Time course of lung ischemia-reperfusion-induced ICAM-1 expression and its role in ischemia-reperfusion lung injury.

Upregulation of intercellular adhesion molecule-1 (ICAM-1) expression is an important mechanism underlying ischemia-reperfusion (I/R) induced neutrophil activation and tissue injury in other organs. However, I/R of the lungs has not been shown to upregulate ICAM-1 expression. We determined the time course profile of lung I/R-induced ICAM-1 expression and assessed the role of ICAM-1 in mediating neutrophil sequestration, transmigration, and I/R injury in the isolated blood-perfused rat lungs. I/R had a biphasic effect on ICAM-1 expression, an early downregulation and a late-phase upregulation. Superoxide dismutase and neutrophil depletion prevented the early ICAM-1 downregulation. The late-phase ICAM-1 upregulation coincided with the I/R-induced increase in pulmonary microvascular leakage index. ICAM-1 monoclonal antibody (MAb) reversed the I/R-induced increase in pulmonary microvascular leakage index, with control antibody being ineffective. Neither I/R nor ICAM-1 MAb affected lung MPO activity and circulating neutrophil count. Lung I/R significantly increased bronchoalveolar lavage fluid neutrophil count and the GSSG-to-(GSSG+GSH) ratio. ICAM-1 MAb blocked the I/R-induced increase in GSSG-to-(GSSG+GSH) ratio but had no effect on bronchoalveolar lavage fluid neutrophil count. Our results demonstrated that lung I/R up- and downregulates ICAM-1 expression depending on the duration of reperfusion. ICAM-1 upregulation is an important mechanism of I/R-induced pulmonary endothelial injury.     

复方清下汤对脓毒症大鼠肺组织ICAM-1及AQP-1基因表达的影响

目的探讨复方清下汤对脓毒症大鼠肺组织ICAM-1及AQP-1基因表达的影响,进一步探讨其减轻肺损伤机制。方法将健康SD大鼠随机分为4组,每组10只：（1）假手术组（SHAM组）,SHAM组只翻动盲肠,不做其他处理;（2）脓毒症肺损伤组（模型组）,以盲肠结扎穿孔诱发ALI模型;（3）盲肠结扎穿孔＋复方清下汤组（造模后立即灌胃给药,造模后8 h再次灌胃1次,剂量：10 m l/kg）;（4）盲肠结扎穿孔＋头孢哌酮舒巴坦（舒普深）（造模后立即静脉注射1次,造模后8 h再次静脉注射1次,剂量：0.2 g/kg）造模24 h后收集标本。应用免疫组织化学和Western blotting法检测肺组织中AQP-1、ICAM-1的表达,RT-PCR检测肺组织上述蛋白mRNA表达。结果与SHAM组比较,模型组应用免疫组织化学及W estern-b lotting法检测ICAM-1的表达均显著升高（P〈0.01）,而AQP-1则表达明显降低（P〈0.01）;RT-PCR法检测mRNA转录水平与蛋白表达结果基本一致。抗生素及中药处理组与模型组比较,上述细胞因子ICAM-1的表达明显降低（P〈0.05）,而AQP-1表达上调（P〈0.01）,抗生素及中药处理组2组检测数据相近。结论脓毒症大鼠肺损伤时细胞因子ICAM-1过度表达而AQP-1蛋白表达下调可能是造成脓毒症肺损伤的重要原因;复方清下汤处理的动物模型肺损伤减轻的同时ICAM-1和AQP-1表达变化,提示它可能通过调控ICAM-1和AQP-1表达起作用。     

KB-R7943 inhibits high glucose-induced endothelial ICAM-1 expression and monocyte-endothelial adhesion

Hyperglycemia is the major cause of diabetic angiopathy. The aim of our study was to evaluate the impact of KB-R7943, an inhibitor of Na⁺/Ca²⁺ exchanger (NCX) on cell growth and function of human “diabetic” endothelial cells (EC). Intercellular adhesion molecule-1 (ICAM-1) expression and NCX activity were determined after EC were exposed to high glucose in the absence and presence of KB-R7943. Coincubation of EC with high glucose for 24 h resulted in a significant increase of monocyte-endothelial cell adhesion and the expression of ICAM-1. These effects were abolished by KB-R7943 and KB-R7943 significantly decreased the activation of NCX induced by high glucose. These findings suggested that KB-R7943 may play a role in inhibiting expression of adhesion molecules by inhibiting the reverse activation of NCX.     

褪黑素对大鼠内毒素性肺损伤抗氧化功能及ICAM-1表达的影响

目的:探讨褪黑素(MT)对大鼠急性肺损伤(ALI)时肺脏的保护作用及其可能机制。方法:将大鼠随机分为4组:对照组;脂多糖(LPS)组;地塞米松(DEX)和MT处理组。各组动物分别于气道内滴注后3、6和12h检测肺组织髓过氧化物酶(MPO)和超氧化物歧化酶(SOD)活性及丙二醛(MDA)含量;免疫组化检测细胞间黏附分子-1(ICAM-1)在肺组织的表达。结果:LPS组SOD活性较对照组明显降低(P<0.01),而MPO活性与MDA含量以及ICAM-1的表达则显著升高(P<0.01);应用MT及DEX均显著缓解上述变化(P<0.05或P<0.01)。结论:MT对ALI时的肺脏起明显的保护作用,其机制可能与MT清除自由基及抑制ICAM-1的表达有关。     

Distinct ICAM-1 forms and expression pathways in synovial microvascular endothelial cells.

Human synovial endothelial cell (HSE) intracellular adhesion molecule-1 (ICAM-1) is upregulated maximally by synergy of tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). Such synergy is not as pronounced in human umbilical vein endothelium (HUVE). ICAM surface staining and ELISA detection reflected similar levels on HUVE and HSE cells, yet mRNA levels were much higher in HSE cells in response to TNF alpha/IFN gamma. To correlate protein and mRNA levels of ICAM-1, both cell types were permeabilized and stained with a monoclonal antibody against ICAM-1. HSE cells displayed a distinct vesicular cytoplasmic staining for ICAM while HUVE cells were devoid of such stained vesicles upon staining with the antibody. ICAM-1 immunostaining of HSE cytoplasmic vesicles appeared enhanced in cells treated with TNF alpha/IFN gamma and monensin, an endosomal processing inhibitor. Monensin inhibited HSE cell surface expression of ICAM-1 routinely up to 70%, while HUVE cell expression was unaffected. In addition, monensin also inhibited soluble ICAM-1 release from HSE cells while not effecting HUVE cells. Immunoprecipitation of ICAM-1 followed by gel electrophoresis indicated that HUVE and HSE cell ICAMs are expressed in cell-specific forms. These results define distinct forms and distinct secretory pathways for ICAM-1 in HSE cells and HUVE cells that indicate functional differences between these human endothelia.     

NHE and ICAM-1 expression in hypoxic/reoxygenated coronary microvascular endothelial cells

Although Na+/H+ exchange (NHE) has been implicated in myocardial reperfusion injury, participation of coronary microvascular endothelial cells (CMECs) in this pathogenesis has been poorly understood. NHE-induced intracellular Ca2+ concentration ([Ca2+]i) overload in CMECs may increase the synthesis of intercellular adhesion molecules (ICAM), which is potentially involved in myocardial reperfusion injury. The present study tested the hypothesis that NHE plays a crucial role in [Ca2+]i overload and ICAM-1 synthesis in CMECs. Primary cultures of CMECs isolated from adult rat hearts were subjected to acidic hypoxia for 30 min followed by reoxygenation. Two structurally distinct NHE inhibitors, cariporide and 5-(N-N-dimethyl)-amiloride (DMA), had no significant effect on the acidic hypoxia-induced decrease in intracellular pH (pH(i)) of CMECs but significantly retarded pH(i) recovery after reoxygenation. These NHE inhibitors abolished the hypoxia- and reoxygenation-induced increase in [Ca2+]i. Expression of ICAM-1 mRNA was markedly increased in the vehicle-treated CMECs 3 h after reoxygenation, and this was significantly inhibited by treatment with cariporide, DMA, or Ca2+-free buffer. In addition, enhanced ICAM-I protein expression on the cell surface of CMECs 8 h after reoxygenation was attenuated by treatment with cariporide, DMA, or Ca2+-free buffer. These results suggest that NHE plays a crucial role in the rise of [Ca2+]i and ICAM-1 expression during acidic hypoxia/reoxygenation in CMECs. We propose that inhibition of ICAM-1 expression in CMECs may represent a novel mechanism of action of NHE inhibitors against ischemia-reperfusion injury.     

Neuropeptide regulation of human dermal microvascular endothelial cell ICAM-1 expression and function

There isincreasing evidence that sensory nerves may participate in cutaneousinflammatory responses by the release of neuropeptides such assubstance P (SP). We examined the direct effect of SP on human dermalmicrovascular endothelial cell (HDMEC) intercellular adhesion molecule1 (ICAM-1) expression and function. Our results indicated that,although cultured HDMEC expressed mRNA for neurokinin receptors 1, 2, and 3 (NK-1R, NK-2R, and NK-3R), SP initiated a rapid increase in HDMECintracellular Ca²⁺ levels,primarily by the activation of NK-1R. Immunohistochemistry studieslikewise demonstrated that HDMEC predominantly expressed NK-1R. Theaddition of SP to HDMEC resulted in a rapid increase in cellular ICAM-1mRNA levels, followed by a fivefold increase in ICAM-1 cell surfaceexpression. This functionally resulted in a threefold increase in⁵¹Cr-labeled binding of J-Ylymphoblastoid cells to HDMEC. In vivo studies demonstrated a markedincrease in microvascular ICAM-1 immunostaining 24 and 48 h afterapplication of capsaicin to the skin. These results indicate thatneuropeptides such as SP are capable of directly activating HDMEC toexpress increased levels of functional ICAM-1 and further support therole of the cutaneous neurological system in modulating inflammatoryprocesses in the skin.

     

Visfatin enhances ICAM-1 and VCAM-1 expression through ROS-dependent NF-kappaB activation in endothelial cells

Visfatin has recently been identified as a novel visceral adipokine which may be involved in obesity-related vascular disorders. However, it is not known whether visfatin directly contributes to endothelial dysfunction. Here, we investigated the effect of visfatin on vascular inflammation, a key step in a variety of vascular diseases. Visfatin induced leukocyte adhesion to endothelial cells and the aortic endothelium by induction of the cell adhesion molecules, ICAM-1 and VCAM-1. Promoter analysis revealed that visfatin-mediated induction of CAMs is mainly regulated by nuclear factor-kappaB (NF-kappaB). Visfatin stimulated IkappaBalpha phosphorylation, nuclear translocation of the p65 subunit of NF-kappaB, and NF-kappaB DNA binding activity in HMECs. Furthermore, visfatin increased ROS generation, and visfatin-induced CAMs expression and NF-kappaB activation were abrogated in the presence of the direct scavenger of ROS. Taken together, our results demonstrate that visfatin is a vascular inflammatory molecule that increases expression of the inflammatory CAMs, ICAM-1 and VCAM-1, through ROS-dependent NF-kappaB activation in endothelial cells.     

Enteric microflora contribute to constitutive ICAM-1 expression on vascular endothelial cells

Quantitative estimates of endothelial cell adhesion molecule expression have revealed that some adhesion molecules [e.g., intercellular adhesion molecule-1 (ICAM-1)] are abundantly expressed in different vascular beds under normal conditions. The objective of this study was to determine whether the enteric microflora contribute to the constitutive expression of ICAM-1 and other endothelial cell adhesion molecules in the gastrointestinal tract and other regional vascular beds. The dual radiolabeled monoclonal antibody technique was used to measure endothelial expression of ICAM-1, ICAM-2, vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in conventional, germ-free mice and germ-free mice receiving the cecal contents of conventional mice to reestablish the enteric microflora (total association). Constitutive ICAM-1 expression was significantly lower in the splanchnic organs (pancreas, stomach, small and large intestine, mesentery, and liver), kidneys, skeletal muscle, and skin of germ-free mice compared with their conventional counterparts. These differences were abolished after total association of germ-free mice with the indigenous gastrointestinal flora. The expression of ICAM-2, VCAM-1, and E-selectin in the various tissues studied did not differ between conventional and germ-free mice. These findings indicate that the indigenous gastrointestinal microflora are responsible for a significant proportion of the basal ICAM-1 expression detected in both intestinal and extraintestinal tissues.     

Hyperketonemia increases monocyte adhesion to endothelial cells and is mediated by LFA-1 expression in monocytes and ICAM-1 expression in endothelial cells

Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. The objective of this study was to examine the hypothesis that hyperketonemia increases monocyte-endothelial cell (EC) adhesion and the development of vascular disease in diabetes. Human U937 and THP-1 monocyte cell lines and human umbilical vein endothelial cells (HUVECs) were cultured with acetoacetate (AA) (0-10 mM) or β-hydroxybutyrate (BHB) (0-10 mM) for 24 h prior to evaluating adhesion and adhesion molecule expression. The results demonstrate a significant (P < 0.01) increase in both U937 and THP-1 adhesion to HUVEC monolayers treated with 4 mM AA compared with control. Equal concentrations of BHB resulted in similar increases in monocyte-EC adhesion. Similarly, treatments of AA or BHB to isolated monocytes from human blood also show increases in adhesion to endothelial cells. intercellular adhesion molecule-1 (ICAM-1) was significantly increased on the surface of HUVECs and an increase in total protein expression with AA treatment compared with control. The expression level of lymphocyte function-associated antigen-1 (LFA-1) was increased in monocytes treated with AA, and LFA-1 affinity was altered from low to high affinity following treatment with both AA and BHB. Monocyte adhesion could be blocked when cells were preincubated with an antibody to ICAM-1 or LFA-1. Results also show a significant increase in IL-8 and MCP-1 secretion in monocytes and HUVECs treated with 0-10 mM AA. These results suggest that hyperketonemia can induce monocyte adhesion to endothelial cells and that it is mediated via increased ICAM-1 expression in endothelial cells and increased expression and affinity of LFA-1 in monocytes.     

Effect of steroid on hyperoxia-induced ICAM-1 expression in pulmonary endothelial cells

Intercellular adhesion molecule-1 (ICAM-1) of the vascular endothelium plays a key role in the development of pulmonary oxygen toxicity. We studied the effect of steroid on hyperoxia-induced ICAM-1 expression using cultured endothelial cells in vitro. Human pulmonary artery endothelial cells (HPAECs) were cultured to confluence, and then the monolayers were exposed to either control (21% O(2)-5% CO(2)) or hyperoxic (90% O(2)-5% CO(2)) conditions with and without a synthetic glucocorticoid, methylprednisolone (MP). MP reduced hyperoxia-induced ICAM-1 and ICAM-1 mRNA expression in a dose-dependent manner. Neutrophil adhesion to hyperoxia-exposed endothelial cells was also inhibited by MP treatment. In addition, MP attenuated hyperoxia-induced H(2)O(2) production in HPAECs as assessed by flow cytometry. An electrophoretic mobility shift assay demonstrated that hyperoxia activated nuclear factor-kappaB (NF-kappaB) but not activator protein-1 (AP-1) and that MP attenuated hyperoxia-induced NF-kappaB activation dose dependently. With Western immunoblot analysis, IkappaB-alpha expression was decreased by hyperoxia and increased by MP treatment. These results suggest that MP downregulates hyperoxia-induced ICAM-1 expression by inhibiting NF-kappaB activation via increased IkappaB-alpha expression.     

RORalpha1 and RORalpha4 suppress TNF-alpha-induced VCAM-1 and ICAM-1 expression in human endothelial cells

Retinoic acid receptor-related orphan receptor-alpha (RORalpha) is a nuclear orphan receptor. Adenovirus-mediated overexpression of RORalpha1 and RORalpha4 suppressed tumor necrosis factor-alpha (TNF-alpha)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells. Overexpression of RORalpha1 and RORalpha4 also suppressed TNF-alpha-stimulated translocation of p50 and p65 to the nucleus. In contrast, dominant-negative deletion mutants of RORalpha1 and RORalpha4 failed to suppress the induction of VCAM-1 and ICAM-1 and translocations of p50 and p65. These results suggest that RORalpha1 and RORalpha4 regulate the inflammatory responses via inhibition of the nuclear factor-kappaB signaling pathway in endothelial cells.     

Mast cells are potent regulators of endothelial cell adhesion molecule ICAM-1 and VCAM-1 expression

To investigate the possible role of mast cells (MC) in regulating leukocyte adhesion to vascular endothelial cells (EC), microvascular and macrovascular EC were exposed to activated MC or MC conditioned medium (MCCM). Expression of intercellular and vascular adhesion molecules (ICAM-1 and VCAM-1) on EC was monitored. Incubation of human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells (HUVEC) with activated MC or MCCM markedly increased ICAM-1 and VCAM-1 surface expression, noted as éarly as 4 hr. Maximal levels were observed at 16 hr followed by a general decline over 48 hr. A dose-dependent response was noted using incremental dilutions of MCCM or by varying the number of MC in coculture with EC. At a ratio as low as 1:1,000 of MC:EC, increased ICAM-1 was observed. The ICAM-1 upregulation by MCCM was >90% neutralized by antibody to tumor necrosis factor alpha (TNF-α), suggesting that MC release of this cytokine contributes significantly to inducing EC adhesiveness. VCAM-1 expression enhanced by MCCM was partly neutralized (70%) by antibody to TNF-α; thus other substances released by MC may contribute to VCAM-1 expression. Northern blot analysis demonstrated MCCM upregulated ICAM-1 and VCAM-1 mRNA in both HDMEC and HUVEC. To evaluate the function of MCCM-enhanced EC adhesion molecules, T cells isolated from normal human donors were used in a cell adhesion assay. T-cell binding to EC was increased significantly after exposure of EC to MCCM, and inhibited by antibodies to ICAM-1 or VCAM-1. Intradermal injection of allergen in human atopic volunteers known to develop late-phase allergic reactions led to marked expression of both ICAM-1 and VCAM-1 at 6 hr, as demonstrated by immunohistochemistry. These studies indicate that MC play a critical role in regulating the expression of EC adhesion molecules, ICAM-1 and VCAM-1, and thus augment inflammatory responses by upregulating leukocyte binding. © 1995 Wiley-Liss Inc.     

Alterations in TGF-beta1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension

The mechanisms responsible for pulmonary vascular remodeling in congenital heart disease with increased pulmonary blood flow remain unclear. We developed a lamb model of congenital heart disease and increased pulmonary blood flow utilizing an in utero placed aortopulmonary vascular graft (shunted lambs). Morphometric analysis of barium-injected pulmonary arteries indicated that by 4 wk of age, shunts had twice the pulmonary arterial density of controls (P < 0.05), and their pulmonary vessels showed increased muscularization and medial thickness at both 4 and 8 wk of age (P < 0.05). To determine the potential role of TGF-beta1 in this vascular remodeling, we investigated vascular changes in expression and localization of TGF-beta1 and its receptors TbetaRI, ALK-1, and TbetaRII in lungs of shunted and control lambs at 1 day and 1, 4, and 8 wk of life. Western blots demonstrated that TGF-beta1 and ALK-1 expression was elevated in shunts compared with control at 1 and 4 wk of age (P < 0.05). In contrast, the antiangiogenic signaling receptor TbetaRI was decreased at 4 wk of age (P < 0.05). Immunohistochemistry demonstrated shunts had increased TGF-beta1 and TbetaRI expression in smooth muscle layer and increased TGF-beta1 and ALK-1 in endothelium of small pulmonary arteries at 1 and 4 wk of age. Moreover, TbetaRI expression was significantly reduced in endothelium of pulmonary arteries in the shunt at 1 and 4 wk. Our data suggest that increased pulmonary blood flow dysregulates TGF-beta1 signaling, producing imbalance between pro- and antiangiogenic signaling that may be important in vascular remodeling in shunted lambs.     

Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-alpha-treated human aortic endothelial cells

Attachment to, and migration of leukocytes into the vessel wall is an early event in atherogenesis. Expression of cell adhesion molecules by the arterial endothelium may play a major role in atherosclerosis. It has been suggested that antioxidants inhibit the expression of adhesion molecules and may thus attenuate the processes leading to atherosclerosis. In the present study, the effects of a potent water-soluble antioxidant, salvianolic acid B (Sal B), and an aqueous ethanolic extract (SME), both derived from a Chinese herb, Salvia miltiorrhiza, on the expression of endothelial-leukocyte adhesion molecules by tumor necrosis factor-alpha (TNF-alpha)-treated human aortic endothelial cells (HAECs) were investigated. When pretreated with SME (50 and 100 microg/ml), the TNF-alpha-induced expression of vascular adhesion molecule-1 (VCAM-1) was notably attenuated (77.2 +/- 3.2% and 80.0 +/- 2.2%, respectively); and with Sal B (1, 2.5, 5, 10, and 20 microg/ml), 84.5 +/- 1.9%, 78.8 +/- 1.2%, 58.9 +/- 0.4%, 58.7 +/- 0.9%, and 57.4 +/- 0.3%, respectively. Dose-dependent lowering of expression of intercellular cell adhesion molecule-1 (ICAM-1) was also seen with SME or Sal B. In contrast, the expression of endothelial cell selectin (E-selectin) was not affected. SME (50 microg/ml) or Sal B (5 microg/ml) significantly reduced the binding of the human monocytic cell line, U937, to TNF-alpha-stimulated HAECs (45.7 +/- 2.5% and 55.8 +/- 1.2%, respectively). SME or Sal B significantly inhibited TNF-alpha-induced activation of nuclear factor kappa B (NF-kappaB) in HAECs (0.36- and 0.48-fold, respectively). These results demonstrate that SME and Sal B have anti-inflammatory properties and may explain their anti-atherosclerotic properties. This new mechanism of action of Sal B and SME, in addition to their previously reported inhibition of LDL, may help explain their efficacy in the treatment of atherosclerosis.     

Influence of polyelectrolyte multilayer films on the ICAM-1 expression of endothelial cells

Recently, the use of polyelectrolyte films has been suggested as a new versatile technique of surface modification aimed at tissue engineering. In the present study, we evaluated the expression of intercellular adhesion molecule (ICAM)-1 of endothelial cells (ECs) seeded on two types of polyelectrolyte multilayer films either terminated by poly(D-lysine) (PDL) or poly(allylamine hydrochloride) (PAH). This work showed that chemical stimulations with tumor necrosis factor (TNF)-alpha induced the ICAM-1 expression of ECs differently depending largely on the film architecture employed. Compared with PAH-ending films, the PDL-ending ones upregulated the ICAM-1 expression of the ECs after a prolonged exposition to TNF-alpha, rendering this film type less favorable in tissue engineering. Cytochalasin D (an F-actin disrupting agent) showed the involvement of the cytoskeleton in the upregulation of ICAM-1 for cells deposited on films terminated by PDL. The PAH-ending films did not perturb the ICAM-1 expression of ECs and might thus enhance the seeding of ECs in vascular engineering.     

MCTR1 alleviates lipopolysaccharide-induced acute lung injury by protecting lung endothelial glycocalyx

Endothelial glycocalyx degradation, critical for increased pulmonary vascular permeability, is thought to facilitate the development of sepsis into the multiple organ failure. Maresin conjugates in tissue regeneration 1 (MCTR1), a macrophage-derived lipid mediator, which exhibits potentially beneficial effects via the regulation of bacterial phagocytosis, promotion of inflammation resolution, and regeneration of tissue. In this study, we show that MCTR1 (100 ng/mouse) enhances the survival of mice with lipopolysaccharide (LPS)-induced (15 mg/kg) sepsis. MCTR1 alleviates LPS (10 mg/kg)-induced lung dysfunction and lung tissue inflammatory response by decreasing inflammatory cytokines (tumor necrosis factor-α, interleukin-1β [IL-1β], and IL-6) expression in serum and reducing the serum levels of heparan sulfate (HS) and syndecan-1. In human umbilical vein endothelial cells (HUVECs) experiments, MCTR1 (100 nM) was added to the culture medium with LPS for 6 hr. MCTR1 treatment markedly inhibited HS degradation by downregulating heparanase (HPA) protein expression in vivo and in vitro. Further analyses indicated that MCTR1 upregulates sirtuin 1 (SIRT1) expression and decreases NF-κB p65 phosphorylation. In the presence of BOC-2 or EX527, the above effects of MCTR1 were abolished. These results suggest that MCTR1 protects against LPS-induced sepsis in mice by attenuating pulmonary endothelial glycocalyx injury via the ALX/SIRT1/NF-κB/HPA pathway.