Sevoflurane Inhibits Nuclear Factor-κB Activation in Lipopolysaccharide-Induced Acute Inflammatory Lung Injury via Toll-Like Receptor 4 Signaling

Abstract

BackgroundInfection is a common cause of acute lung injury (ALI). This study was aimed to explore whether Toll-like receptors 4 (TLR4) of airway smooth muscle cells (ASMCs) play a role in lipopolysaccharide (LPS)-induced airway hyperresponsiveness and potential mechanisms.Methods In vivo: A sensitizing dose of LPS (50 µg) was administered i.p. to female mice before anesthesia with either 3% sevoflurane or phenobarbital i.p. After stabilization, the mice were challenged with 5 µg of intratracheal LPS to mimic inflammatory attack. The effects of sevoflurane were assessed by measurement of airway responsiveness to methacholine, histological examination, and IL-1, IL-6, TNF-α levels in bronchoalveolar lavage fluid (BALF). Protein and gene expression of TLR4 and NF-κB were also assessed. In vitro: After pre-sensitization of ASMCs and ASM segments for 24h, levels of TLR4 and NF-κB proteins in cultured ASMCs were measured after continuous LPS exposure for 1, 3, 5, 12 and 24h in presence or absence of sevoflurane. Constrictor and relaxant responsiveness of ASM was measured 24 h afterwards.ResultsThe mRNA and protein levels of NF-κB and TLR4 in ASM were increased and maintained at high level after LPS challenge throughout 24h observation period, both in vivo and in vitro. Sevoflurane reduced LPS-induced airway hyperresponsiveness, lung inflammatory cell infiltration and proinflammatory cytokines release in BALF as well as maximal isometric contractile force of ASM segments to acetylcholine, but it increased maximal relaxation response to isoproterenol. Treatment with specific NF-κB inhibitor produced similar protections as sevoflurane, including decreased expressions of TLR4 and NF-κB in cultured ASMCs and improved pharmacodynamic responsiveness of ASM to ACh and isoproterenol.ConclusionsThis study demonstrates the crucial role of TLR4 activation in ASMCs during ALI in response to LPS. Sevoflurane exerts direct relaxant and anti-inflammatory effects in vivo and in vitro via inhibition of TLR4/NF-κB pathway.

Personalized analysis of pathway aberrance induced by sevoflurane and propofol

“…Three pathways involved in vitamin metabolism were also significantly altered, which was consistent with the fact that vitamin C supplementation offers significant protection against anesthetic-induced neurotoxicity and behavioral alterations, as proposed by Xu et al ( 27 ). Seven pathways involving the Toll like receptor (TLR) were significantly altered, which is consistent with the report by Sun et al which demonstrated that sevoflurane exerts direct relaxant and anti-inflammatory effects by inhibiting the TLR4/ nuclear factor-κB pathway ( 28 ). The present results indicate that these identified pathways were closely related to sevoflurane treatment, and suggest that special attention should be given to patients with correlated diseases when administering sevoflurane anesthesia.…”

Upregulation of miRNA‑140‑5p inhibits inflammatory cytokines in acute lung injury through the MyD88/NF‑κB signaling pathway by targeting TLR4

“…ALI, a kind of severe lung infectious disease, is mainly caused by bacterial infection-induced sepsis. LPS, the main component of the cell wall of gram negative bacteria, is the major pathogenic factor of ALI ( 9 ). LPS interacts with the receptor on the effector cell membrane to initiate an intracellular signal transduction system, which causes the activation of nuclear transcription factor NF-κB, to initiate gene transcription and to produce a variety of proinflammatory cytokines.…”

“…Nuclear factor (NF)-κB collectively refers to many DNA binding proteins which specifically bind to κB site of promoters of a variety of genes, and promotes transcription, which plays an important role in immune response, inflammatory response and cell growth regulation ( 7 ). NF-κB signal pathway is the most important downstream pathway among all signal transduction pathways mediated by LPS, suggesting that TLR4/NF-κB pathway may be the key target to trigger inflammatory response and organ injury ( 9 ). Zhang and Xu ( 10 ) has indicated that miRNA-140-5p regulates hypoxia-mediated human pulmonary artery smooth muscle cell proliferation.…”

Picrasma quassiodes (D. Don) Benn. attenuates lipopolysaccharide (LPS)-induced acute lung injury

“…ALI is characterized by an uncontrolled inflammatory response in the lungs, resulting in airway dysfunction (3). The most common cause of ALI is an exposure to the structural component of a Gramnegative bacterial membrane, lipopolysaccharide (LPS) (4). In response to bacterial LPS stimulation, neutrophils migrate across the endothelium and epithelium into the alveolar space, and are subsequently activated, causing the excessive production of proinflammatory molecules, such as reactive oxygen species (ROS) and pro-inflammatory cytokines (5).…”