Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease resulted
from airflow obstructions, and there is a driving requirement for novel and effective
preventive and therapeutic agents of COPD. Nuclear factor-erythroid 2-related factor
2 (Nrf2) has been regarded to be a promising therapeutic target for COPD. Resveratrol
is a natural Nrf2 activator with antioxidant and anti-inflammatory properties, however,
its application is limited by its relative low efficiency and poor bioavailability.
Herein, based on the skeleton of resveratrol, trans-4,4'-dihydroxystilbene (DHS) has
been firstly identified to be an Nrf2 activator, which is more potent than the well-known
sulforaphane (SF) and resveratrol. Our results indicate that DHS blocks Nrf2 ubiquitylation
through specifically reacting with Cys151 cysteine in Keap1 protein to activate Nrf2-regulated
defensive response, and thus enhances intracellular antioxidant capability. Furthermore,
DHS relieves lipopolysaccharide (LPS)-stimulated inflammatory response via inhibition
of NF-κB. Importantly, DHS significantly ameliorates pathological alterations (e.g.
infiltration of leukocytes and fibrosis), downregulates the levels of oxidant biomarkers
malondialdehyde (MDA) and 8-oxo-7,8-dihydro-2'-deoxyguanosin (8-oxo-dG), and inhibits
the overproductions of inflammatory mediators [e.g. tumor necrosis factor α (TNF-α),
cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9)] in a cigarette smoke
(CS)-induced pulmonary impairment mice model. Taken together, this study demonstrates
that DHS attenuates the CS-induced pulmonary impairments through inhibitions of oxidative
stress and inflammatory response targeting Nrf2 and NF-κB in vitro and in vivo, and
could be developed into a preventive agent against pulmonary impairments induced by
CS.