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Molecular and Cellular Microbiology (MCM)  |  Host-Microbe Interaction and Pathogenesis

Microbiol. Biotechnol. Lett. 2022; 50(2): 310-318

Received: December 29, 2021; Revised: April 12, 2022; Accepted: May 10, 2022

Protective Effect of Paulownia tomentosa Fruits in an Experimental Animal Model of Acute Lung Injury

Seong-Man Kim1,2†, Hyung Won Ryu1†, Ok-Kyoung Kwon1, Jae-Hong Min4, Jin-Mi Park1,3, Doo-Young Kim1, Sei-Ryang Oh1, Seung Jin Lee2*, Kyung-Seop Ahn1*, and Jae-Won Lee1*

1Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang 28116, Republic of Korea
2College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
3College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea
4Laboratory Animal Resources Division, Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong Health Technology Administration Complex, Cheongju, Chungcheongbuk 28159, Republic of Korea

Correspondence to :
S.-J. Lee
K.-S. Ahn
J.-W. Lee
These authors contributed equally to this work.

The fruits of Paulownia tomentosa (Thunb.) (PT) Steud. have been reported to exert a variety of biological activities. A previous study confirmed that compounds isolated from PT fruits (PTF) exerted anti-inflammatory effects on TNF-α-stimulated airway epithelial cells. However, there is no report on the protective effects of PTF on acute lung injury (ALI). Here, we examined the ameliorative effects of PTF in an experimental animal model of lipopolysaccharide (LPS)-induced ALI. In ALI mice, increased levels of inflammatory cell influx were confirmed in the lungs of mice, and an increase of microphage numbers, TNF-α, IL-6 and MCP-1 production and protein content were detected in mouse bronchoalveolar lavage fluid. However, these increases were significantly reversed with PTF pretreatment. In addition, PTF inhibited the increased expression of iNOS and COX-2 in the lungs of ALI mice. Furthermore, the upregulation of MAPK and NF-κB activation was decreased in the lungs of ALI mice by PTF. In the in vitro experiment, PTF pretreatment exerted an anti-inflammatory effect by inhibiting the secretion of nitric oxide, TNF-α and IL-6 in LPS-stimulated RAW264.7 macrophages. Collectively, these results indicated that PTF has ameliorative effects on airway inflammation in an experimental animal model of ALI.

Keywords: Acute lung injury, Paulownia tomentosa fruits, macrophage, cytokines, NF-κB

Graphical Abstract

Elevated airway inflammation is one of the major characteristics of acute lung injury (ALI) [1]. Macrophage influx and macrophage-derived cytokine and chemokine production lead to airway inflammation in ALI [2]. It has been reported that the upregulation of tumor necrosis factor-α (TNF-α) and interleukine-6 (IL- 6) promotes inflammatory response in the airways during ALI development [3-5]. Macrophage-released monocyte chemoattractant protein 1 (MCP-1) elevates airway inflammation, leading to inflammatory cell influx [5, 6]. In ALI pathogenesis, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) cause peroxynitrite generation and pain sensitization, respectively [7, 8]. Accumulating evidence shows that airway inflammation in ALI is closely associated with mitogenactivated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathways [9-11] and emphasized that the suppression of MAPK/NF-κB activation ameliorates airway inflammation, leading to the inhibition of cytokines, chemokines and mediators [12, 13]. Therefore, it is important to regulate macrophage influx, macrophage- derived molecules and MAPK/NF-κB activation in the amelioration of ALI development.

Paulownia tomentosa (Thunb.) (PT) is a member of the plant family Paulowniaceae, distributed in China and Korea, and PT fruits (PTF) exerted protective effects against a variety of diseases including bronchitis and enteritis [14, 15]. Navratilova et al. have reported that flavanones from PTF exert an antibacterial activity against Gram-negative bacterial species [14]. Ali et al. have shown that the chloroform extract of PTF, as well as the ursolic acid isolated from this extract, have been shown to improve N-diethylnitrosamine (NDEA)-induced heaptocarcinogenesis in rats [16]. Recently, experimental results from Ryu et al. indicated that the ethyl acetate fraction of PTF and new compounds isolated from this fraction have anti-inflammatory effects on TNF-α- induced inflammatory response in A549 airway epithelial cells by reducing interleukin-8 (IL-8), which is associated with airway inflammation [15]. Based on this result the protective effect of PTF in airway inflammation in ALI was evaluated using experimental animal models of lipopolysaccharide (LPS)-induced ALI.

PTF extraction preparation

PTF was collected at Sancheong (Republic of Korea) and formally identified by a researcher of the Korea Research Institute of Bioscience and Biotechnology (KRIBB). A voucher specimen was deposited in the herbarium of KRIBB (KRIB 0059121-0059123). A total of 3.8 kg powder-dried PTF was extracted 100% methanol (18 L × 3) overnight at room temperature (RT). The methanol extract was combined and concentrated in vacuo at 40℃ to obtain a dried extract [15].

Cell culture

A RAW264.7 murine macrophage cell line was obtained from American Type Culture Collection (ATCC), and maintained in DMEM supplemented with 10% fetal bovine serum and 1% antibiotic/antimycotic reagent at 37℃ in a humidified atmosphere with 5% CO2. To determine cell viability, cells were seeded into 96-well plates at a density of 1 × 104 cells/well and were maintained with PTF (10, 20 and 40 μg/ml) at 37℃ in 5% CO2 for 24 h, and subsequently MTT assays were carried out as previously described [17]. To detect the secretion of NO, TNF-α and IL-6, cells were seeded at a density of 2.5 × 104 cells per well onto 96-well plates and were then treated with 10 or 20 μg/ml PTF for 16 h in the absence or presence of LPS (500 ng/ml).

Mouse model of LPS-induced ALI

Male C57BL/6 mice (n = 30; age, 6 weeks old; body weight, 18 ± 1 g) were purchased from Koatech Co., Ltd. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the KRIBB (KRIBB-AEC-21111). To induce ALI, mice were administered LPS intranasally, as previously described [6]. The experimental groups used for the in vivo study were divided into the following five groups: Normal control (NC group), ALI (LPS only group), LPS + dexamethasone (DEX; LPS + 1 mg/kg DEX group), LPS + PTF 10 (LPS + 10 mg/kg PTF group) and LPS + PTF 20 (LPS + 20 mg/kg PTF group). Oral administration of PTF or DEX was performed on days 1-3. On day 3, 1 h after PTF or DEX administration, mice were intranasally administered LPS (0.5 mg/kg LPS per mouse). DEX was used as the positive control.

Measurement of macrophage number and cytokine secretion in bronchoalveolar lavage fluid (BALF)

To detect the numbers of macrophages and the levels of TNF-α, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production, BALF was isolated from mice. Briefly, on day 5, a mixture of Zoletil (30-50 mg/kg i.p.; Virbac) and xylazine (5-10 mg/kg i.p.; bayer-Korea, Ltd.) was intraperitoneally injected for anesthesia, as previously described [18]. The trachea was then intubated using a cannula and ice-cold PBS (700 μl) was infused into the trachea for BALF collection. BALF cells were transferred onto glass slides using Cytospin (1,000 rpm, 5 min, RT) [19] and stained with Diff-Quik® staining solution to distinguish the morphological traits of macrophages. Subsequently, the number of macrophages was measured using light microscopy (magnification, x400). The secretion levels of TNF-α, IL-6 and MCP-1 in the BALF supernatant were detected using the corresponding ELISA kits. The levels of protein concentration in BALF was detected by BCA assay.

Western blotting

Following BALF collection, mice were sacrificed using cervical dislocation, as previously described [18]. Lung tissue was isolated from mice, and lung tissue lysate was prepared by homogenization in lysis buffer, as previously described [20]. Protein concentration was determined using a BCA assay. Proteins were separated using SDSPAGE, and separated proteins were then transferred from the gel onto the PVDF membranes. The membranes were incubated in blocking solution at RT and maintained at 4℃ overnight with primary antibodies against iNOS (cat. no. 905-431; dilution, 1:1,000; Enzo Life Sciences, Inc.), COX-2 (cat. no. sc-1747, dilution, 1:1,000; Santa Cruz Biotechnology, Inc.), phosphorylated (p)-p38 (cat. no. 9211), p-JNK (cat. no. 4668), p- ERK (cat. no. 9101), p-p65 (cat. no. 3033), p-IκBα (cat. no. 2859), p38 (cat. no. 9212), JNK (cat. no. 9252), ERK (cat. no. 9102), p65 (cat. no. 8242) and β-actin (cat. no. 4967; dilution, 1;1,000; Cell Signaling Technology, Inc.). Subsequently, the membranes were washed with Trisbuffered saline with Tween 20 at RT and secondary antibodies were maintained with each membrane. An ECL kit was then used to visualize proteins.

Histological analysis

On day 5, the isolated lung from mice was washed with PBS, fixed with 10% formalin and embedded in paraffin to detect histological changes. Subsequently, a microtome was used to cut 4-μm paraffin-embedded lung sections, and hematoxylin and eosin (H&E) staining solution was used to stain the lung section [20].

Statistical analysis

Values are presented as the mean ± SD. One-way ANOVA with Tukey’s multiple comparison post-hoc test was used to determine significant differences among multiple groups (SPSS 20.0 IBM Corp.). p < 0.05 was considered to indicate a statistically significant difference.

Inhibitory effect of PTF on inflammatory cell influx in ALI mice

ALI was provoked by intranasal LPS administration (Fig. 1). The results obtained from H&E staining indicated that the degree of inflammatory cell influx was markedly increased near the airways of the lungs of LPS-induced ALI mice, which was suppressed by PTF pretreatment (Figs. 2A and B).

Figure 1.Experimental design for ALI induction in mice and treatment of PTF or DEX. PTF (10 or 20 mg/kg) or DEX (1 mg/ kg) was orally administrated to C57BL/6 mice from days 1-3. On day 3, LPS was intranasally administered 1 h after PTF or DEX treatment. BALF collection and lung tissue isolation were performed on day 5. ALI, acute lung injury; DEX, dexamethasone; PTF, Paulownia tomentosa fruits extract; LPS, lipopolysaccharide; BALF, bronchoalveolar lavage fluid.

Figure 2.PTF reduces inflammatory cell recruitment and molecules in the lungs of ALI mice. The existence of inflammatory cells near the airway epithelium in the lungs of mice was confirmed by H&E staining (A, magnification, x100; scale bar, 100 μm: B, magnification, x200; scale bar, 50 μm, respectively). (C) The macrophage number in the BALF of mice was detected using Diff-Quik® staining and light microscopy. The levels of (D) TNF-α, (E) IL-6 and (F) MCP-1 in BALF were determined using ELISA kits. (G) The levels of protein in BALF were determined using BCA assays. Data are expressed as the mean ± SD. Data are expressed as the mean ± SD. #p < 0.05 compared to NC group; *p < 0.05 compared to LPS group. PTF, Paulownia tomentosa fruits extract; DEX, dexamethasone; BALF, bronchoalveolar lavage fluid; PTF, P. tomentosa fruits; H&E, hematoxylin and eosin; NC, normal control; LPS, lipopolysaccharide; MCP-1, monocyte chemoattractant protein-1.

Inhibitory effect of PTF on macrophage recruitment and inflammatory molecule production in ALI mice

The results obtained from Diff-Quik® staining showed that the marked increase in macrophage numbers was confirmed in the BALF of ALI mice, a trend that was reduced following pretreatment with PTF (Fig. 2C). In addition, ELISA results indicated that the increase in TNF-α, IL-6 and MCP-1 secretion in the BALF of ALI mice was reduced by PTF (Figs. 2D-F). In addition, PTF reduced the upregulation of total protein content in the BALF of ALI mice (Fig. 2G). These results showing that PTF could ameliorate airway inflammation by inhibiting the influx of inflammatory cells and the production of inflammatory molecules in the LPS-induced ALI mice.

Inhibitory effect of PTF on iNOS and COX-2 expression in ALI mice

The western blotting results showed that the increased expression of iNOS in the lungs of ALI mice was ameliorated by PTF pretreatment (Figs. 3A and B). Similar to that of iNOS, the increased expression of COX-2 in the lungs of ALI mice was also suppressed by PTF pretreatment (Figs. 3A and B). These results indicate that PTF possesses anti-inflammatory effect in the LPS-induced ALI mice by suppressing the expression of iNOS and COX-2.

Figure 3.PTF inhibits iNOS and COX-2 expression in the lungs of ALI mice. (A) The expression of iNOS and COX-2 was detected by western blotting. (B) The quantification of iNOS and COX-2 was performed using densitometric analysis. Data are expressed as the mean ± SD. #p < 0.05 compared to NC group; *p < 0.05 compared to LPS group. iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2.

Inhibitory effect of PTF on MAPK activation in ALI mice

Next, the inhibitory effect of PTF on MAPK activation was evaluated using western blotting. The results revealed that the phosphorylation of p38 was markedly upregulated in the lungs of ALI mice, while this trend was reduced by PTF (Figs. 4A and B). Consistent with this result, PTF exerted an inhibitory effect on JNK and ERK phosphorylation in the lungs of ALI mice (Figs. 4A and B). Thus, these results suggest that PTF may exert anti-inflammatory effects by controlling MAPKs signaling pathways in the LPS-induced ALI mice.

Figure 4.PTF suppresses MAPK activation in the lungs of ALI mice. (A) The levels of MAPK phosphorylation were determined using western blotting. (B) The quantification of p-p38, p-JNK and p-ERK was performed using densitometric analysis. Data are expressed as the mean ± SD. #p < 0.05 compared to NC group; *p < 0.05 compared to LPS group.

Inhibitory effect of PTF on NF-κB activation in ALI mice

Based on the suppressive effect of PTF on inflammatory cytokine and chemokine secretion in ALI mice, the inhibitory effect of PTF on NF-κB activation was evaluated by western blotting. A significant increase in NF-κB p65 and IκBα phosphorylation was observed in the lungs of ALI mice, which was suppressed by PTF pretreatment (Figs. 5A and B). These results suggest that PTF may have anti-inflammatory properties by negatively regulating NF-κB signaling pathways in the LPS-induced ALI mice.

Figure 5.PTF downregulates NF-κB activation in the lungs of ALI mice. (A) The levels of NF-κB activation were determined by western blotting. (B) The quantification of p-NF-κB p65 and p-IκBα was performed using densitometric analysis. Data are expressed as the mean ± SD. #p < 0.05 compared to NC group; *p < 0.05 compared to LPS group.

Anti-inflammatory effect of PTF in LPS-stimulated RAW264.7 macrophages

Subsequently, it was evaluated whether PTF could exert an anti-inflammatory effect in LPS-stimulated RAW264.7 macrophages. Through the MTT assays, the outstanding cell death was not confirmed until 20 μg/ml PTF (Fig. 6A). Based on the result of MTT assays, the dosage of PTF (10 and 20 μg/ml) was selected. The results obtained from the NO assay showed that 500 ng/ ml LPS induced a notable increase in NO generation (Fig. 6B). However, this increase was decreased by PTF pretreatment. In addition, PTF had an inhibitory effect on LPS-induced TNF-α and IL-6 secretion in RAW264.7 macrophages (Figs. 6C and D). Collectively, these results present that PTF has anti-inflammatory effect in LPS-stimulated macrophages via suppressing the generation of inflammatory molecules.

Figure 6.PTF reduces NO, TNF-α and IL-6 secretion in LPS-stimulated RAW264.7 cells. (A) Cell viability was determined using MTT assay. (B) The level of nitrite was determined using NO assay. The levels of (C) TNF-α and (D) IL-6 were determined using ELISA. Data are expressed as the mean ± SD. #p < 0.05 compared to NC group; *p < 0.05 compared to LPS group.

The increase in TNF-α, IL-6 and MCP-1 is an important marker for ALI [21] and macrophages are the main producer of these molecules [2]. Macrophage-derived iNOS and COX-2 cause hyper-inflammation and edema in ALI, respectively [7, 8, 22]. In the present study, PTF ameliorated airway inflammation by suppressing the recruitment of macrophages and the production of cytokines (TNF-α and IL-6), a chemokine (MCP-1) and mediators (iNOS and COX-2) in ALI mice. Furthermore, PTF had inhibitory effect on BALF protein, which is related to lung edema [18]. Generally, the inhibitory effects of 20 mg/kg PTF on production of inflammatory molecules were comparable to that of 1 mg/kg DEX, which was used as a positive control. Furthermore, similar to in vivo results, PTF inhibited NO, TNF-α and IL-6 secretion in LPS-stimulated RAW264 macrophages. These aforementioned findings suggested that PTF may have an ameliorative effect on bacterial infectioninduced inflammation in ALI.

As mentioned earlier, the expression of inflammatory cytokines, chemokines and mediators is associated with MAPK and NF-κB activation in ALI development [2, 23, 24]. Therefore, targeting MAPK and NF-κB signaling pathways has been suggested as a potential strategy for the prevention or treatment of ALI [6, 13, 18]. In the present study, PTF reduced TNF-α, IL-6 and MCP-1 secretion, as well as iNOS and COX-2 expression, in ALI mice. It was therefore expected that PTF could regulate MAPK and NF-κB activation. As expected, PTF exerted regulatory effect on endotoxininduced MAPK/NF-κB activation.

Accumulating evidence shows the beneficial effect of natural plants in acute or chronic inflammatory lung diseases, such as ALI [6, 11, 25-28]. This effect is based on the suppression of inflammatory molecules and cell recruitment, and the regulation of MAPK/NF-κB activation. In the previous study, PTF exerted anti-inflammatory effect in activated-airway epithelial cells by suppressing IL-8 [15]. Although previous study from Ryu et al. showed the anti-inflammatory effect of PTF in human alveolar basal epithelial cells [15], the protective effect and potential therapeutic mechanism of PTF in LPS-induced pulmonary inflammation was not investigated. Herein, we confirmed that PTF inhibited macrophage recruitment and MCP-1 secretion in vivo. PTF also ameliorated airway inflammation by suppressing TNF-α and IL-6. In addition, PTF had a regulatory effect on MAPK/NF-κB activation. Furthermore, PTF inhibited macrophage-derived NO, TNF-α and IL-6 in vitro. Collectively, PTF had protective effects in LPS-induced inflammatory response in both in vivo and in vitro. Through previous and present results, it has been revealed that PTF exerted anti-inflammatory effect in both airway epithelial cells/macrophages and experimental animal model of ALI. Furthermore, toxic signs, such as dyspnea and vomiting, were not observed following PTF administration. Further experiments, which show hepatotoxicity tests may highlight the utility and applicability of PTF. In conclusion, these results revealed the beneficial effect of PTF on the progression of airway inflammation and its underlying mechanism in endotoxin-induced ALI, suggesting that PTF may be used as adjuvant treatment for ALI.

This study was supported by grants from the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program (KRIBB) of the Republic of Korea (grant. nos. KGM5522211 and KGS1232221).

The authors have no financial conflicts of interest to declare.

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