Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: Therapeutic potential of NOX2 and p38MAPK inhibitors

Abstract

Neutrophil is a significant contributor to ischemia reperfusion (IR) induced liver tissue damage. However, the exact role of neutrophils in IR induced innate immune activation and liver damage is not quite clear. Our study sheds light on the role of chronic oxidative stress end products in worsening the IR inflammatory process by neutrophil recruitment and activation following liver surgery. We employed specific inhibitors for molecular targets-NOX2 (NADPH oxidase 2) and P38 MAPK (Mitogen activated protein kinase) signal to counteract neutrophil activation and neutrophil extracellular trap (NET) release induced liver damage in IR injury. We found that acrolein initiated neutrophil chemotaxis and induced NET release both in vitro and in vivo. Acrolein exposure caused NET induced nuclear and mitochondrial damage in HepG2 cells as well as aggravated the IR injury in rat liver. Pretreatment with F-apocynin and naringin, efficiently suppressed acrolein induced NET release in vitro. Notably, it suppressed the expression of inflammatory cytokines, P38MAPK-ERK activation, and apoptotic signals in rat liver exposed to acrolein and subjected to IR. Moreover, this combination effectively attenuated acrolein induced NET release and hepatic IR injury. In the current study we have shown that the acrolein accumulation in liver due to chronic stress, is responsible for neutrophil recruitment and its activation leading to NET induced liver damage during surgery. Our study shows that therapeutic targeting of NOX2 and P38MAPK signaling in patients with chronic hepatic disorders would improve post operative hepatic function and survival.

E-Cigarette Use Causes a Unique Innate Immune Response in the Lung, Involving Increased Neutrophilic Activation and Altered Mucin Secretion

“…NETs are the result of a specific type of cell death called NETosis (15) and consist of chromatin filaments and specific granule proteins, including neutrophil elastase (NE) and myeloperoxidase (MPO) (16), which have been associated with the bronchial inflammation and structural damage observed in diseases, such as cystic fibrosis and COPD (17,18). Although NET formation is an antibacterial immune response, it has also been shown to be triggered by constituents of smoke and e-cigarette vapors, such as acrolein (19). E-cigarettes are fairly new products, and data on the effects of their long-term use remain scarce.…”

Upregulation of FSHR and PCNA by administration of coenzyme Q10 on cyclophosphamide‐induced premature ovarian failure in a mouse model

“…It has been implicated that CTX, in the presence of cytochrome P450, is metabolized into two unstable and transient intermediates namely, 4‐hydroxycyclophosphamide and aldophosphamide which are both, in turn, converted into two stable toxic compounds, namely acrolein (propenal, C 3 H 4 O) and phosphoramide mustard (H 6 N 3 OP) (Figure A) . Between these two chemical agents, acrolein, as a highly electrophilic and α, β‐unsaturated aldehyde, has greater toxicity as it generates higher levels of ROS …”

Neutrophil Extracellular Traps Induced in Rheumatoid Arthritis Conditioned Animals are Inhibited Through Selenium Nanoparticles Supplementation

“…Since oxidative stress is considered as one of the main mediator that induces the NETs [36,37], we have assayed the intracellular oxidative stress neutrophils of different experimental animals. Quite interestingly we found that oxidative stress is increased (P < 0.001) in neutrophils isolated from RA rats than that of normal (Fig.…”