Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

Abstract

Nicotinic α-7 acetylcholine receptor (nAChRα7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of α7nAChR as a therapeutic target, we evaluated whether PNU-282987, an α7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL-1β, TNF-α, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P< 0.05). In addition, lung NF-κB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9 and -2 cells, whereas the number of tissue inhibitor of metalloproteinase-1 cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, an agonist of α7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on α7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Câmara, N. O. S., Wensing, L. A., Prado, V. F., Tibério, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the α7nAChR agonist PNU-282987 through changes in the macrophage profile.

Acetylcholine regulates pulmonary inflammation and facilitates the transition from active immunity to tissue repair during respiratory viral infection

“…Recently, loss of α7nAChR signal transduction was shown to decrease expression of the canonical M2 marker Arginase-1(52). In addition, use of an α7nAchR agonist decreased the LPS-induced inflammatory response and reversed the inflammatory profile, particularly regarding M1 and M2 polarization, while also improving lung function and remodeling in a model of acute lung injury (15). Based on these findings and those in the current study, we hypothesize that ACh produced by cholinergic lymphocytes acts on macrophages to decrease pro-inflammatory cytokine release and initiate tissue repair during the recovery phase of respiratory viral infection.…”

“…LPS, E. coli), where injury is increased when cholinergic signaling is inhibited and decreased when it is augmented (15,42,50).…”

“…Signal transduction via the alpha-7 nicotinic ACh receptor (7-nAChR) decreases nuclear translocation of the Nf-κB transcription factor, ultimately reducing macrophage production of the pro-inflammatory cytokine TNF (10,14). Ligation of 7-nAChR significantly reduces lung injury and overall mortality in septic shock models (14,15). In addition, proinflammatory cytokines TNF, IFN-γ, and IL-6 are increased in mice lacking the 7-nAChR, further indicating that 7-nAChRs play a critical role in regulating macrophage-associated inflammation (16).…”

Modulation of neuroinflammation and memory dysfunction using percutaneous vagus nerve stimulation in mice

“…Cholinergic agonists can also affect microglial activation and improve cognitive outcomes after trauma and common perioperative complications, such as infection or stroke [31, 32]. Although pharmacological agonists attenuate inflammation in several disease models, they exert off-target effects in other organs, which likely affect multiple physiologic processes ranging from gastrointestinal motility to wound healing [29, 33–35]. VNS holds promise also for a more localized response and better patient-specific therapeutic outcomes with fewer side effects, especially through the implementation of targeted and minimally invasive approaches.…”

Manipulation of macrophage polarization by peptide-coated gold nanoparticles and its protective effects on acute lung injury

“…It is known that the activation of pulmonary macrophages played a critical role in the initiation and development of ALI/ARDS [8]. Recent studies suggested that reprograming macrophages toward M2 phenotype may be an effective strategy to treat ALI/ARDS and other inflammatory diseases [38,39]. Our previous study showed that P12 intervention increased the number of regulatory T (Treg) cells in the lung and draining lymph nodes of ALI mice [24].…”