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Protectin D1 Protects Against Lipopolysaccharide‑Induced Acute

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Protectin D1 Protects Against Lipopolysaccharide‑Induced Acute EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 1074, 2021 Protectin D1 protects against lipopolysaccharide‑induced acute lung injury through inhibition of neutrophil infiltration and the formation of neutrophil extracellular traps in lung tissue ZHIYANG WU1*, LUYAO ZHANG2*, XIANGYANG ZHAO1, ZHI LI1, HAINING LU1, CHANYUAN BU1, RUI WANG1, XIAOFEI WANG1, TIANTIAN CAI1 and DAWEI WU1 1Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong 266035; 2Department of Pathology, School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China Received July 6, 2020; Accepted January 28, 2021 DOI: 10.3892/etm.2021.10508 Abstract. Protectin D1 (PD1), a DHA‑derived lipid mediator, inhibition of neutrophil extracellular trap formation in lung has recently been shown to possess anti‑inflammatory and tissue. Therefore, PD1 administration may serve to be a new pro‑resolving properties. To date, little is known about the strategy for treating ALI. effect of PD1 on lipopolysaccharide (LPS)‑induced acute lung injury (ALI) in mice. The aim of the present study was to Introduction investigate the therapeutic effects of PD1 on LPS‑induced ALI and its potential mechanisms of action. ALI was induced via Acute lung injury (ALI) and its most severe form, acute respira‑ an intraperitoneal injection of LPS, where PD1 (2 ng/mouse) tory distress syndrome (ARDS), are widespread inflammatory was administered intravenously 30 min after LPS challenge. processes in the lung caused by pneumonia, sepsis, trauma Mice were sacrificed 24 h after modeling. Lung histopatho‑ and aspiration. ALI is characterized by pulmonary interstitial logical changes were assessed using hematoxylin and eosin edema, deteriorated lung compliance and subsequent severe staining and myeloperoxidase (MPO) activity was tested using hypoxemia (1,2). Despite great progress in our understanding immunohistochemistry. Tumor necrosis‑α and interleukin‑6 of the pathophysiology of the condition, ALI still has a rela‑ levels in the bronchoalveolar lavage fluid (BALF) and serum tively high mortality of 30‑40% in intensive care units of the were measured using ELISA. To detect neutrophil extracellular United States and no specific drug has been approved for traps produced by infiltrated neutrophils in the lung tissue, clinical treatment. To reduce this mortality rate treatment and immunofluorescence staining was performed using anti‑MPO prevention strategies for ALI need to be improved (3‑5). and anti‑histone H3 antibodies. The results indicated that PD1 Lipopolysaccharide (LPS), a glycolipid of the outer significantly attenuated histological damage and neutrophil membrane of gram‑negative bacteria (6), has been determined infiltration in lung tissue, reduced the lung wet/dry weight to be an important factor in the activation of inflammatory ratio, protein concentration and proinflammatory cytokine signaling cascades in ALI development (5). Intraperitoneal levels in BALF and decreased proinflammatory cytokine injection of LPS in mice is an effective method to establish an levels in serum. Moreover, neutrophil citrullinated histone H3 ALI model. (CitH3) expression was also reduced after PD1 administration. Protectin D1 (PD1) is a bioactive product generated from In conclusion, PD1 attenuated LPS‑induced ALI in mice via docosahexaenoic acid (DHA) and has been reported to exert anti‑inflammatory effects in various disorders, including acute kidney injury and neurodegenerative diseases (7,8). A previous study suggested that PD1 could promote the resolu‑ tion of inflammation in a murine model of LPS‑induced Correspondence to: Dr Dawei Wu, Department of Critical Care ALI (9). However, the underlying molecular mechanism of the Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, anti‑inflammatory effect of PD1 in ALI is not well understood. Shandong University, 758 Hefei Road, Qingdao, Shandong 266035, Neutrophils are part of the host's first line of defense P. R. Ch i na E‑mail: [email protected] against invading pathogens. Activated neutrophils can release networks of nuclear DNA, enzymes and histones, which are *Contributed equally known as neutrophil extracellular traps (NETs) (10). This process, known as NETosis (11), was initially considered to Key words: protectin D1, acute lung injury, neutrophil infiltration, play a host‑protective role against infection (12). NETosis neutrophil extracellular trap is important in the pathophysiology of many conditions, including rheumatoid arthritis (13), small vessel vasculitis (14) and diabetes (15). Recently, NETs formation was identified in 2 WU et al: PROTECTIN D1 PREVENTS ACUTE LUNG INJURY VIA NEUTROPHIL INFILTRATION LPS‑induced ALI (16) and further studies revealed that NETs Pulmonary wet/dry weight ratios were calculated as was directly responsible for alveolar damage and epithelial follows: Wet/dry weight ratio=(wet lung weight‑dry lung cell death (17). Targeting NET formation in ALI may provide weight)/dry lung weight. an avenue for treatment that has yet to be explored. However, little is known regarding the beneficial role of PD1 in inflam‑ Measurement of protein concentrations and cytokines in matory responses and NETs formation in ALI. bronchoalveolar lavage fluid (BALF). The left lungs were In the present study, the significance of PD1 in mouse rinsed with 1 ml of PBS through the tracheal cannula three models of LPS induced ALI was explored and the effect of times to obtain BALF. The BALF was centrifuged at 850 x g PD1 on NETs formation evaluated. for 10 min at 4˚C. The supernatant was collected for protein measurement using a bicinchoninic acid protein assay kit Materials and methods (Thermo Fisher Scientific, Inc.) according to the manufacturer's protocols. Tumor necrosis factor (TNF‑α) and interleukin‑6 Animals. A total of 28 male ICR mice (age, 6‑8 weeks; weight, (IL‑6) levels in BALF were measured using TNF‑α ELISA kit 21‑28 g) were obtained from Jinan Pengyue Experimental [cat. no. EK282/3; MultiSciences (Lianke) Biotech. Co., Ltd.] Animal Breeding Co. Ltd. All mice were housed at an and IL‑6 ELISA kit [cat. no. EK206/3; MultiSciences (Lianke) ambient temperature of 20‑22˚C with a relative humidity of Biotech. Co., Ltd.]. 5±5% and on a 12‑h light‑dark cycle in specific pathogen‑free (SPF) facilities with free access to food and water. All animal Measurement of serum TNF‑α and IL‑6. The serum levels protocols were approved by the Institutional Animal Care and of TNF‑α and IL‑6 were determined using TNF‑α ELISA Use Committee of Qilu Hospital (Qingdao; China) and were kit [cat. no. EK282/3; MultiSciences (Lianke) Biotech. Co., performed in accordance with the guidelines of the Animal Ltd.] and IL‑6 ELISA kit [cat. no. EK206/3; MultiSciences Care and Use Committee (18). (Lianke) Biotech. Co., Ltd.] according to the manufacturer's instructions. Experimental model and treatments. The mice were randomly divided into four groups (7 mice per group): The Immunohistochemical analysis of myeloperoxidase (MPO). control group, control + PD1 group, LPS group and LPS + Immunohistochemical analysis of MPO was performed PD1 group. The LPS model was induced by intraperitoneal according to previously described methods (22,23). One injection of 10 mg/kg LPS, as previous described (19,20). portion of the lungs was fixed overnight at 4˚C in freshly Mice in the control group and the control + PD1 group prepared formaldehyde (Sigma‑Aldrich; Merck KGaA) in were administered an equal volume of PBS. At 30 min PBS, pH 7.4. The tissues were then embedded in paraffin. after LPS/PBS treatment, PD1 treated mice were injected Lung tissue sections (at a thickness of 5 µm) were depa‑ with PD1 (2 ng/mouse) via the angular vein. All mice were raffinized in xylene at room temperature for 15 min, sacrificed 24 h after the first administration of LPS. All rehydrated using a descending ethanol gradient and heated animals were anesthetized with an intraperitoneal adminis‑ in 10 mM sodium citrate buffer (pH 6.0) at 95˚C for 5 min tration of sodium pentobarbital (50 mg/kg) before sacrifice. in a microwave oven for antigen retrieval. Endogenous Euthanasia was performed under anesthesia using cardiac peroxidase activity was blocked by immersing the slides in puncture resulting in exsanguination. Death was confirmed 3% hydrogen peroxide at 15‑25˚C for 10 min. After antigen by cervical dislocation. Complete cessation of heartbeat and retrieval, the tissue sections were immersed in 5% BSA breathing and disappearance of reflexes were used as indi‑ (Sigma‑Aldrich; Merck KGaA) for 1 h at room temperature. cators to judge the death of mice. Lung tissues and blood The tissue sections were then incubated with a primary samples were obtained for further analyzes. antibody against MPO (1:100 dilution; cat. no. ab9535; Abcam, Inc.) at 4˚C overnight. The tissue sections were Histological analysis. The inferior lobe of the right lung was then rinsed in TBS and incubated with a horseradish peroxi‑ fixed for 24 h at room temperature with 4% formaldehyde, dase (HRP)‑conjugated secondary anti‑rabbit antibody embedded in paraffin and sectioned at a thickness of 5‑µm. (1:1,000 dilution; cat. no. ab97080; Abcam) for 1 h at room The sections were stained with hematoxylin at 25˚C for temperature. The tissue sections were again washed in TBS 10 min and eosin (H&E) at 25˚C for 3 min. Histopathological and the bound peroxidase was detected by incubating the scoring analysis of the lung tissues was evaluated by TC tissue sections in 3,3'‑diaminobenzidine substrate at room and XW who were blinded to the group information, with temperature for 3 min. The tissue sections were then washed a light microscope at magnifications of x400 according to in distilled water and the nuclei were counterstained with the criteria previously described (21). Briefly, 24 areas in the Mayer's hematoxylin for 1 min at room temperature, followed lung parenchyma were graded on a scale of 0‑4 (0, absent and by two rinses in distilled water.
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