Cholestatic liver damage is mediated by lymphocyte function antigen-1–dependent recruitment of leukocytes

Adhesive Mechanisms of Histone-Induced Neutrophil-Endothelium Interactions in the Muscle Microcirculation

“…Considered together, these results indicate that P-selectin/PSGL-1-mediated rolling is a precondition for histone-induced adhesion and tissue accumulation of neutrophils in vivo. Our novel data extend on previous studies showing that P-selectin and PSGL-1 play a critical role in supporting leukocyte rolling in TNF-induced inflammation [21] as well as in models of septic lung injury [16], reperfusion injury [9] and cholestatic liver damage [41]. …”

“…We show for the first time that inhibition of Mac-1 and LFA-1 decreased histone 3-evoked neutrophil adhesion on the venular endothelium in vivo, suggesting that both LFA-1 and Mac-1 support adhesive interactions between circulating neutrophils and endothelial cells in response to histone challenge. Previous work has reported conflicting data on the individual role of Mac-1 and LFA-1 in specific models of inflammation [9,22,23,24,25,26]; however, taking more recent studies into consideration, it is comprehensible that both of these adhesion molecules may cooperate for optimal recruitment of inflammatory cells. For example, a recent study reported that LFA-1 may initiate first stable contact and that Mac-1 establishes more sustainable adhesion onto the endothelium of inflamed organs [42].…”

“…Extracellular histones have also been shown to increase thrombin generation, which could cause dysfunctional coagulation in systemic inflammation [6]. In this context, it is important to note that leukocyte recruitment is a rate-limiting step in mediating tissue damage in many inflammatory diseases, including sepsis, acute pancreatitis [7] and colitis [8] as well as cholestatic liver injury [9] and ischemia reperfusion [10]. Interestingly, inhibition of histone function has been associated with reduced levels of tissue accumulation of leukocytes in disease models, such as endotoxemia and acute kidney injury [5,11,12].…”

“…P-selectin glycoprotein ligand-1 (PSGL-1) is one of the best-characterized selectin counter-receptors, which preferentially binds to P-selectin but can also bind to E-selectin with low affinity [16]. It is well-documented that inhibition of P-selectin and PSGL-1 effectively inhibits leukocyte recruitment in different models of inflammation, including reperfusion injury [9] and septic lung damage [17]. Certain studies have reported that subsets of integrins could support rolling under special conditions [18].…”

“…Firm adhesion of leukocytes to the microvascular endothelium is mainly mediated by β 2 -integrins, including lymphocyte function antigen-1 (LFA-1; CD11a/CD18), membrane-activated complex-1 (Mac-1; CD11b/CD18) and p150, 95 (CD11c/CD18). The literature is rather complex and partly contradictory with respect to the role of β 2 -integrins in leukocyte adhesion, and the relative importance of specific β 2 -integrins appears to vary depending on the type of inflammatory stimulus and experimental model [9,23,24,25,26,27]. Taken together, the importance of selectins and β 2 -integrins for histone-induced leukocyte recruitment is not known and deserves further investigations.…”