Meso-Dihydroguaiaretic Acid Ameliorates Acute Respiratory Distress Syndrome through Inhibiting Neutrophilic Inflammation and Scavenging Free Radical

Abstract

The pathogenesis of acute respiratory distress syndrome (ARDS) is very complex. Patients with ARDS still suffer high mortality rates. Infiltration and activation of neutrophils in lungs are critical pathogenic factors in ARDS. In this study, we demonstrate that meso-dihydroguaiaretic acid (MDGA), a natural lignan, inhibits inflammatory responses in human neutrophils and ameliorates ARDS in mice. MDGA inhibited superoxide anion generation and elastase release in various G-protein coupled receptor agonists-induced human neutrophils. However, MDGA did not alter superoxide anion generation and elastase activity in cell-free systems. These results suggest that the anti-inflammatory effects of MDGA are mediated by regulating cellular signals in human neutrophils. In consistent with this, MDGA suppressed phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in activated human neutrophils. Moreover, MDGA inhibited CD11b expression and adhesion in activated human neutrophils. Interestingly, MDGA reduced reactive oxygen species (ROS) generation but not superoxide anion generation in protein kinase C (PKC) activator-induced human neutrophils, suggesting that MDGA may also have ROS scavenging ability. Indeed, MDGA showed strong free radical scavenging activity in cell-free assays. Significantly, MDGA suppressed PKC-induced neutrophil extracellular trap formation. Additionally, treatment of MDGA attenuated neutrophil infiltration and lung damage on lipopolysaccharide-induced ARDS in mice. In conclusion, our results demonstrate that MDGA has anti-neutrophilic inflammatory effects and free-radical scavenging activity. We also suggest that MDGA has potential to serve as a lead for developing new therapeutics to treat ARDS.

Lignans as Pharmacological Agents in Disorders Related to Oxidative Stress and Inflammation: Chemical Synthesis Approaches and Biological Activities

“…Meso-dihydroguaiaretic acid demonstrated strong free radical scavenging activity in various cell-free assays, modulated MAPKs/Akt signal pathways in G-protein coupled receptor agonists-induced human neutrophils, and reduced ROS generation. In a murine model of LPS-induced acute respiratory distress syndrome, the lignan application showed anti-neutrophilic inflammatory effects [ 58 ].…”

Targeting formyl peptide receptor 1 with anteiso‐C13‐surfactin for neutrophil‐dominant acute respiratory distress syndrome

“…Our data showed that IA‐1 attenuated elastase release in LPS‐induced inflamed lung tissue and in activated human neutrophils. Oxidative stress induced by excess ROS generation leads to proinflammatory cytokine production and lung tissue damage in ARDS (Lee et al, 2022). In our study, LPS‐induced oxidative stress was diminished in IA‐1‐pretreated mice compared to sham‐treated mice.…”

Antioxidant Activity and Volatile Oil Analysis of Ethanol Extract of Phoebe zhennan S. Lee et F. N. Wei Leaves

“…Free radicals break down cells and tissues, affecting metabolic function and causing varying degrees of health problems. For example, common cancers [1], aging [2], diabetes [3], respiratory diseases [4], nervous system diseases [5], and so on are all related to oxidative free radicals. If excessive oxidative free radicals are eliminated, many aging and related diseases caused by free radicals can be prevented.…”