T cell–derived MPs may give rise to their exploitation as
novel diagnostic markers and potential antifibrotic agents. LX-2 HSCs were kindly donated by Scott L. Friedman. We thank Gunda Millonig (Beth Israel Deaconess Medical Center) and Veronika Lukacs-Kornek (Dana-Farber Cancer Institute) for help with initial FACS experiments and Franck Grall (Beth Israel Deaconess Medical selleck Center) for help with mass spectroscopy. Additional Supporting Information may be found in the online version of this article. “
“Acetaminophen (APAP) is one of the most commonly used drugs for treating pain and fever. Although it is safe at therapeutic dosage levels, overdose of APAP causes severe liver injury (APAP-induced liver injury; AILI), with the potential to progress to liver failure. Up to 40% of patients who suffer from liver failure will die (or undergo liver transplant).1 Data combined from 22 specialty medical centers in the United States revealed that AILI accounts for approximately half of acute liver failure cases and results in more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths each year.1 AILI, APAP-induced liver injury; APAP, acetaminophen; ATP, adenosine triphosphate; DAMP, damage-associated molecular pattern; FPR1, formyl peptide receptor 1; IL, interleukin; mtDNA, mitrochondrial
DNA; NAPQI, N-acetyl-p-benzoquinone BGJ398 concentration imine; TLR-9, Toll-like receptor 9. APAP hepatotoxicity is initiated by the generation of a chemically reactive metabolite (N-acetyl-p-benzoquinone imine; NAPQI). NAPQI depletes liver glutathione and covalently binds to cellular proteins, thereby causing mitochondrial dysfunction.2-6 Studies using rodent models in the last four decades have 上海皓元 demonstrated that mitochondrial disruption is the key underlying mechanism of AILI (Fig. 1FIG1)). Covalent binding to mitrochondrial
proteins by NAPQI causes oxidative stress and mitochondrial membrane permeability transition pore opening, which triggers the collapse of membrane potential, cessation of adenosine triphosphate (ATP) production, and the release of apoptosis-inducing factor and endonuclease G.7-11 Together, the mitochondrial dysfunction, energy crisis, and nuclear DNA damage result in hepatocyte necrosis. In recent years, there has been a growing interest to investigate whether downstream events of early hepatocyte necrosis contribute to the aggravation and progression of AILI. Necrotic cells release a number of damage-associated molecular pattern (DAMP) molecules, such as high-mobility group box-1, heat-shock proteins, hyaluronan, fibronectin, cardiolipin, and DNA fragments. Upon activation by DAMP molecules, innate immune cells infiltrate the damaged area and release cytokines and cheomokines, thereby causing tissue sterile inflammation.12-22 The soluble products of innate immune cells can exacerbate tissue damage, as well as promote wound healing (Fig. 1).