P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice

Dold, Stefan; Laschke, Matthias W.; Zhau, Yilin; Schilling, Martin K.; Menger, Michael D.; Jeppsson, Bengt; Thorlacius, Henrik

doi:10.1007/s00011-009-0099-2

Cited by 12 publications

(15 citation statements)

References 39 publications

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“…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]. …”

Section: Discussionsupporting

confidence: 87%

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

Puegge

Wang²,

Roller³

et al. 2015

Eur Surg Res

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Background: Extracellular histones released during cell damage have the capacity to cause tissue injury associated with increased leukocyte accumulation. However, the molecular mechanisms regulating histone-induced leukocyte recruitment remain elusive. The objective of this study was to examine the role of adhesion molecules in histone-dependent leukocyte accumulation by use of intravital microscopy of the mouse cremaster microcirculation. Methods: Histone 3 and TNF-α were intrascrotally administered, and anti-P-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti-lymphocyte function antigen-1 (LFA-1) antibody and neutrophil depletion antibody were injected intravenously or intraperitoneally. Results: Intrascrotal injection of histone 3 dose-dependently increased leukocyte recruitment. Neutrophil depletion abolished intravascular and extravascular leukocytes after histone 3 challenge, suggesting that neutrophils were the dominating leukocyte subtype responding to histone stimulation. Pretreatment with an anti-P-selectin and an anti-PSGL-1 antibody abolished histone-stimulated neutrophil rolling, adhesion and emigration. When the anti-P-selectin or the anti-PSGL-1 antibody was administrated after histone 3 stimulation, neutrophil rolling was reduced, whereas the number of firmly adherent and emigrated neutrophils were unchanged, suggesting that the inhibitory effect of blocking P-selectin and PSGL-1 on neutrophil adhesion and recruitment was due to the reduction in neutrophil rolling. Moreover, pretreatment with antibodies against Mac-1 and LFA-1 had no effect of neutrophil rolling but abolished adhesion and emigration evoked by histone 3. Thus, our data demonstrate that P-selectin and PSGL-1 play an important role in histone-induced inflammatory cell recruitment by mediating neutrophil rolling as a precondition for histone-provoked firm adhesion and emigration in vivo. Moreover, we conclude that both Mac-1 and LFA-1 are critical in supporting histone-provoked firm adhesion of neutrophils to endothelial cells. Conclusion: These novel findings define specific selectins and integrins as potential targets for pharmacological intervention in histone-dependent inflammatory diseases.

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Section: Discussionsupporting

confidence: 87%

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

Puegge

Wang²,

Roller³

et al. 2015

Eur Surg Res

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“…Subsequently, BDL was shown to cause an increase in chemoattractants in the liver [53]. Mice deficient in ICAM-1 or CD18, which are important for neutrophil extravasation and cytotoxicity [54], are both protected against BDL-induced liver injury [5, 55]. In addition, depletion of P-selectin glycoprotein ligand 1 attenuated neutrophil-mediated injury after BDL [56].…”

Section: Inflammation As a Mechanism Of Injury During Cholestasismentioning

confidence: 99%

“…Neutrophils express myeloperoxidase, which is responsible for the generation of hypochlorous acid, a potent oxidant. The areas of biliary infarction that characterize the focal necrosis immunostain positive for chlorotyrosine adducts, indicative of release of the highly toxic hypochlorous acid in the region [5, 55, 59]. While these data support a hypothesis where neutrophils are the predominant source of injury, the idea that neutrophils caused cholestatic liver injury was controversial.…”

Section: Inflammation As a Mechanism Of Injury During Cholestasismentioning

confidence: 99%

“…Kupffer cell and monocyte levels stay fairly consistent during the first two weeks of cholestasis and depletion of Kupffer cells worsens the injury due to a reduction in protective acute phase cytokines and protein production [67]. More importantly, chlorotyrosine-protein adducts are prevalent in the areas of necrosis after acute BDL injury [5, 55, 59]. These chlorotyrosine-protein adducts are indicative of an intracellular oxidant stress in hepatocytes and nearby endothelium, suggesting that neutrophil-derived hypochlorous acid must diffuse into local hepatocytes, where it causes toxicity [91].…”

Section: Inflammation As a Mechanism Of Injury During Cholestasismentioning

confidence: 99%

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Therapeutic targets for cholestatic liver injury

Woolbright

Jaeschke

2015

Expert Opinion on Therapeutic Targets

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Introduction Cholestasis is a reduction in bile flow that occurs during numerous pathologies. Blockage of the biliary tracts results in hepatic accumulation of bile acids or their conjugate bile salts. The molecular mechanisms behind liver injury associated with cholestasis are extensively studied, but not well understood. Multiple models of obstructive cholestasis result in a significant inflammatory infiltrate at the sites of necrosis that characterize the injury. Areas Covered This review will focus on direct bile acid toxicity during cholestasis, bile acid signaling processes and on the development and continuation of inflammation during cholestasis, with a focus on novel proposed molecular mediators of neutrophil recruitment. While significant progress has been made on these molecular mechanisms, a continued focus on how cholestasis and the innate immune system interact is necessary to discover targetable therapeutics that might protect the liver while leaving global immunity intact. Expert Opinion While bile acid toxicity likely occurs in humans and other mammals when toxic bile acids accumulate, persistent inflammation is likely responsible for continued liver injury during obstructive cholestasis. Targeting molecular mediators of inflammation may help prevent liver injury during acute cholestasis both in murine models and human patients.

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“…Nonetheless, CD162 is a well-accepted high-affinity ligand of P-selectin in spite of the fact that CD162 also binds to E-selectin (24,47). Convincing studies have shown that inhibition of CD162 effectively decreases leukocyte recruitment in different models of inflammation (1,8,22). However, the role of CD162 in mediating M1 protein-induced leukocyte-endothelial cell interactions in the pulmonary microcirculation is not known.…”

mentioning

confidence: 99%

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

Zhang

Song

Wang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Zhang S, Song L, Wang Y, Herwald H, Thorlacius H. Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury. Am J Physiol Lung Cell Mol Physiol 305: L756 -L763, 2013. First published September 13, 2013 doi:10.1152/ajplung.00220.2013.-Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 proteinprovoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by Ͼ54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 protein-treated animals. In addition, inhibition of CD162 decreased M1 protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 protein-treated animals. Our findings suggest that CD162 plays an important role in M1 protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections. adhesion; chemokines; inflammation and leukocyte CLINICAL MANIFESTATIONS OF Streptococcus pyogenes infections vary from uncomplicated cases to severe and fatal conditions, such as streptococcal toxic shock syndrome (STSS), which is associated with a mortality exceeding 50% (7, 15). Despite significant investigative efforts, management of patients with STSS is largely restricted to antibiotics and supportive care, which is partly due to an incomplete understanding of the basic pathophysiology in STSS. S. pyogenes express several different virulence factors, including M proteins, of which there are more than 80 different serotypes described in the literature (15,26). The M1 serotype of Streptococcus pyogenes is most commonly linked to STSS (7). Numerous studies have documented that M1 protein is a powerful stimulator of innate immune cells, such as monocytes (26) and neutrophils (15). In addition, the M1 protein has the capacity to induce formation of cytokines (26), chemokines (9), and tissue factor (25), which all contribute to M1 protein-induced edema formation and tissue damage in the lung. Several studies have shown that lung failure is an insidious feature in STSS patie...

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P-selectin glycoprotein ligand-1-mediated leukocyte recruitment regulates hepatocellular damage in acute obstructive cholestasis in mice

Cited by 12 publications

References 39 publications

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

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

Therapeutic targets for cholestatic liver injury

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

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