Research Paper Volume 12, Issue 13 pp 13400—13421

Penehyclidine hydrochloride inhibits renal ischemia/reperfusion-induced acute lung injury by activating the Nrf2 pathway

Zhaohui Liu1,2, , Yan Li2, , Lili Yu2, , Yulin Chang2, , Jingui Yu1, ,

  • 1 Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  • 2 Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou, Hebei, China

Received: February 13, 2020       Accepted: May 25, 2020       Published: July 11, 2020
How to Cite

Copyright © 2020 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The nuclear factor (NF)-κB and NOD-like receptor protein 3 (NLRP3) pathways promote inflammatory signaling that injures the kidneys, whereas the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway promotes anti-inflammatory signaling that inhibits oxidative damage. Penehyclidine hydrochloride (PHC) inhibits NF-κB and activates Nrf2 signaling. We investigated whether PHC induces communication between the Nrf2 and NF-κB/NLRP3 pathways, thereby protecting against renal ischemia/reperfusion (rI/R)-induced lung inflammation. Rat alveolar macrophages (NR8383 cells) were stimulated for 24 h with PHC with or without brusatol (a Nrf2 antagonist), after which they were treated for 4 h with tert-butyl hydroperoxide (10 mM). PHC Nrf2-dependently alleviated tert-butyl hydroperoxide-induced reactive oxygen species production in alveolar macrophages. Additionally, wild-type and Nrf2−/− rats were each divided into four groups: (1) sham, (2) PHC (1 mg/kg), (3) rI/R and (4) rI/R + PHC (1 mg/kg). PHC markedly induced the Nrf2 and adenosine monophosphate-activated protein kinase pathways and suppressed rI/R-induced NF-κB and NLRP3 activation in the lungs. Nrf2 deficiency diminished the ability of PHC to ameliorate rI/R-induced histopathological alterations and reactive oxygen species release in the lungs; however, PHC inhibited NLRP3 signaling Nrf2-dependently, while it inhibited NF-κB signaling Nrf2-independently. Our findings demonstrate the beneficial effects of PHC on rI/R-induced lung inflammation.


PHC: penehyclidine hydrochloride; NLRP3: NOD-like receptor protein 3; Nrf2: nuclear factor erythroid-2 related factor 2; ROS: reactive oxygen species; Keap1: Kelch-like ECH-associated protein 1; AMPK: adenosine monophosphate-activated protein kinase; GSK3β: glycogen synthase kinase 3β; NF-κB: nuclear factor kappa B; rI/R: renal ischemia/reperfusion; t-BHP: tert-butyl hydroperoxide; CC: compound C; MDA: malondialdehyde; MPO: myeloperoxidase; GSH: glutathione; SOD: superoxide dismutase; CCK8: Cell Counting Kit 8; H&E: hematoxylin and eosin; BALF: bronchoalveolar lavage fluid; ELISA: enzyme-linked immunosorbent assay; DCFH-DA: 2’, 7’-dichlorofluorescein diacetate.