OBJECTIVE:This study was undertaken to uncover the pathophysiologic role of discoidin domain receptor 2 (DDR-2), a putative fibrillar collagen receptor, in inflammation promotion and joint destruction in rheumatoid arthritis (RA).METHODS:In synovial tissue from patients with RA and from mice with collagen antibody-induced arthritis (CAIA) (using Ddr2-/- and DBA/1 mice), gene and protein expression levels of DDR-2, interleukin-15 (IL-15), and Dkk-1 were measured by quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Gene knockdown of DDR2 in human RA fibroblast-like synoviocytes (FLS) was conducted via small interfering RNA. Interaction between the long noncoding RNA H19 and microRNA 103a (miR-103a) was assessed in RA FLS using RNA pulldown assays. Cellular localization of H19 was examined using fluorescence in situ hybridization assays. Chromatin immunoprecipitation and dual luciferase reporter assays were applied to verify H19 transcriptional and posttranscriptional regulation by miR-103a.RESULTS:DDR2 messenger RNA (mRNA) expression was significantly associated with the levels of IL-15 and Dkk-1 mRNA in the synovial tissue of RA patients (r2 = 0.2022-0.3293, all P < 0.05; n = 33) and with the serum levels of IL-15 and Dkk-1 in mice with CAIA (P < 0.05). In human RA FLS, activated DDR-2 induced the expression of H19 through c-Myc. Moreover, H19 directly interacted with and promoted the degradation of miR-103a.CONCLUSION:These results indicate a novel role for activated DDR-2 in RA FLS, showing that DDR-2 is responsible for regulating the expression of IL-15 and Dkk-1 in RA FLS and is involved in the promotion of inflammation and joint destruction during pathophysiologic development of RA. Moreover, DDR-2 inhibition, acting through the H19-miR-103a axis, leads to reductions in the inflammatory reaction and severity of joint destruction in mice with CAIA, suggesting that inhibition of DDR-2 may be a potential therapeutic strategy for RA.

Objective: Chondrocyte apoptosis is a pathological manifestation of osteoarthritis. The goal of this report was to explore the role of nitric oxide in chondrocyte apoptosis in osteoarthritic mandibular condylar cartilage. Design: This study used our reported experimental unilateral anterior crossbite in vivo rat model and chondrocyte fluid flow shear stress in vitro model. In the in vivo model, apoptosis in the mandibular condylar cartilage was assessed by detection of the TUNEL-positive cells, the expression levels of inducible nitric oxide synthase (iNOS), caspase-9, and caspase-3. In the in vitro model, mitochondria] injury was evaluated, the nitric oxide and superoxide dismutase (SOD) production levels were measured, and the cytochrome C (Cyt C) expression level was detected. The expression levels of apoptosis-related proteins B cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, and poly-ADP-ribose polymerase 1 (PARP1) were analyzed in both in vivo and in vitro models. The effects of iNOS inhibitor on chondrocyte apoptosis were also investigated. Results: The data indicated that the unilateral anterior crossbite induced cartilage degeneration with enhanced cell apoptosis and stimulated the expression of caspase-3/-9 and iNOS. The fluid flow shear stress upregulated the expression of iNOS, SOD, and nitric oxide, reduced mitochondrial membrane potential, and promoted Cyt C to enter the cytoplasm. All of these changes were reversed by iNOS inhibitors. Conclusion: The abnormal occlusion stimulated mitochondrial damage and apoptosis of the chondrocytes in the mandibular condylar cartilage mediated by nitric oxide. Inhibiting nitric oxide production could be a therapeutic strategy.

Inflammatory bowel disease (IBD) is a chronic, recurrent, and remitting inflammatory disease resulting from immune dysregulation in the gut. As a clinically frequent disease, it can affect individuals throughout their lives, with multiple complications. Glucagon-like peptide 2 (GLP-2) is a potent epithelium-specific intestinal growth factor. However, native GLP-2 has a relatively short half-life in human circulation because of extensive renal clearance and rapid degradation by the proteolytic enzyme dipeptidyl peptidase-IV (DPP-IV). Previously, We prepared a recombinant GLP-2 variant (GLP-2②), which has increased half-life and activity as compared to the [Gly2]GLP-2 monomer. The aim of the present study was to investigate the protective potential of GLP-2② in IBD models. LPS-induced in vitro model and dextran sulfate sodium (DSS)-induced in vivo model were used to study the anti-inflammatory and therapeutic effect of GLP-2②. We found that treated with GLP-2② showed a significantly reduction in the secretion of inflammatory cytokines. Furthermore, GLP-2② alleviated symptoms of DSS-induced colitis. GLP-2② treated mice displayed an increase in body weight, lower colitis scores, and fewer mucosal damage compared with GLP-2 treated mice. MPO activities, protein expression of NLRP3 and COX2 in the colon tissues were significantly reduced in GLP-2② groups. Importantly, the ameliorative effect of GLP-2② was related to anti-apoptosis effect in colon tissues. These findings demonstrated that GLP-2② may offer a superior therapeutic benefit over [Gly2]GLP-2 monomer for treatment of IBD.

Pterostilbene (PT), an analog of resveratrol, exerts a potent anti-inflammatory effect. However, the protective effects of PT against inflammation in endothelial cells have not been elucidated. Previous studies have confirmed that endoplasmic reticulum stress (ERS) plays an important role in regulating the pathological process of endothelial cell inflammation. In this study, we explored the effect of PT on the tumor necrosis factor-α (TNF-α)-induced inflammatory response in human umbilical vein endothelial cells (HUVECs) and elaborated the role of ERS in this process. TNF-α treatment significantly upregulated the levels of inflammation-related molecules in cell culture media, increased the adhesion of monocytes to HUVECs, and enhanced the expression of the MMP9 and ICAM proteins in HUVECs. Additionally, TNF-α potently increased ERS-related protein levels, such as GRP78 and p-eIF2α. However, PT treatment reversed the increased production of inflammatory cytokines and the adhesion of monocytes to HUVECs, as well as reduced the TNF-α-induced effects exerted by ERS-related molecules. Furthermore, thapsigargin (THA), an ERS inducer, attenuated the protective effect of PT against TNF-α-induced inflammation and ERS in HUVECs. Additionally, the downregulation of ERS signaling using siRNA targeting eIF2α and IRE1 not only inhibited ERS-related molecules but also simulated the therapeutic effects of PT on TNF-α-induced inflammation. In summary, PT treatment potently attenuates inflammation in vascular endothelial cells, which at least partly depends on the reduction of ERS.

Ischemia reperfusion (IR) injury (IRI) is associated with poor prognoses in the settings of both cardiac surgery and ischemic heart disease and causes mitochondrial oxidative stress and cell death. Silent information regulator 1 (SIRT1), a member of the histone deacetylase family, exerts anti-IRI effects. Bakuchiol (BAK), an analog of resveratrol and a monoterpene phenol isolated from the seeds of Psoralea corylifolia (Leguminosae), protects tissues from injury. This study was designed to investigate the protective effects of BAK treatment in the setting of myocardial IRI and to elucidate the potential mechanism of those effects. Prior to induction of IR, isolated rat hearts or cardiomyocytes were exposed to BAK in either the absence or presence of the SIRT1 inhibitors Sirtinol and SIRT1 siRNA. BAK exerted cardioprotective effects, as evidenced by the improvements noted in cardiac function following ischemia, attenuated myocardial apoptosis, and changes in several biochemical parameters (including increases in the level of the anti-apoptotic protein Bcl2, decreases in the level of the pro-apoptotic protein Bax, and decreases in the cleaved Caspase 3 level). However, Sirtinol and SIRT1 siRNA each blocked BAK-induced cardioprotection by inhibiting SIRT1 signaling. Additionally, BAK significantly increased the activities of mitochondrial succinate dehydrogenase, cytochrome c oxidase, and mitochondrial superoxide dismutase and decreased the production of malondialdehyde. These findings suggested that BAK significantly attenuated IR-induced mitochondrial oxidative damage. However, Sirtinol and SIRT1 siRNA abolished BAK-dependent mitochondrial function. In summary, our results demonstrate that BAK treatment attenuates IRI by attenuating IR-induced mitochondrial oxidative damage via the activation of SIRT1/PGC-1α signaling.

Atherosclerosis is a chronic inflammatory disease associated with increased expression of adhesion molecules in vascular smooth muscle cells (VSMCs). Matrine is a main active ingredient of Sophora flavescens roots, which are used to treat inflammatory diseases. However, the effects of matrine on the expression of adhesion molecules in VSMCs have largely remained elusive. Therefore, the present study investigated the effects of matrine on the expression of adhesion molecules in tumor necrosis factor (TNF)‑α‑stimulated human aortic smooth muscle cells (HASMCs). The results showed that matrine inhibited the expression of vascular cell adhesion molecule‑1 (VCAM‑1) and intercellular adhesion molecule‑1 (ICAM‑1) in TNF‑α‑stimulated HASMCs. Matrine markedly inhibited the TNF‑α‑induced expression of nuclear factor (NF)‑κB p65 and prevented the TNF‑α‑caused degradation of inhibitor of NF‑κB; it also inhibited TNF‑α‑induced activation of mitogen‑activated protein kinases (MAPKs). Furthermore, matrine inhibited the production of intracellular reactive oxygen species (ROS) in TNF‑α‑stimulated HASMCs. In conclusion, the results of the present study demonstrated that matrine inhibited the expression of VCAM‑1 and ICAM‑1 in TNF‑α‑stimulated HASMCs via the suppression of ROS production as well as NF‑κB and MAPK pathway activation. Therefore, matrine may have a potential therapeutic use for preventing the advancement of atherosclerotic lesions.

OBJECTIVE:To investigate the protective effects and related mechanisms of soybean isoflavone (SI) on human umbilical vein endothelial cells (HUVECs) injury induced by H₂O₂ and lipopolysaccharide (LPS).METHODS:H₂O₂ and LPS were used to induce HUVECs injury in vitro. Nine experimental groups were examined: control group, H₂O₂ (2 mmol/L for 4 h), LPS (2 mmol/L for 4 h), H₂O₂+low dose SI (1 mg/ml), H₂O₂+moderate dose SI (2.5 mg/ml), H₂O₂+high dose SI (5 mg/ml), LPS+low dose SI (1 mg/ml), LPS+moderate dose SI (2.5 mg/ml), LPS+high dose SI (5 mg/ml). The survival ratio of HUVECs was detected with MTT assay. The cultured cells were loaded by Fura-2/AM and the change of [Ca²⁺] in HUVECs was measured by fluorospectrophotometry. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH-Px) were measured by the commercial kits. The levels of tissue plasminogen activator IL-6 in the supematant were measured by enzyme linked immunosorbent assay (ELISA) kits. Apoptosis rate of the HUVECs was analyzed by flow cytometry.RESULTS:H₂O₂ and LPS significantly decreased HUVECs viability, increased the contents of MDA, IL-6 and decreased the contents of SOD and GSH-Px, and increased the apoptosis rate [(37.8 ± 1.8)% and (38.9 ± 1.1)%]. Co-treatment with SI could reduce MDA and IL-6 while increase SOD and GSH-Px and reduce apoptosis in a dose-dependent manner.CONCLUSION:The findings demonstrate that soybean isoflavone could attenuate H₂O₂ and LPS induced injury in human umbilical vein endothelial cells through protecting mitochondrial function, improving antioxygenic activity, and suppressing the mobilization of cytosolic calcium.

BACKGROUND:Cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) 3 has been recently reported to play a role in regulating inflammation of vascular endothelial cells. However, the role of CCN3 in atherosclerosis, which is characterized by vascular inflammation, remains unclear.HYPOTHESIS AND OBJECTIVES:Overexpression of CCN3 may relieve the inflammation response in and inhibit the progress of atherosclerosis. We aimed to explore the potential roles of CCN3 in inflammation in atherosclerosis.STRATEGY AND MAIN RESULTS:In in vitro studies using cultured human aortic endothelial cells and human umbilical vein endothelial cells, CCN3 mRNA and protein expression significantly decreased in response to tumor necrosis factor-α and interleukin-1β treatments (p<0.05), when analyzed by quantitative real-time polymerase chain reaction and Western blot. Using a mouse model of atherosclerosis, the mRNA and protein levels of CCN3 decreased by 72.2% (p = 0.041) and 86.4% (p = 0.036), respectively, compared with levels in wild-type control mice, respectively. Overexpression of CCN3 by adenovirus-mediated gene overexpression decreased low-density lipoprotein cholesterol by 48.9% (p = 0.017), total cholesterol by 58.9% (p = 0.031), and triglycerides by 56.8% (p = 0.022), and it increased high-density lipoprotein cholesterol level by 2.16-fold (p = 0.039), compared with control groups. Additionally, a reduced plaque area and increased fibrous cap were observed (p<0.05). Furthermore, CCN3 overexpression decreased cell adhesion molecule-1 mRNA expression by 84.7% (p = 0.007) and intercellular adhesion molecule-1 mRNA expression by 61.2% (p = 0.044). Inflammatory factors, including matrix metalloproteinases, cyclooxygenase 2, and tissue factor also significantly (p<0.05) decreased with CCN3 overexpression in the atherosclerotic mouse model. Additionally, CCN1 and CCN2, which have been reported to be highly expressed in aortic atherosclerotic plaques, were significantly downregulated (p<0.05) by CCN3 overexpression.CONCLUSION:CCN3 overexpression is associated with control of inflammatory processes and reversion of dyslipidemia in the process of atherosclerosis, which implies that CCN3 may be a promising target in the treatment of atherosclerosis.

Ion channels have been suggested to be important in the development and progression of tumors, however, chloride channels have rarely been analyzed in tumorigenesis. More recently, transmembrane protein with unknown function 16A (TMEM16A), hypothesized to be a candidate calcium‑activated Cl‑ channel, has been found to be overexpressed in a number of tumor types. Although several studies have implicated the overexpression of TMEM16A in certain tumor types, the exact role of TMEM16A in gliomas and the underlying mechanisms in tumorigenesis, remain poorly understood. In the present study, the role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed. TMEM16A was highly abundant in various grades of gliomas and cultured glioma cells. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion. Furthermore, nuclear factor‑κB (NF‑κB) was activated by overexpression of TMEM16A. In addition, TMEM16A regulated the expression of NF‑κB‑mediated genes, including cyclin D1, cyclin E and c‑myc, involved in cell proliferation, and matrix metalloproteinases (MMPs)‑2 and MMP‑9, which are associated with the migration and invasion of glioma cells. Collectively, results of the present study provide evidence for the involvement of TMEM16A in gliomas and the potential mechanism through which TMEM16A promotes glioma formation.

With the objective of identifying promising antitumor agents for human leukemia, we carried out to determine the anticancer ability of oxymatrine on the human leukemia HL-60 cell line. In vitro experiments demonstrated that oxymatrine reduced the proliferation of HL-60 cells in a dose- and time-dependent manner via the induction of apoptosis and cell cycle arrest at G2/M and S phases. The proteins involved in oxymatrine-induced apoptosis in HL-60 cells were also examined using Western blot. The increase in apoptosis upon treatment with oxymatrine was correlated with downregulation of anti-apoptotic Bcl-2 expression and upregulation of pro-apoptotic Bax expression. Furthermore, oxymatrine induced the activation of caspase-3 and caspase-9 and the cleavage of poly(ADP-ribose) polymerase (PARP) in HL-60 cells. In addition, pretreatment with a specific caspase-3 (Z-DEVD-FMK) or caspase-9 (Z-LEHD-FMK) inhibitor significantly neutralized the pro-apoptotic activity of oxymatrine in HL-60 cells, demonstrating the important role of caspase-3 and caspase-9 in this process. Taken together, these results indicated that oxymatrine-induced apoptosis may occur through the activation of the caspase-9/caspase-3-mediated intrinsic pathway. Therefore, oxymatrine may be a potential candidate for the treatment of human leukemia.

Smooth muscle cell (SMC) proliferation and migration are known to play a critical role in the development of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) is involved in the generation of atherosclerotic lesions. Recent studies have indicated that oxLDL is a well-established risk factor for atherosclerosis that induces vascular smooth muscle cell (VSMC) proliferation and migration; however, the exact mechanisms involved have not been fully elucidated. In this study, the proliferation of human coronary artery smooth muscle cells (HCASMCs) was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell migration was determined by Transwell assay. Osteopontin (OPN), matrix metaloproteinase-9 (MMP-9) and αvβ3 integrin expression were measured by mRNA and western blot analysis. OPN and MMP-9 knockdown cells were established through transfection with OPN siRNA or MMP-9 siRNA, respectively. Our results revealed that oxLDL makredly promoted HCASMC proliferation and migration in a dose-dependent manner. Further experiments demonstrated that oxLDL upregulated the expression of OPN and oxLDL. Cell proliferation and migration were markedly reduced following the knockdown of the OPN gene in the HCASMCs. We then found that treatment with oxLDL induced a concentration-dependent increase in MMP-9 mRNA and protein levels in the HCASMCs. These effects were partially abrogated by silencing OPN expression or blocking the αvβ3 integrin pathway. Moreover, cells treated with MMP-9 siRNA or αvβ3 antibody showed lower proliferation and migration rates. This study provides direct in vitro evidence that the exposure of HCASMCs to oxLDL induces the activation of OPN, leading to higher protein levels of MMP-9, and to an increased proliferation and migration of HCASMCs.

A neutral polysaccharide fraction (CGPP) was extracted from Gynostemma pentaphyllum by water extraction and ethanol precipitation. Gas chromatography (GC) analysis showed that the CGPP was mainly composed of mannose, glucose, arabinose, rhamnose, galactose and glucuronic acid in molar ratios of 2.0:2.2:1.3:2.2:1.2:2.5. The present study aimed at evaluating the antitumor potentials of CGPP on the growth of H22 tumor transplanted in mice and the underlying mechanism. The results showed that CGPP (50 and 200 mg/kg) could effectively inhibit the solid tumor growth of H22 hepatocarcinoma transplanted in ICR mice. Besides, the body weight, spleen/thymus indexes and splenocytes proliferation of H22 tumor bearing mice were also improved in CGPP-treated groups. Furthermore, the level of the cytokines, such as IL-2, TNF-α and IFN-γ, as well as the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) in tumor-bearing mice were markedly promoted by CGPP oral administration. In addition, CGPP treatment greatly prolonged the survival period in H22 ascites tumor-bearing mice. Taken together, these findings indicate that CGPP has antitumor activity in vivo at least partly via improving immune responses of host organism, and seems to be a safe and effective supplementary agent for the treatment of hepatocellular carcinoma (HCC).

Substantial evidence suggests that inflammation is an important contributor to many neurodegenerative disorders. Activated microglial cells play an important role in releasing pro-inflammatory factors, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) for inducing inflammation. Recently, some reports have suggested that glycoprotein nonmetastatic melanoma B (GPNMB) is highly expressed in microglia after LPS treatment. However, the role of GPNMB in activated microglia is not clearly understood. In this study, we used RT-PCR and Western blotting to detect GPNMB and matrix metalloproteinase-3 (MMP-3) expressions in activated microglia. GPNMB small interfering RNA (siRNA) or MMP-3 inhibitor was applied on microglial BV2 cells, and ELISA was performed to measure the expressions of TNF-α and IL-1β in BV2 cells. Levels of iNOS and NO in BV2 cells were also determined. We found that the levels of GPNMB and MMP-3 were significantly increased in BV2 cells after LPS treatment. Moreover, we found that GPNMB significantly upregulated the expression of MMP-3 in BV2 cells, and high expression of MMP-3 was dependent on the level of GPNMB. Inhibition of GPNMB or MMP-3 expression by GPNMB siRNA or MMP-3 inhibitor dramatically suppressed the expressions of TNF-α, IL-1β, iNOS, and NO in activated microglia. All of these results suggest that GPNMB is involved in the inflammatory responses of microglia.

Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immunity are involved. Although there have been major advances in the involvement of toll-like receptor 4 (TLR4) and CD36 in the initiation and development of this disease, detailed mechanisms remain unknown. Here, we show that tenascin-C (TN-C) can stimulate foam cell formation and this can be inhibited by a TLR4-blocking antibody or CD36 gene silencing. Our results identify TN-C-TLR4 activation as a common molecular mechanism in oxLDL-stimulated foam cell formation and atherosclerosis. In addition, CD36 is the major scavenger receptor responsible for the TN-C-mediated foam cell formation. Taken together, we have identified that TNC produced by oxLDL-stimulated macrophages increases foam cell formation through TLR4 and scavenger receptor CD36.

Background/Purpose: Ginsenosides have many biomedical efficacies, such as anti-aging, antioxidation, and anti-inflammatory activities. Compound K (CK), one of the major metabolites of ginsenosides, mediates the antimetastatic and anti-allergic activities of the ginsenosides. The purpose of this study was to investigate the effect of CK on level of type I collagen, matrix metalloproteinase (MMP)-1 activity, and protein level in ultraviolet (UV)A-irradiated fibroblasts.Methods: Fibroblasts were cultured with and without CK (0.01 mu M, 0.1 mu M or 1 mu M) for 2 hours. Cells were sham-irradiated and irradiated with 50 kJ/m(2), 100 kJ/m(2) or 200 kJ/m(2) UVA, and incubated in serum-free Dulbecco's modified Eagle's medium, with or without CK for 24 hours. MMP-1 activity in the supernatants and protein levels in the cells were assessed by zymography and western blotting, respectively. Level of type I collagen was assessed by enzyme-linked immunosorbent assay.Results: MMP-1 activity and protein level were increased by UVA, which was downregulated by CK. Production of type I collagen was inhibited in UVA-irradiated fibroblasts, which was upregulated by CK.Conclusion: CK is a potential agent for the prevention and treatment of skin photo-aging.

Aim: To study the expression of tumor necrosis factor-α (TNF-α) in the dental pulp tissue indirectly induced by maxillofacial gunshot injury, and to investigate the its effect on the traumatic inflammation so as to provide a theoretical basis for diagnosis and therapy of the gunshot wounds. Methods: The injured model of lower jaw in dog were established by a gun in 5.80 mm diameter. The dynamic changes of of TNF-α level in different dental pulp tissues of lower jaw in different stages were studied by using immunohistochemical method and quantitative analysis. Results: Positive expression of TNF-α was detected by immunohistochemical assay, and changed as the time went by, which was a course of dynamic change. Conclusion: TNF-α participates in the occurrence and development of pulpitis caused by firearm and is related to injury and repair of the dental pulp tissue.

目的:研究白细胞介素-8（IL-8）在狗颌面部火器伤间接损伤牙髓中的表达情况。方法:采用直径5.80mm制式枪弹致伤狗下颌部的模型,并利用免疫组化染色及定量分析方法检测颌面部火器伤后不同时间、下颌不同牙齿的牙髓组织中IL-8的动态变化。结果:IL-8在伤后牙髓组织中有阳性表达,并随时间的改变,呈动态变化过程。结论:狗牙髓的血管内皮细胞能分泌合成IL-8,可能参与火器性牙髓炎症发生、发展,并与牙髓损伤、修复有关。

OBJECTIVE:To explore the role of leukocyte adhesion in the pathophysiology of glycerol-induced acute renal tubular necrosis (ATN).METHODS:Rat models of ATN were established by intramuscular injection of glycerol in 24 Wistar rats, which were divided randomly into 3 groups of equal number according to the agents coinjected with glycerol for the prevention of ATN, with another 8 rats serving as normal control. One of the 3 groups received a monoclonal antibody (mAb) against intercellualr adhesion molecule-1 (anti-ICAM-1) and another received CD3 mAb, leaving one group untreated. Both functional impairment and histological changes in the rats were observed.RESULTS:Plasma creatinine measured 24 h after the injection of glycerol was 412.31+/-94.42 micromol/L in rats treated with anti-ICAM-1, significantly lower than that in CD3 mAb-treated rats (990.21 +/-171.25 micromol/L, P<0.05). Moderate to severe necrosis in the outer renal medulla with frequent mitoses was present in rats with ATN receiving CD3 mAB or nothing, but only mild necrosis with few mitoses occurred in merely 2 of those rats with anti-ICAM-1 treatment.CONCLUSION:Leukocytes and adhesion molecules play critical roles in the pathophysiology of glycerol-induced ATN, and anti-ICAM-1 which blocks the adhesion of the leukocytes may alleviate the pathological changes in the kidney.

A monoclonal antibody (McAb) against lymphocyte function-associated antigen-1, administered after the intraperitoneal injection of gentamicin in the rats, prevented both functional impairment and histological changes of rats' kidneys. Creatinine values in blood measured 24 h after the second injection of gentamicin was 134.6 �� 15.1 ��mol/L in the anti-lymphocyte function-associated antigen-1 McAb treated animals compared with 366.7 �� 28.3 ��mol/L in the irrelevant McAb treated group (P < 0.05). There was moderate to severe necrosis in the outer medulla with frequent mitoses in irrelevant McAb treated kidneys. Necrosis was mild with few mitoses only in one case of anti-lymphocyte function-associated antigen-1 treated animals. These results suggest a possible critical role for leukocytes and adhesion molecules in the pathophysiology of the nephrotoxicity of gentamicin and may have important therapeutic implications.