator of oxidative stress and inﬂammatory diseases and ROS 400 x 100 x Water content (g/g dry weight of lung tissue) SOD (U/mg) GSHPx activity Journal of Healthcare Engineering 5 25 60 25 ** ** ** 20 20 ## ## ## 15 15 10 10 5 5 0 0 0 Control ALI ALI-Dex Control ALI ALI-Dex Control ALI ALI-Dex (a) (b) (c) Figure 3: Dexmedetomidine attenuates the inﬂammatory response in rats with acute lung injury. ELISA for TNF-α (a), IL-1β (b), and IL-6 ∗∗ ## (c) in alveolar lavage ﬂuid of rats. N � 6, P< 0.01 vs. the control group; P< 0.011 vs. the ALI group. Control ALI ALI-Dex 1.5 Nrf2 1.0 ## Lamin B ** 0.5 0.0 Control ALI ALI-Dex (a) (b) Control ALI ALI-Dex 1.5 HO-1 1.0 ## ## NQO1 0.5 ** ** GAPDH 0.0 HO-1 NQO1 Control ALI ALI-Dex (c) (d) Figure 4: Dexmedetomidine activates the Nrf2/ARE pathway in the lung tissue of rats with acute lung injury. Western blot detection of ∗∗ nucleus Nrf2 (a) and the grayscale analysis (b). Western blot detection of cellular HO-1, NQO1 (c), and the grayscale analysis (d). P< 0.01 ## vs. the control group; P< 0.01 vs. the ALI group. bronchopulmonary dysplasia, ALI, and other diseases . conditions. Some Nrf2/ARE inducers, such as bardoxolone, dimethyl fumarate, and sulforaphane, have entered phase III Nrf2 translocation into the nucleus contributes to activating clinical trials  and have been used as chemopreventive ARE-dependent expression of genes and proteins involved agents for cancer, diabetes, neurological diseases, or as in antioxidant defence and cytoprotecting . -e Nrf2/ therapeutic agents for inﬂammation-related diseases, ARE signaling pathway is important in preventing the oc- showing good progress . It has also been shown that currence of ALI/ARDS, and activation of Nrf2 can prevent Nrf2, which is mainly expressed in epithelium and alveolar or reduce the severity of ALI/ARDS . Furthermore, macrophages, protects the lung from oxidative stress, al- activated Nrf2 was translocated into the nucleus to regulate veolar apoptosis, extracellular matrix protein hydrolysis, and the expression of HO-1-related genes. Activated HO-1 in- chronic inﬂammation . Activated Nrf2 has a therapeutic hibits the inﬂammatory cascade and reduces inﬂammation- role in idiopathic pulmonary ﬁbrosis, asthma, induced ALI, thereby protecting organs . Dex, in our TNF-α (ng/L) IL-1β (ng/L) Relative protein expression Relative protein expression IL-6 (ng/L) 6 Journal of Healthcare Engineering  D. S. Carollo, B. D. Nossaman, and U. Ramadhyani, “Dex- study, signiﬁcantly increased Nrf2 aggregation in the nu- medetomidine: a review of clinical applications,” Current cleus, suggesting that Dex treats ALI through the Nrf2/ARE Opinion in Anaesthesiology, vol. 21, no. 4, pp. 457–461, 2008. pathway. Compared with the above three Nrf2/ARE in-  C. Perez ´ Piñero, A. Bruzzone, M. G. Sarappa, L. F. Castillo, ducers, bardoxolone, dimethyl fumarate, and lycopene, Dex and I. A. 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