Critical role of P-selectin-dependent rolling in tumor necrosis factor-a-induced leukocyte adhesion and extravascular recruitment in vivo

Månsson, Peter; Zhang, Xiaowei; Jeppsson, Bengt; Thorlacius, Henrik

doi:10.1016/s0016-5085(00)85344-5

Cited by 19 publications

(30 citation statements)

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“…Moreover, we observed that inhibition of P-selectin function not only abolished leukocyte rolling but also concomitantly completely inhibited endotoxemia-induced firm adhesion of leukocytes, indicating that P-selectin-dependent rolling is indeed a precondition for LPS-induced leukocyte adhesion in postsinusoidal venules. This notion is in line with previous findings showing that pretreatment with fucoidan inhibits both leukocyte rolling and firm adhesion, whereas late treatment with fucoidan only inhibits leukocyte rolling (15,22).…”

Section: Discussionsupporting

confidence: 93%

Important Role of P-Selectin for Leukocyte Recruitment, Hepatocellular Injury, and Apoptosis in Endotoxemic Mice

Klintman

Thorlacius

2004

Clin Vaccine Immunol

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Leukocyte recruitment in the liver includes a two-step procedure in which selectin-dependent leukocyte rolling is a prerequisite for subsequent CD18-dependent leukocyte firm adhesion in postsinusoidal venules. However, the roles of the individual selectins in leukocyte rolling and adhesion, hepatocellular injury, and apoptosis remain elusive. Therefore, we examined the pathophysiological role of P-, E-, and L-selectin in male C57BL/6 mice challenged with lipopolysaccharide (LPS) and D-galactosamine (Gal) by use of intravital microscopy of the liver microcirculation. In control animals, administration of LPS-Gal provoked reproducible hepatic damage, including marked increases of leukocyte recruitment, liver enzymes, and hepatocyte apoptosis and reduced sinusoidal perfusion. Interestingly, pretreatment with an anti-P-selectin antibody (RB40.34) markedly reduced leukocyte rolling and firm adhesion by 65 and 71%, respectively. Moreover, interference with P-selectin function significantly improved sinusoidal perfusion and reduced the increase in liver enzymes by 49 to 84% in endotoxemic mice. Moreover, the activity of caspase-3 and the number of apoptotic hepatocytes were significantly reduced by 55 and 54%, respectively, in RB40.34-treated animals. In contrast, administration of an anti-E-selectin antibody (10E9.6) and an anti-L-selectin antibody (Mel-14) did not protect against endotoxin-induced leukocyte responses or hepatic injury. In conclusion, our novel findings document a principal role of P-selectin in mediating leukocyte rolling, a precondition to the subsequent firm adhesion of leukocytes in liver injury. Furthermore, our novel data demonstrate that inhibition of P-selectin function reduces hepatocellular injury and apoptosis, suggesting a causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand. Based on these findings, it is suggested that P-selectin may be an important therapeutic target in endotoxin-induced liver injury.Activation and recruitment of leukocytes are features associated with liver injury in, e.g., ischemia-reperfusion and endotoxemia (10,12,23). In general, studies of various tissues have shown that infiltration of leukocytes involves a multistep cascade in which the initial rolling interaction between leukocytes and the endothelium is predominately mediated by the selectin family of adhesion molecules, including P-, E-, and L-selectin (1,15,20,31). Subsequent firm adhesion of leukocytes to the endothelium is dependent on the function of ␤ 1 -and ␤ 2 -integrins (CD11/18) on leukocytes, interacting with members of the immunoglobulin supergene family expressed on activated endothelial cells, such as ICAM-1 and -2 and VCAM-1 (1,12,15,16,20,21,31).However, the literature on the specific roles of P-, E-, and L-selectin and the relationship between leukocyte recruitment, cellular injury, and apoptosis is contradictory. For example, when blood flow velocity and shear rates are reduced, it has been suggested that leukocytes may bypass...

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Section: Discussionsupporting

confidence: 93%

Important Role of P-Selectin for Leukocyte Recruitment, Hepatocellular Injury, and Apoptosis in Endotoxemic Mice

Klintman

Thorlacius

2004

Clin Vaccine Immunol

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“…For example, tumor necrosis factor (TNF)-a, which is a pleiotrophic cytokine and plays a fundamental role in inflammatory conditions such as colitis by triggering leukocyte activation and tissue accumulation [7]. The leukocyte extravasation process in TNF-a activated tissues is characterized by a series of sequential steps among which slow rolling along the endothelial lining is a precondition for subsequent firm adhesion [8]. The leukocyte rolling adhesive interaction is mediated through a transient and reversible interaction between leukocytic and endothelial cell surface molecules of the selectin family (L-, P-and E-selectin) [9].…”

Section: Introductionmentioning

confidence: 99%

Low molecular weight heparin inhibits tumor necrosis factor α-induced leukocyte rolling

et al. 2001

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“…Although blocking P-selectin, L-selectin, and ␣ 4 -integrin re-duced rolling, only the lack of ICAM-1 was able to reduce venular adhesion completely. In contrast, it has been reported that P-selectin-dependent rolling is a precondition for leukocyte adhesion in TNF-␣-stimulated cremaster muscle microcirculation (35). Leukocyte adhesion in the postsinusoidal venules was at baseline levels prior to antibody introduction, which could account for not visualizing any effect of anti-Pselectin.…”

Section: Discussionmentioning

confidence: 85%

Hepatic leukocyte recruitment in response to time-limited expression of TNF-α and IL-1β

Patrick

Rullo²,

Beaudin³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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The development of chronic liver diseases is mediated by sustained hepatic inflammation. Our objective was to characterize the molecular mechanisms responsible for the hepatic inflammatory response to time-limited TNF-α and IL-1β expression. C57Bl/6 mice were injected with 2 × 107plaque forming units intraperitoneally of an adenoviral vector containing TNF-α or IL-1β (AdTNF-α or AdIL-1β). A nonreplicating adenoviral vector served as control. Four days later, under ketamine and xylazine anesthesia, the liver microvasculature was examined by intravital microscopy. In the postsinusoidal venules, leukocyte rolling increased significantly in response to both AdTNF-α and AdIL-1β, compared with controls. This response was significantly reduced following injection of an anti-α4-integrin monoclonal antibody (MAb). Postsinusoidal rolling was further reduced to baseline following injection of an anti-P-selectin or anti-L-selectin MAb. Sinusoidal adhesion was greater in mice treated with AdIL-1β than with AdTNF-α. Blocking α4-integrin, P-selectin, or L-selectin had no significant effect on sinusoidal or postsinusoidal adhesion. In separate experiments, we administered AdTNF-α or AdIL-1β to mice deficient in ICAM-1. In ICAM-1−/− mice, postsinusoidal leukocyte rolling significantly increased following expression of IL-1β but not TNF-α. AdIL-1β- but not AdTNF-α-mediated sinusoidal adhesion was ICAM-1 dependent. AdTNF-α-induced sinusoidal adhesion was significantly reduced following 4 days of anti-MIP-2 MAb and anti-KC MAb. Prolonged expression of the cytokines TNF-α and IL-1β increases hepatic leukocyte-endothelial cell interactions. Interestingly, the mechanisms through which these cytokines bring about adhesion within the sinusoids differ; AdIL-1β sinusoidal adhesion uses an ICAM-1-dependent mechanism whereas AdTNF-α-mediated adhesion is ICAM-1 independent but CXC chemokine dependent.

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Critical role of P-selectin-dependent rolling in tumor necrosis factor-a-induced leukocyte adhesion and extravascular recruitment in vivo

Cited by 19 publications

References 0 publications

Important Role of P-Selectin for Leukocyte Recruitment, Hepatocellular Injury, and Apoptosis in Endotoxemic Mice

Important Role of P-Selectin for Leukocyte Recruitment, Hepatocellular Injury, and Apoptosis in Endotoxemic Mice

Low molecular weight heparin inhibits tumor necrosis factor α-induced leukocyte rolling

Hepatic leukocyte recruitment in response to time-limited expression of TNF-α and IL-1β

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