Butorphanol Promotes Macrophage Phenotypic Transition to Inhibit Inflammatory Lung Injury via κ Receptors

Abstract

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by diffuse inflammation of the lung parenchyma and refractory hypoxemia. Butorphanol is commonly used clinically for perioperative pain relief, but whether butorphanol can regulate LPS-induced alveolar macrophage polarization is unclear. In this study, we observed that butorphanol markedly attenuated sepsis-induced lung tissue injury and mortality in mice. Moreover, butorphanol also decreased the expression of M1 phenotype markers (TNF-α, IL-6, IL-1β and iNOS) and enhanced the expression of M2 marker (CD206) in alveolar macrophages in the bronchoalveolar lavage fluid (BALF) of LPS-stimulated mice. Butorphanol administration reduced LPS-induced numbers of proinflammatory (M1) macrophages and increased numbers of anti-inflammatory (M2) macrophages in the lungs of mice. Furthermore, we found that butorphanol-mediated suppression of the LPS-induced increases in M1 phenotype marker expression (TNF-α, IL-6, IL-1β and iNOS) in bone marrow-derived macrophages (BMDMs), and this effect was reversed by κ-opioid receptor (KOR) antagonists. Moreover, butorphanol inhibited the interaction of TLR4 with MyD88 and further suppressed NF-κB and MAPKs activation. In addition, butorphanol prevented the Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF)-mediated IFN signaling pathway. These effects were ameliorated by KOR antagonists. Thus, butorphanol may promote macrophage polarization from a proinflammatory to an anti-inflammatory phenotype secondary to the inhibition of NF-κB, MAPKs, and the TRIF-mediated IFN signaling pathway through κ receptors.

The impact of stress and anesthesia on animal models of infectious disease

“…The authors induced lung tissue injury in mice via sepsis resulting from intraperitoneal lipopolysaccharide injection, then administered butorphanol to one group of mice whilst the other group remained untreated. They found that mice administered butorphanol had lower numbers of pro-inflammatory and higher numbers of anti-inflammatory macrophages compared to untreated mice ( 128 ). A reduction in pro-inflammatory macrophages result in a reduction in IL-1β, IL-6, and IL-12, whilst an increase in anti-inflammatory macrophages causes an increase in cytokines including IL-10 ( 129 ).…”

“…Butorphanol is another commonly used opioid in laboratory animal medicine and is known to have dose-dependent antiinflammatory and immunosuppressive effects (127). One mechanism of the anti-inflammatory action of butorphanol was demonstrated in a study by Luan et al (128). The authors induced lung tissue injury in mice via sepsis resulting from intraperitoneal lipopolysaccharide injection, then administered butorphanol to one group of mice whilst the other group remained untreated.…”

Classic Signaling Pathways in Alveolar Injury and Repair Involved in Sepsis-Induced ALI/ARDS: New Research Progress and Prospect

“…For sepsis-induced ALI/ARDS, new drug therapy studies related to this pathway have shown some success. For example, butorphanol significantly reduced sepsis-induced lung tissue injury and mortality by promoting M2 macrophage polarization and inhibiting M1 macrophage polarization through the NF- κ B pathway in a mouse model of sepsis-induced ALI [ 18 ]. M1 macrophages produce proinflammatory factors, such as reactive oxygen species and reactive nitrogen intermediates, as well as the cytokines tumor necrosis factor-alpha (TNF- α ) and IL-6 [ 19 , 20 ].…”

Macrophage Subsets and Death Are Responsible for Atherosclerotic Plaque Formation

“…TRIF could activate the transcription factor interferon-responsive factor 3 (IRF3) and then promotes IFNα and IFNβ secretion. Therefore, interferons bind to the interferon receptor (IFNAR) to activate the transcription factor STAT1 to skew macrophages to M1-like or M1 polarization ( 35 ) M1 macrophages are pro-inflammatory to destruct tissue and secrete cytokines, for example, IL-1β, IL-6, TNF-α, and IL-12 ( 36 ). Pro-inflammatory cytokines sustain to recruit immune cells, causing many macrophages to migrate to lesion sites.…”