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• W2024952909 abstract "Vascular endothelial activation, marked by de novo expression of E-selectin, is an early and essential event in the process of leukocyte extravasation and inflammation. Evidence suggests that hepatocyte growth factor (HGF) ameliorates inflammation in animal models of renal disease, implying that HGF might inhibit specific components of the inflammatory response. This study examined the effect of HGF on endothelial E-selectin expression in acute inflammation induced by tumor necrosis factor (TNF)-α. In vitro, HGF suppressed TNF-α-induced cell surface expression of E-selectin in human umbilical vein endothelial cells (HUVEC) and inhibited E-selectin mediated monocytic adhesion to endothelial monolayers. HGF activated phosphatidylinositol 3-kinase (PI3K)–Akt that in turn inhibited its downstream transducer glycogen synthase kinase (GSK)3. Blockade of the PI3K–Akt pathway with specific inhibitors abrogated HGF induced inhibitory phosphorylation of GSK3 and suppression of E-selectin. In addition, selective inhibition of GSK3 activity by lithium suppressed TNF-α-induced E-selectin expression and monocytic adhesion, reminiscent of the action of HGF. Moreover, ectopic expression of an uninhibitable mutant GSK3β, in which the regulatory serine-9 is replaced by alanine, abolished HGF's suppressive effect on endothelial E-selectin. In vivo, administration of exogenous HGF reduced endothelial expression of E-selectin induced by bolus injection of TNF-α. This was associated with less sequestration of circulating fluorescence-labeled macrophages in the kidney. These findings suggest that HGF ameliorates acute renal inflammation in part by downregulating E-selectin mediated macrophage adhesion to the inflamed endothelium. Vascular endothelial activation, marked by de novo expression of E-selectin, is an early and essential event in the process of leukocyte extravasation and inflammation. Evidence suggests that hepatocyte growth factor (HGF) ameliorates inflammation in animal models of renal disease, implying that HGF might inhibit specific components of the inflammatory response. This study examined the effect of HGF on endothelial E-selectin expression in acute inflammation induced by tumor necrosis factor (TNF)-α. In vitro, HGF suppressed TNF-α-induced cell surface expression of E-selectin in human umbilical vein endothelial cells (HUVEC) and inhibited E-selectin mediated monocytic adhesion to endothelial monolayers. HGF activated phosphatidylinositol 3-kinase (PI3K)–Akt that in turn inhibited its downstream transducer glycogen synthase kinase (GSK)3. Blockade of the PI3K–Akt pathway with specific inhibitors abrogated HGF induced inhibitory phosphorylation of GSK3 and suppression of E-selectin. In addition, selective inhibition of GSK3 activity by lithium suppressed TNF-α-induced E-selectin expression and monocytic adhesion, reminiscent of the action of HGF. Moreover, ectopic expression of an uninhibitable mutant GSK3β, in which the regulatory serine-9 is replaced by alanine, abolished HGF's suppressive effect on endothelial E-selectin. In vivo, administration of exogenous HGF reduced endothelial expression of E-selectin induced by bolus injection of TNF-α. This was associated with less sequestration of circulating fluorescence-labeled macrophages in the kidney. These findings suggest that HGF ameliorates acute renal inflammation in part by downregulating E-selectin mediated macrophage adhesion to the inflamed endothelium. Inflammation, characterized by tissue infiltration by leukocytes, is a basic biological reaction and part of the innate defense to injuries induced by various pathogenic factors.1.Ward P.A. Marks R.M. The acute inflammatory reaction.Curr Opin Immunol. 1989; 2: 5-9Crossref PubMed Scopus (22) Google Scholar An inflammatory response of appropriate magnitude and timing is crucial to tissue repair and homeostasis.1.Ward P.A. Marks R.M. The acute inflammatory reaction.Curr Opin Immunol. 1989; 2: 5-9Crossref PubMed Scopus (22) Google Scholar, 2.Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2051) Google Scholar Most inflammatory responses are acute and self-limiting; however, an excessive inflammatory reaction may result in critical and fatal conditions as systemic inflammatory response syndrome, severe acute respiratory syndrome, and acute renal failure. In addition, if the inflammatory response is prolonged or frequently relapsing chronic persistent inflammation develops, which may promote fibrosis and loss of organ function.3.Levy J.H. The human inflammatory response.J Cardiovasc Pharmacol. 1996; 27: S31-S37Crossref PubMed Scopus (46) Google Scholar Immunosuppressants including glucocorticoids are widely used to treat patients with excessive or chronic inflammation and reduce the likelihood of these complications, despite an increased risk of opportunistic infections.1.Ward P.A. Marks R.M. The acute inflammatory reaction.Curr Opin Immunol. 1989; 2: 5-9Crossref PubMed Scopus (22) Google Scholar, 2.Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2051) Google Scholar, 3.Levy J.H. The human inflammatory response.J Cardiovasc Pharmacol. 1996; 27: S31-S37Crossref PubMed Scopus (46) Google Scholar Vascular endothelial activation and dysfunction play a critical role in the inflammatory response.4.Hack C.E. Zeerleder S. The endothelium in sepsis: source of and a target for inflammation.Crit Care Med. 2001; 29: S21-S27Crossref PubMed Scopus (246) Google Scholar, 5.Ali H. Haribabu B. Richardson R.M. Snyderman R. Mechanisms of inflammation and leukocyte activation.Med Clin N Am. 1997; 81: 1-28Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 6.Kevil C.G. Endothelial cell activation in inflammation: lessons from mutant mouse models.Pathophysiology. 2003; 9: 63-74Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 7.Luscinskas F.W. Gimbrone Jr, M.A. Endothelial-dependent mechanisms in chronic inflammatory leukocyte recruitment.Annu Rev Med. 1996; 47: 413-421Crossref PubMed Scopus (158) Google Scholar, 8.Bevilacqua M.P. Nelson R.M. Mannori G. Cecconi O. Endothelial–leukocyte adhesion molecules in human disease.Annu Rev Med. 1994; 45: 361-378Crossref PubMed Scopus (430) Google Scholar Normally, leukocytes continuously patrol the vasculature, alert for signals of inflammation. Proinflammatory substances released by pathogens (e.g. lipopolysaccharide) or by damaged tissue (e.g. tumor necrosis factor (TNF)-α) upregulate the expression of adhesion molecules on the endothelium and initiate the migration of leukocytes to the inflamed area. Leukocyte migration from blood to tissues involves several steps: rolling, sticking, diapedesis, and chemotaxis.9.Carlos T.M. Harlan J.M. Leukocyte–endothelial adhesion molecules.Blood. 1994; 84: 2068-2101Crossref PubMed Google Scholar Among these processes, rolling is the earliest and indispensable event initiating leukocyte extravasation and inflammation. Rolling is mediated by the selectin family of adhesion molecules, endothelial E-selectin, platelet P-selectin, and leukocyte L-selectin.10.Ley K. The role of selectins in inflammation and disease.Trends Mol Med. 2003; 9: 263-268Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar Both E- and P-selectins are expressed by endothelial cells; L-selectin is found only on leukocytes. P- and L-selectins are constitutively expressed whereas E-selectin is elicited by proinflammatory stimulate and is considered essential for leukocyte trafficking.10.Ley K. The role of selectins in inflammation and disease.Trends Mol Med. 2003; 9: 263-268Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar The importance of E-selectin in initiating inflammation is demonstrated by the potent anti-inflammatory effect of E-selectin blockade.11.Welply J.K. Keene J.L. Schmuke J.J. Howard S.C. Selectins as potential targets of therapeutic intervention in inflammatory diseases.Biochim Biophys Acta. 1994; 1197: 215-226Crossref PubMed Scopus (50) Google Scholar, 12.Singbartl K. Ley K. Protection from ischemia–reperfusion induced severe acute renal failure by blocking E-selectin.Crit Care Med. 2000; 28: 2507-2514Crossref PubMed Scopus (121) Google Scholar, 13.Gotoh R. Suzuki J. Kosuge H. et al.E-selectin blockade decreases adventitial inflammation and attenuates intimal hyperplasia in rat carotid arteries after balloon injury.Arterioscler Thromb Vasc Biol. 2004; 24: 2063-2068Crossref PubMed Scopus (33) Google Scholar, 14.Azuma A. Takahashi S. Nose M. et al.Role of E-selectin in bleomycin induced lung fibrosis in mice.Thorax. 2000; 55: 147-152Crossref PubMed Scopus (42) Google Scholar, 15.Friedman G. Jankowski S. Shahla M. et al.Administration of an antibody to E-selectin in patients with septic shock.Crit Care Med. 1996; 24: 229-233Crossref PubMed Scopus (35) Google Scholar, 16.Huang J. Choudhri T.F. Winfree C.J. et al.Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke.Stroke. 2000; 31: 3047-3053Crossref PubMed Scopus (135) Google Scholar Hepatocyte growth factor (HGF) is a mesenchymal-derived, pleiotropic multifunctional growth factor.17.Boros P. Miller C.M. Hepatocyte growth factor: a multifunctional cytokine.Lancet. 1995; 345: 293-295Abstract PubMed Google Scholar Upon binding to its receptor, c-Met, HGF triggers several signal transduction pathways, including phosphatidylinositol 3-kinase (PI3K)–Akt, Ras–Mek–Erk, and Stat3 pathway, and modulates diverse cell processes including mitogenesis, motogenesis, morphogenesis, and antiapoptosis/survival in epithelial and endothelial cells.17.Boros P. Miller C.M. Hepatocyte growth factor: a multifunctional cytokine.Lancet. 1995; 345: 293-295Abstract PubMed Google Scholar, 18.Birchmeier C. Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase.Trends Cell Biol. 1998; 8: 404-410Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar Evidence suggests that HGF ameliorates both acute and chronic injury in various organs including kidney,19.Liu Y. Hepatocyte growth factor and the kidney.Curr Opin Nephrol Hypertens. 2002; 11: 23-30Crossref PubMed Scopus (111) Google Scholar liver,20.Matsumoto K. Nakamura T. Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration.J Gastroenterol Hepatol. 1991; 6: 509-519Crossref PubMed Scopus (116) Google Scholar lung,21.Ware L.B. Matthay M.A. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L924-L940Crossref PubMed Scopus (289) Google Scholar and intestine.22.Dignass A.U. Sturm A. Peptide growth factors in the intestine.Eur J Gastroenterol Hepatol. 2001; 13: 763-770Crossref PubMed Scopus (144) Google Scholar Of note, inflammation is an invariable finding in both acute and chronic disease. Inflammation subsides in response to HGF treatment; however, the potential beneficial effects of HGF on inflammation have been largely overlooked. Recently, we reported that HGF treatment substantially attenuated inflammation in the rat remnant kidney model of chronic renal failure;23.Gong R. Rifai A. Tolbert E.M. et al.Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of MCP-1 and RANTES.J Am Soc Nephrol. 2004; 15: 2868-2881Crossref PubMed Scopus (96) Google Scholar however, the mechanisms responsible for this action remain uncertain. In this study, we show that HGF abrogates monocyte to endothelial adhesion and ameliorates acute renal inflammation by suppressing endothelial E-selectin expression. These findings suggest that the beneficial effects of HGF in both acute and chronic disease may be partially ascribed to its systemic anti-inflammatory action on the endothelium. As presented in Figure 1a, TNF-α strongly stimulated E-selectin expression at low doses without significantly reducing the human umbilical vein endothelial cells (HUVEC) viability. Western immunoblot of whole-cell lysates showed that HGF treatment suppressed TNF-α induced total E-selectin expression in a time-dependent manner. E-selectin is found both on the cell membrane and in the intracellular reservoir in activated endothelial cells.24.Grabner R. Till U. Heller R. Flow cytometric determination of E-selectin, vascular cell adhesion molecule-1, and intercellular cell adhesion molecule-1 in formaldehyde-fixed endothelial cell monolayers.Cytometry. 2000; 40: 238-244Crossref PubMed Scopus (48) Google Scholar Only membrane E-selectin is accessible to leukocytes and functionally active in mediating the endothelial–leukocyte adhesion. To examine whether HGF treatment modulated cell surface expression of E-selectin, flow cytometry (Figure 1b) and fluorescent immunocytochemistry (Figure 1c–f) without cell membrane permeabilization were employed. As shown in Figure 1c–f, control and HGF alone treated HUVEC cells are negative for E-selectin. TNF-α markedly induced E-selectin expression with a typical surface distribution pattern, and HGF pretreatment significantly decreased the surface E-selectin staining. Flow cytometry analysis corroborated the immunocytochemistry findings. HGF prevented TNF-α induced surface expression of E-selectin in HUVEC cells. To determine whether HGF suppression of endothelial E-selectin expression reduces leukocyte adhesion to endothelium, we employed the monocytic static adhesion assay.25.Ludwig A. Lorenz M. Grimbo N. et al.The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells.Biochem Biophys Res Commun. 2004; 316: 659-665Crossref PubMed Scopus (189) Google Scholar Few fluorescent THP-1 cells were found adherent to vehicle (Figure 2a) or HGF (Figure 2b) treated HUVEC monolayers. TNF-α promoted monocyte adhesion (Figure 2c), and HGF strikingly prevented it (Figure 2d). To quantify monocytes adherent to HUVEC monolayers, cells were lysed and subjected to fluorometric analysis (Figure 2f), which was in agreement with the microscopic findings. Of note, addition of a specific rabbit anti-E-selectin antibody blocked monocyte adhesion, suggesting that E-selectin mediates endothelial to monocyte adhesion and that suppression of endothelial expression of E-selectin by HGF accounts for the reduction in monocytic adhesion. After binding to its cognate receptor, c-Met, HGF triggers multiple signaling pathways including the PI3K–Akt pathway, Ras–Mek–Erk pathway, and Stat3 pathway.18.Birchmeier C. Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase.Trends Cell Biol. 1998; 8: 404-410Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar HGF activated all three pathways in HUVEC cells, while TNF-α had only a minor effect (Figure 3a). To determine which signaling pathway mediates HGF suppression of E-selectin, we pretreated HUVEC with various inhibitors specific for each pathway. As shown in Figure 3b, the suppressive effect of HGF on TNF-α -induced E-selectin was blocked by two different inhibitors specific for the PI3K–Akt pathway, wortmannin and LY294002. In contrast, U0126, the selective inhibitor for the Ras–Mek–Erk pathway and PpYLKTK-mts, the Stat3 inhibitor, failed to abolish the HGF's inhibitory action (Figure 3c). These data suggest that the PI3K–Akt pathway mediates HGF's suppression of E-selectin in endothelial cells. GSK3 is an important downstream transducer of the PI3K–Akt signaling pathway. GSK3 is inactivated in response to PI3K signaling, as a result of Akt-mediated phosphorylation of an N-terminal serine, serine-9 in GSK3β and Ser-21 in GSK3α.26.Jope R.S. Johnson G.V. The glamour and gloom of glycogen synthase kinase-3.Trends Biochem Sci. 2004; 29: 95-102Abstract Full Text Full Text PDF PubMed Scopus (1334) Google Scholar Because phosphorylation of GSK3 at these two residues denotes GSK3 inactivation, we probed using a specific antibody against phosphorylated GSK3α (S21) and GSK3β (S9). In HUVEC cells, HGF treatment immediately elicited inhibitory phosphorylation of GSK3β and, to a lesser extent, GSK3α (Figure 4a). This effect persisted for at least 90 min in the presence or absence of TNF-α, while TNF-α alone had only a minor effect. In addition, HGF-induced inhibitory phosphorylation of GSK3 was abolished by wortmannin (Figure 4b), implying that activation of PI3K–Akt pathway is required for this action. To avoid cell loss due to induction of apoptosis, the general apoptosis inhibitor BOC-Asp-CH2F was added to the culture.27.Sanchez J.F. Sniderhan L.F. Williamson A.L. et al.Glycogen synthase kinase 3β-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor κB signaling.Mol Cell Biol. 2003; 23: 4649-4662Crossref PubMed Scopus (123) Google Scholar At the optimal concentration not associated with significant apoptosis, lithium (20 mM), a selective inhibitor for GSK3,28.Cohen P. Goedert M. GSK3 inhibitors: development and therapeutic potential.Nat Rev Drug Discov. 2004; 3: 479-487Crossref PubMed Scopus (677) Google Scholar induced inhibitory phosphorylation of GSK3 (Figure 5a), and attenuated basal and TNF-α-induced E-selectin in HUVEC (Figure 5b), reminiscent of the action of HGF. Sodium, an osmolality control, had no effect. The finding that activation of PI3K–Akt and subsequent inhibition of GSK3 mediates HGF suppression of E-selectin prompted us to investigate whether the PI3K–Akt–GSK3 cascade regulates endothelial to monocyte adhesion. HUVEC monolayers were activated with TNF-α and subjected to static adhesion assay after pretreatment with HGF or different selective chemical inhibitors of the PI3K–Akt–GSK3 pathway. Fluorometric analysis of cell lysates demonstrated that inhibition of GSK3 by lithium attenuates TNF-α-induced endothelial to monocyte adhesion, similar to the effect of HGF. Sodium, the osmolality control, had no effect. Blockade of PI3K activation by wortmannin also blocked the inhibitory action of HGF on monocytic adhesion from 4 h on (Figure 6). GSK3 consists of two distinct isoforms, GSK3α and GSK3β. Previous studies suggested that GSK3β, but not GSK3α, is essential for TNF-α or IL-1β-induced inflammatory responses.29.Hoeflich K.P. Luo J. Rubie E.A. et al.Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation.Nature. 2000; 406: 86-90Crossref PubMed Scopus (1228) Google Scholar To further examine the role of inhibitory phosphorylation of GSK3β in HGF inhibition of E-selectin, we studied the effect of forced expression of GSK3β on E-selectin in HUVEC cells. Vectors encoding the hemagglutin (HA) tagged wild type (WT) GSK3β or uninhibitable mutant GSK3β,30.Cho J.H. Johnson G.V. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau's ability to bind and stabilize microtubules.J Neurochem. 2004; 88: 349-358Crossref PubMed Scopus (209) Google Scholar in which the regulatory serine-9 residue was replaced by alanine (S9A-GSK3β), were transfected into HUVEC cells. As a control, pcDNA3 was used in transfection. To evaluate the levels of expression, whole-cell lysates were analyzed by immunoblotting for HA or HA-GSK3β (Figure 7a). Immunofluorescent detection using an antibody against the HA epitope revealed that over 50% of the cells expressed the HA-tagged constructs 24 h after transfection. As shown in Figure 7a–c, HGF inhibition of TNF-α induced E-selectin expression was evident in HUVEC cells transfected with pcDNA3 or WT-GSK3β. In contrast, ectopic expression of S9A-GSK3β abolished the suppressive action of HGF on E-selectin expression. Collectively, these findings suggest that inhibitory phosphorylation of GSK3β at serine-9 is required for HGF inhibition of E-selectin in HUVEC cells. The behavior of endothelial cells in vivo may differ from HUVEC cells in culture. To examine the effect of HGF on E-selectin expression in acute inflammation in vivo, rats were given a bolus intra-arterial injection of TNF-α. After 4 h, fluorescent immunohistochemistry revealed abundant staining for E-selectin in the kidney (Figure 8c) that was distributed in the pattern of the interstitial microvasculature (Figure 8e). HGF treatment reduced E-selectin staining (Figure 8d). The quantitative fluorescence intensity of E-selectin (Figure 8f) was significantly weakened in kidneys from HGF treated group. Western immunoblot analysis of total kidney homogenates confirmed that HGF prevented TNF-α induced E-selectin expression (Figure 8g). To confirm the functional significance of HGF suppression of E-selectin in the kidney, fluorescent viable rat alveolar macrophages (RAM) were infused into the carotid artery after administration of HGF and/or TNF-α as described in Materials and Methods. Tissues were processed for fluorescent histological analysis after 30 min. As shown in Figure 9c, many fluorescent RAM cells were found in the kidneys in TNF-α treated animals, most prominently in the interstitium of juxtamedullary cortex. An anti-E-selectin blocking antibody (figure not shown) or HGF (Figure 9d) markedly decreased the number of RAM cells. Quantification of RAM cells by fluorometric analysis of kidney homogenates (Figure 9e) was in agreement with the morphologic findings. Inflammation is a common finding in both acute and chronic injuries of diverse etiologies. Leukocyte to endothelium adhesion mediated by the selectin family of adhesion molecules, in particular E-selectin, is an indispensable event initiating the inflammatory reaction.6.Kevil C.G. Endothelial cell activation in inflammation: lessons from mutant mouse models.Pathophysiology. 2003; 9: 63-74Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 7.Luscinskas F.W. Gimbrone Jr, M.A. Endothelial-dependent mechanisms in chronic inflammatory leukocyte recruitment.Annu Rev Med. 1996; 47: 413-421Crossref PubMed Scopus (158) Google Scholar, 8.Bevilacqua M.P. Nelson R.M. Mannori G. Cecconi O. Endothelial–leukocyte adhesion molecules in human disease.Annu Rev Med. 1994; 45: 361-378Crossref PubMed Scopus (430) Google Scholar, 9.Carlos T.M. Harlan J.M. Leukocyte–endothelial adhesion molecules.Blood. 1994; 84: 2068-2101Crossref PubMed Google Scholar, 10.Ley K. The role of selectins in inflammation and disease.Trends Mol Med. 2003; 9: 263-268Abstract Full Text Full Text PDF PubMed Scopus (547) Google Scholar In the present study, we found that HGF suppresses monocyte to endothelial adhesion and attenuates acute renal inflammation via inhibition of endothelial E-selectin expression. HGF exerts this action via activation of PI3K–Akt–GSK3β pathway in endothelial cells. This finding complements our recent report demonstrating that HGF attenuates renal inflammation in the rat remnant kidney model of chronic renal disease.23.Gong R. Rifai A. Tolbert E.M. et al.Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of MCP-1 and RANTES.J Am Soc Nephrol. 2004; 15: 2868-2881Crossref PubMed Scopus (96) Google Scholar HGF has also recently been reported to be anti-inflammatory in non-renal diseases.21.Ware L.B. Matthay M.A. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L924-L940Crossref PubMed Scopus (289) Google Scholar, 31.Oh K. Iimuro Y. Takeuchi M. et al.Ameliorating effect of hepatocyte growth factor on inflammatory bowel disease in a murine model.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G729-G735Crossref PubMed Scopus (33) Google Scholar, 32.Arthur L.G. Schwartz M.Z. Kuenzler K.A. Birbe R. Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel disease.J Pediatr Surg. 2004; 39: 139-143Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 33.Arthur L.G. Kuenzler K.A. Schwartz M.Z. Hepatocyte growth factor ameliorates inflammatory bowel disease in a rat model.J Gastrointest Surg. 2003; 7: 1062-1068Crossref PubMed Scopus (13) Google Scholar, 34.Ito W. Kanehiro A. Matsumoto K. et al.Hepatocyte growth factor attenuates airway hyperresponsiveness, inflammation, and remodeling.Am J Respir Cell Mol Biol. 2005; 32: 268-280Crossref PubMed Scopus (58) Google Scholar In a murine model of inflammatory bowl disease (IBD), HGF gene transfection diminished inflammatory infiltrates in the intestinal epithelium.31.Oh K. Iimuro Y. Takeuchi M. et al.Ameliorating effect of hepatocyte growth factor on inflammatory bowel disease in a murine model.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G729-G735Crossref PubMed Scopus (33) Google Scholar Similarly, Arthur et al.32.Arthur L.G. Schwartz M.Z. Kuenzler K.A. Birbe R. Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel disease.J Pediatr Surg. 2004; 39: 139-143Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 33.Arthur L.G. Kuenzler K.A. Schwartz M.Z. Hepatocyte growth factor ameliorates inflammatory bowel disease in a rat model.J Gastrointest Surg. 2003; 7: 1062-1068Crossref PubMed Scopus (13) Google Scholar reported that direct intravenous infusion of exogenous HGF to rats with IBD significantly ameliorated gross and microscopic bowl inflammation. In a murine model of airway hyperresponsiveness, airway inflammation was reduced by administration of recombinant HGF.34.Ito W. Kanehiro A. Matsumoto K. et al.Hepatocyte growth factor attenuates airway hyperresponsiveness, inflammation, and remodeling.Am J Respir Cell Mol Biol. 2005; 32: 268-280Crossref PubMed Scopus (58) Google Scholar In the present study, exogenous HGF significantly attenuated TNF-α induced macrophage infiltration and acute renal inflammation in rats. The finding that HGF has systemic anti-inflammatory effects suggests that HGF may intercept common processes in the general inflammatory reaction rather than organ-specific mechanisms. Leukocyte adhesion to an activated endothelium is a prerequisite for generating an inflammatory infiltrate and is found in virtually all-inflammatory diseases.8.Bevilacqua M.P. Nelson R.M. Mannori G. Cecconi O. Endothelial–leukocyte adhesion molecules in human disease.Annu Rev Med. 1994; 45: 361-378Crossref PubMed Scopus (430) Google Scholar, 9.Carlos T.M. Harlan J.M. Leukocyte–endothelial adhesion molecules.Blood. 1994; 84: 2068-2101Crossref PubMed Google Scholar Increased expression of particular adhesion molecules is an important early marker of endothelial activation. E-selectin is of particular interest because it is only found on the inflamed endothelium in contrast to other adhesion molecules, which have a wide constitutive tissue distribution.9.Carlos T.M. Harlan J.M. Leukocyte–endothelial adhesion molecules.Blood. 1994; 84: 2068-2101Crossref PubMed Google Scholar Previous studies demonstrated that inhibition of endothelial activation by glucocorticoids35.Cronstein B.N. Kimmel S.C. Levin R.I. et al.A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial–leukocyte adhesion molecule 1 and intercellular adhesion molecule 1.Proc Natl Acad Sci USA. 1992; 89: 9991-9995Crossref PubMed Scopus (665) Google Scholar or statins36.Omi H. Okayama N. Shimizu M. et al.Statins inhibit high glucose-mediated neutrophil–endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide.Microvasc Res. 2003; 65: 118-124Crossref PubMed Scopus (43) Google Scholar attenuates inflammation by decreasing endothelial expression of adhesion molecules, including E-selectin. Similarly, blocking the interaction between the endothelium and leukocytes with E-selectin antibodies as well as selectin antagonists also ameliorates various inflammatory diseases.11.Welply J.K. Keene J.L. Schmuke J.J. Howard S.C. Selectins as potential targets of therapeutic intervention in inflammatory diseases.Biochim Biophys Acta. 1994; 1197: 215-226Crossref PubMed Scopus (50) Google Scholar, 12.Singbartl K. Ley K. Protection from ischemia–reperfusion induced severe acute renal failure by blocking E-selectin.Crit Care Med. 2000; 28: 2507-2514Crossref PubMed Scopus (121) Google Scholar, 13.Gotoh R. Suzuki J. Kosuge H. et al.E-selectin blockade decreases adventitial inflammation and attenuates intimal hyperplasia in rat carotid arteries after balloon injury.Arterioscler Thromb Vasc Biol. 2004; 24: 2063-2068Crossref PubMed Scopus (33) Google Scholar, 14.Azuma A. Takahashi S. Nose M. et al.Role of E-selectin in bleomycin induced lung fibrosis in mice.Thorax. 2000; 55: 147-152Crossref PubMed Scopus (42) Google Scholar, 15.Friedman G. Jankowski S. Shahla M. et al.Administration of an antibody to E-selectin in patients with septic shock.Crit Care Med. 1996; 24: 229-233Crossref PubMed Scopus (35) Google Scholar, 16.Huang J. Choudhri T.F. Winfree C.J. et al.Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke.Stroke. 2000; 31: 3047-3053Crossref PubMed Scopus (135) Google Scholar For instance, anti-E-selectin blocking antibody or E-selectin gene disruption protected mice from ischemia–reperfusion induced acute renal failure.12.Singbartl K. Ley K. Protection from ischemia–reperfusion induced severe acute renal failure by blocking E-selectin.Crit Care Med. 2000; 28: 2507-2514Crossref PubMed Scopus (121) Google Scholar Similarly, antibody blockade of E-selectin decreased adventitial inflammation and attenuated intimal hyperplasia in rat carotid arteries after balloon injury.13.Gotoh R. Suzuki J. Kosuge H. et al.E-selectin blockade" @default.
• W2024952909 created "2016-06-24" @default.
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• W2024952909 date "2006-04-01" @default.
• W2024952909 modified "2023-09-27" @default.
• W2024952909 title "Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin" @default.
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