Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice
Highlights
► Kaempferol could alleviate tissue oxidative injury in LPS-induced ALI. ► Effect of kaempferol on ALI is attributed to mitigating pulmonary inflammatory response. ► Kaempferol exhibits a protective effect on ALI via suppression of MAPKs and NF-κB signaling pathways. ► Our findings support the potential use of kaempferol for ALI associated with infection by Gram-negative bacteria.
Introduction
Acute lung injury (ALI) and its severest form, acute respiratory distress syndrome (ARDS), are implicated in the development of multiple organ failure, which plays an essential role in the death of patients with sepsis, shock, trauma, pneumonia, multiple transfusions and pancreatitis [1]. A defining feature of ALI/ARDS is the intense inflammatory parenchymal process, resulting in lung tissue destruction, neutrophil infiltration and release of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 [2]. Moreover, these cytokines act in concert to promote PMN migration into the pneumonic interstitium and alveolar space. Activated neutrophils propagate inflammation and injury by production of reactive oxygen species (ROS) and proteolytic enzymes [3]. Over the past decades, despite increasing insights into ALI/ARDS pathobiology, its serious mortality (approximately 40%) involved is poorly understood and remains unacceptably high [1], [4].
Lipopolysaccharide (LPS), a primary component of endotoxin, has been recognized as the most important pathogen in the pulmonary inflammation and sepsis leading to ALI/ARDS [5]. LPS, activating numerous inflammatory cells [6], is believed to induce ALI through multiple signaling pathways. Toll-like receptor 4 (TLR4), which plays an important role in LPS recognition, triggers activation of an intracellular signaling pathway involving nuclear factor-кB (NF-кB), leading to the up-regulation of many genes responsible for the release of inflammatory mediators [3]. Studies have shown that reactive oxygen species (ROS), over-production in cases challenged by LPS, are directly implicated as the second messengers in activation of NF-κB [7]. Meanwhile, LPS induces mitogen-activated protein kinase (MAPK) activation, events that are likely responsible for a potential therapeutic target for ALI/ARDS [8], [9]. The mechanism of LPS-induced ALI/ARD is not completely elucidated, though previous studies have shown that participation of MAPKs and NF-кB is involved in its pathophysiology [10], [11]. Inspired by our precious studies [12], [13], we considered that a possible approach to the treatment of ALI/ARDS had evolved from remedies modifying MAPKs and NF-кB pathways combined with alleviation of inflammatory reaction and tissue oxidative injury in the lung. Agents with anti-inflammatory properties may therefore offer promise to this clinical problem.
Flavonoids, some naturally occurring polyphenolic compounds, have been suggested to exert a wide range of biological activities, including anti-tumor, antiatherogenic, antioxidant and anti-inflammatory activities [14], [15], [16]. Among the known flavonoids, kaempferol (Kae), a phytoestrogen and one of the most common dietary flavonoids, is widely distributed in tea, broccoli, gingko biloba, onions, grapes, apples, medicinal herbs and other plant sources [17]. Growing evidences have indicated that Kae has antioxidative [18], [19] and anti-inflammatory properties [20], [21]. Previous studies demonstrate that Kae reduces LPS-challenged IL-1β and TNF-α expression in activated macrophages [22] and inhibits TNF-α induced the translocation of NF-κB subunit p65 to the nucleus and the secretion of IL-6 and monocyte chemoattractant protein-1 (MCP-1) [23]. As mentioned above, these results can conclude that Kae is a potent antioxidative and anti-inflammatory agent and may modulate inflammatory process.
Considering that endotoxin or LPS derived from Gram-negative bacteria has been well recognized in the pathogenesis of ALI/ARDS [24]. Intranasal instillation of LPS, characterized by confined inflammation pattern to the lung without causing systemic inflammation, has been extensively used for establishing an experimental model of ALI for preliminary pharmacological studies of potential therapeutic drugs and agents [25]. In our present study, we explored the effect of Kae on LPS-induced acute lung injury in mice and the underlying mechanism, attempting to provide a new potential treatment for ALI from traditional Chinese herbal medicine.
Section snippets
Animals and materials
Adult male BALB/c mice, weighing approximately 18 to 20 g, were purchased from Shanghai Jingke Industrial Co., Ltd. (Shanghai, China). The experiments were approved by the Ethical Committee on Animal Research of Hunan Agricultural University. Mice were housed in microisolator cages and received food and water ad libitum. The laboratory temperature was maintained at 24 ± 1 °C, and relative humidity was maintained at 40–80%. All animal experiments were performed in accordance with the guide for the
Effects of kaempferol on LPS-induced mortality in mice
To evaluate the protective effect of Kae on mice with endotoxemia, Kae (25, 50 or 100 mg/kg) was administrated intragastrically 1 h prior to LPS injection. As shown in Fig. 1, the accumulative mortality during 72 h in high dose (100 mg/kg) of KaeLPS treatment group (50%) was significantly lower than that in the LPS group (85%, P < 0.01). However, no protection was observed when mice received Kae pretreatment at doses of 25 mg/kg (vs. LPS group, P = 0.334) and 50 mg/kg (vs. LPS group, P = 0.063).
Discussion
The objective of this investigation was to explore the protective effect of Kae on ALI/ARDS and the mechanisms involved. Some accumulated evidence has shown that Kae exerts potent anti-inflammatory effect in human endothelial cells [29]. Moreover, this compound can also effectively reduce LPS-elicited MAPKs and NF-κB activation and control proinflammatory mediators such as NO, PGE(2), TNF-α, IL-1β and ROS release from microglia stimulated with LPS [30]. In our present study, we demonstrated
Acknowledgment
This work was supported by the National Nature Science Foundation of China (no. 31072167).
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Xiaojun Chen and Xiaofeng Yang contributed equally to this work.