In this issue of HEPATOLOGY, Marques et al.23 report on a study demonstrating that DAMP molecules released from necrotic hepatocytes recruit and activate neutrophils in the liver, which, in turn, amplify AILI. Three experimental approaches were employed to elucidate the pathological role of neutrophils in AILI. Consistent with published reports,24, 25 the present study shows that neutrophil depletion by an anti-Gr-1 antibody significantly attenuates AILI. Furthermore, the combined use of a CXC chemokine receptor 2 antagonist and a formyl peptide receptor 1 (FPR1) antagonist also blocks hepatic recruitment of neutrophils and mitigates AILI. This approach is based on the

investigators’ previous finding that an intravascular gradient of chemokines and mitochondria-derived formyl peptides collaboratively guide neutrophils Z-VAD-FMK supplier to sites of ABT-263 liver necrosis.26 These two separate in vivo studies demonstrate that liver injury initiated by APAP challenge is amplified by infiltrating neutrophils. The investigators

further examined the cytotoxic potential of neutrophils against hepatocytes. Neutrophils isolated from healthy individuals were cocultured with APAP-treated HepG2 cells. Data show that the cytotoxicity of HepG2 cells is enhanced by neutrophils in a cell-contact–dependent manner, and that necrotic HepG2 cells significantly increase reactive oxygen species production by netrophils. Collectively, these findings provide evidence to support a pathological role of neutrophils during AILI. Traumatic injury is known to cause “septic-like” systemic MCE公司 inflammatory response in the absence of infection.27 The underlying mechanism is recently elucidated by the detection of mitrochondrial DNA (mtDNA) and formyl peptides released in the serum of trauma patients.28 Circulating mitochondrial DAMPs activate neutrophils through Toll-like receptor 9 (TLR-9) and FPR1, respectively, thereby eliciting neutrophil-mediated organ injury.28 Because APAP causes mitochrondria damage, it is likely that mitochondrial

contents are released into the circulation. Evidence supporting this hypothesis is provided by a recent study detecting circulating mitochondrial biomarkers, including mtDNA and glutamate dehydrogenase, in the serum of patients with AILI.29 Similarly, the present study shows a significant increase in serum mtDNA levels in acute liver failure patients, compared to healthy volunteers. The elevation of circulating mtDNA is also observed in APAP-treated mice. The effect of mtDNA release on AILI is revealed by a significant decrease of liver injury in TLR-9−/− mice, compared to wild-type mice. This finding is consistent with a published report of protection against AILI by TLR-9 antagonists and in TLR-9−/− mice.30 APAP-induced liver failure is accompanied by other tissue complications, such as encephalopathy, coagulopathy, renal failure, metabolic derangements, cardiovascular compromises, and severe lung injury.