Possible mechanisms underlying the role of plasmin and HK cleavage in AILI. Acetaminophen overdose induces plasmin generation by tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA), which degrades the extracellular matrix (ECM) component fibronectin and cleaves HK. Cleaved HK induces apoptosis of endothelial cells (ECs) and inhibits angiogenesis. Thus, both plasmin and cleaved HK could disrupt sinusoidal vascular integrity and repair. Cleaved HK stimulates leukocytes to release inflammatory and chemotactic cytokines, inducing systemic and local inflammation and regulating neutrophil recruitment in the resolution phase. Through these multiple pathways, plasma and HK cleavage mediates AILI. APAP, N-acetyl-para-aminophenol.