Antioxidative effect of p38 mitogen-activated protein kinase inhibitor in the kidney of hypertensive rat

OBJECTIVE: Nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase is regulated by angiotensin II, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha via p38 mitogen-activated protein kinase (MAPK). We hypothesized that p38 MAPK inhibitor, FR167653, may suppress NAD(P)H oxidase and its oxygen radical production and ameliorate renal damage in Dahl salt-sensitive rats with heart failure (DSHF). METHODS: DSHF rats were fed with 8% NaCl diet from 6 to 18 weeks old. Eleven-week-old DSHF rats received either vehicle or FR167653 (2 mg/kg per day) for 7 weeks and the renal NAD(P)H oxidase p47phox and nitric oxide synthase (NOS), superoxide production and renal damage were evaluated in comparison with the control Dahl salt-resistant rat fed with 8% NaCl diet. RESULTS: In the kidney of DSHF rat, phosphorylated p38 MAPK was enhanced with an increased IL-1beta and TNF-alpha production compared with control rats. Treatment with FR167653 significantly suppressed p38 MAPK, IL-1beta and TNF-alpha. Renal NAD(P)H oxidase p47phox expression and superoxide production were significantly increased in the DSHF rats and treatment with FR167653 suppressed NAD(P)H oxidase expression and reduced superoxide formation. Renal endothelial and inducible NOS were reduced in DSHF rats compared with control rats, but FR167653 increased NOS and NO production in the kidney. Proteinuria, glomerulosclerosis and interstitial macrophage migration via intercellular adhesion molecule-1 (ICAM-1) were enhanced in DSHF rat and they were ameliorated by FR167653. CONCLUSION: The inhibition of p38 MAPK by FR167653 reduced renal IL-1beta and TNF-alpha production and ameliorated renal damage in hypertensive rat via suppression of NAD(P)H oxidase and enhanced NO bioavailability.     

Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653

OBJECTIVE: FR167653 is a potent inhibitor of p38 mitogen-activated protein kinase (MAPK) and inhibits tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1 beta) production in inflammatory cells. In this study we investigated the effect of FR167653 on collagen-induced arthritis (CIA). METHODS: Rats with CIA were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection (day 7) in the prophylactic treatment group and after the onset of arthritis (day 21) in the therapeutic treatment group. Hind-paw swelling, body weight, radiographic and histologic scores, and osteoclast number were evaluated. Cytokine levels in the serum and tissue were assessed by enzyme-linked immunosorbent assays. Flow cytometric analysis of T lymphocytes from bone marrow was performed. The effect of FR167653 on in vitro osteoclast formation induced by soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and TNFalpha was examined. RESULTS: Swelling of hind paws and loss of weight occurred in the CIA rats, but this was not evident in the prophylactic treatment group. Therapeutic treatment also significantly reduced paw swelling. The mean radiographic and histologic scores as well as the osteoclast numbers were significantly lower in the treatment group than in the CIA rats without treatment. FR167653 treatment reduced the serum levels of TNFalpha and IL-1 beta, lowered the IL-1 beta concentration in the ankle joints, and decreased the CD4-,CD8a+ T cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast-like cell differentiation induced by both sRANKL and TNFalpha in vitro. CONCLUSION: FR167653 prevents the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAPK is a potential therapeutic target for rheumatoid arthritis.     

FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice

AIM： To investigate the effects of FR167653 on the development of dextran sulfate sodium （DSS）-induced colitis in mice. METHODS： BALB/c mice were fed rodent chow containing 3.5% （wt/wt） DSS. The recipient mice underwent intra-peritoneal injection of vehicles or FR167653 （30 mg/kg per day）. The mice were sacrificed on day 14, and the degree of colitis was assessed. Immunohistochemical analyses for CD4^＋ T cell and F4/80^＋ macrophage infiltration were also performed. Mucosal cytokine expression was analyzed by RT-PCR. RESULTS： The body weight loss was more apparent in the FR167653-treated DSS mice than in the vehicletreated DSS mice. The colon length was shorter in the FR167653-treated DSS mice than in the vehicle-treated DSS mice. Disease activity index and histological colitis score were significantly higher in FR167653- than in vehicle-treated DSS animals. Microscopically, mucosal edema, cellular infiltration （CD4 T cells and F4/80 macrophages）, and the disruption of the epithelium were much more severe in FR167653-treated mice than in controls. Mucosal mRNA expression for interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α） were found to be markedly reduced in FR167653-treated DSS mice. CONCLUSION： Treatment with FR167653 aggravated DSS colitis in mice. This effect was accompanied by a reduction of mucosal IL-1β and TNF-α expression, suggesting a role of p38 mitogen-activated protein kinase （MAPK）-mediated proinflammatory cytokine induction in host defense mechanisms.     

Attenuation of microcirculatory disturbance after liver ischemia by newly synthesized inflammatory cytokine suppressor,FR167653

BACKGROUND/AIMS: Inflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, which activate neutrophils, contribute to hepatic warm ischemia-reperfusion injury. However, the role of the cytokines in hepatic microcirculation immediately after reperfusion is still unclear. This study was carried out to investigate whether FR167653, a dual inhibitor of interleukin-1 beta and tumor necrosis factor-alpha, attenuates hepatic microcirculatory disturbance at the initial phase of reperfusion following liver ischemia. METHODOLOGY: Adult mongrel dogs were subjected to 90 minutes of liver ischemia by a Pringle's maneuver under portosystemic bypass. The animals were divided into two groups: a control group (n = 10), subjected to hepatic warm ischemia only, and a FR167653 administered group (n = 5), which received 1 mg/kg/h FR167653 for 4 hours since 30 minutes before the ischemia to 2 hours after the reperfusion continuously. Seven days animal survival, hepatic tissue blood flow, liver function test, hepatic venous blood concentration of endothelin-1 and plasminogen activator inhibitor-1, liver tissue biochemistry, and histopathology were analyzed. RESULTS: The treatment with FR167653 attenuated microcirculatory disturbance, lessened liver injury, enhanced adenine nucleotides resynthesis, and improved animal survival after liver ischemia. In addition, FR167653 significantly inhibited release of both endothelin-1 and plasminogen activator inhibitor-1 from the liver cells. CONCLUSIONS: These results suggest that the inflammatory cytokines induce microcirculatory disturbance in the initial phase of reperfusion following liver ischemia.     

Apoptosis induction by p38 MAPK inhibitor in human colon cancer cells

BACKGROUND/AIMS: The p38 mitogen-activated protein kinases (p38 MAPKs) function in a wide variety of signaling pathways. However, the role of p38s is cell type- and stimulus-dependent. The present study aimed to evaluate the effects of p38 MAPK inhibitor on human colon cancer cells. METHODOLOGY: The effect of p38 MAPK inhibitor, FR167653, on DLD-1 and SW480 was investigated related to cell proliferation, apoptosis induction and caspase activity. Additionally, the effect of FR167653 on colon cancer cell migration, MMPs production and ability to adhere to extracellular matrix was investigated. RESULTS: Inhibitor of p38 MAPK dose-dependently suppressed the proliferative activity of both cell lines, and increased the induction of cell apoptosis. The caspase-3, 8, and 9 activities were accompanied in the pathway. Neither cell migration, MMPs production, nor the ability to adhere extracellular matrix were affected by FR167653. CONCLUSIONS: Inhibitor of p38 MAPK suppressed the proliferation of colon cancer cells by induction of cell apoptosis through the caspase activation. The present results suggest the pro-oncogenic role ofp38 in colon cancer, and its inhibition would be a novel strategy for the prevention and treatment of colon cancer.     

Myocardial protection evoked by hyperoxic exposure involves signaling through nitric oxide and mitogen activated protein kinases

Background Hyperoxic exposure in vivo (> 95% oxygen) attenuates ischemia-reperfusion injury, but the signaling mechanisms of this cardioprotection are not fully determined. We studied a possible role of nitric oxide (NO) and mitogen activated protein kinases (MAPK) in hyperoxic protection. Methods Mice (n = 7–9 in each group) were kept in normoxic or hyperoxic environments for 15 min prior to harvesting the heart and Langendorff perfusion with global ischemia (45 min) and reperfusion (60 min). Endpoints were cardiac function and infarct size. Additional hearts were collected to evaluate MAPK phosphorylation (immunoblot). The nitric oxide synthase inhibitor L-NAME, the ERK1/2 inhibitor PD98059 and the p38 MAPK inhibitor FR167653 were injected intraperitoneally before hyperoxia or normoxia. Results Hyperoxia improved postischemic functional recovery and reduced infarct size (p < 0.05). Hyperoxic exposure caused cardiac phosphorylation of the MAPK family members p38 and ERK1/2, but not JNK. L-NAME, PD98059 and FR167653 all reduced the protection afforded by hyperoxic exposure, but did not influence performance or infarction in hearts of normoxic mice. The hyperoxia-induced phosphorylation of ERK1/2 and p38 was reduced by L-NAME and both MAPK inhibitors. Conclusion Nitric oxide triggers hyperoxic protection, and ERK1/2 and p38 MAPK are involved in signaling of protection against ischemia-reperfusion injury.     

Prevention of the onset and progression of collagen‐induced arthritis in rats by the potent p38 mitogen‐activated protein kinase inhibitor FR167653

Objective

FR167653 is a potent inhibitor of p38 mitogen‐activated protein kinase (MAPK) and inhibits tumor necrosis factor α (TNFα) and interleukin‐1β (IL‐1β) production in inflammatory cells. In this study we investigated the effect of FR167653 on collagen‐induced arthritis (CIA).

Methods

Rats with CIA were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection (day 7) in the prophylactic treatment group and after the onset of arthritis (day 21) in the therapeutic treatment group. Hind‐paw swelling, body weight, radiographic and histologic scores, and osteoclast number were evaluated. Cytokine levels in the serum and tissue were assessed by enzyme‐linked immunosorbent assays. Flow cytometric analysis of T lymphocytes from bone marrow was performed. The effect of FR167653 on in vitro osteoclast formation induced by soluble receptor activator of nuclear factor κB ligand (sRANKL) and TNFα was examined.

Results

Swelling of hind paws and loss of weight occurred in the CIA rats, but this was not evident in the prophylactic treatment group. Therapeutic treatment also significantly reduced paw swelling. The mean radiographic and histologic scores as well as the osteoclast numbers were significantly lower in the treatment group than in the CIA rats without treatment. FR167653 treatment reduced the serum levels of TNFα and IL‐1β, lowered the IL‐1β concentration in the ankle joints, and decreased the CD4−,CD8a+ T cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast‐like cell differentiation induced by both sRANKL and TNFα in vitro.

Conclusion

FR167653 prevents the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAPK is a potential therapeutic target for rheumatoid arthritis.

     

Systemic inflammation induced by lipopolysaccharide increases neointimal formation after balloon and stent injury in rabbits

BACKGROUND: Emerging data indicate that the inflammatory response after mechanical arterial injury correlates with the severity of neointimal hyperplasia in animal models and postangioplasty restenosis in humans. The present study was designed to examine whether a nonspecific stimulation of the innate immune system, induced in close temporal proximity to the vascular injury, would modulate the results of the procedure. Methods and Results- Rabbits subjected to iliac artery balloon injury (balloon denudation with or without stent deployment) were injected twice with a bacterial lipopolysaccharide (LPS) (500 ng/rabbit) before and after surgery. The dose was chosen to be sufficient to induce systemic inflammation but not septic shock. A systemic marker of inflammation (serum interleukin-1beta levels measured by ELISA) and monocytic stimulation (CD14 levels on monocytes measured by flow cytometry) were increased after LPS administration. Arterial macrophage infiltration at 7 days after injury was 1.7+/-1.2% of total cells in controls and 4.2+/-1.8% in LPS-treated rabbits (n=4, P<0.05). Morphometric analysis of the injured arteries 4 weeks after injury revealed significantly increased luminal stenosis (38+/-4.2% versus 23+/-2.6, mean+/- SEM; n=8, P<0.05) and neointima-to-media ratio (1.26+/-0.21 versus 0.66+/- 0.09, P<0.05) in LPS-treated animals compared with controls. This effect was abolished by anti-CD14 Ab administration. Serum interleukin-1beta levels and monocyte CD14 expression were significantly increased in correlation with the severity of intimal hyperplasia. LPS treatment increased neointimal area after stenting from 0.57+/-0.07 to 0.77+/- 0.1 mm(2) and stenosis from 9+/-1% to 13+/-1.7% (n=5, P< 0.05). CONCLUSIONS: Nonspecific systemic stimulation of the innate immune system concurrently with arterial vascular injury facilitates neointimal formation, and conditions associated with increased inflammation may increase restenosis.     

A dual inhibitor of TNF-alpha and IL-1 mitigates liver and kidney dysfunction and improves survival in rat endotoxemia

BACKGROUND/AIMS: Endotoxin shock induces multiple organ dysfunction syndromes that are associated with a substantial increase in mortality. In this study, we evaluated the effect of FR167653, a potent suppressant of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) production, on lipopolysaccharide (LPS)-induced liver and kidney injury and lethality in rats. METHODOLOGY: Male Sprague-Dawley rats weighing from 200 to 270g received an injection of LPS. The FR group received an infusion of FR167653 at 0.2 mg/kg/hr, commencing 30 min prior to the LPS injection and continuing for 5.5 hr, while the control group received an infusion of a vehicle in the same fashion. Separate groups of animals were used for the survival study (n=5 each), and for blood sampling (n=5 each group, each time point). RESULTS: The FR group showed a significantly better survival rate'than the control group. Serum levels of GOT, Cr, and BUN were significantly lower in the FR group than in the control group. The elevation of TNF-alpha and IL-1beta at 2 hr after LPS administration was significantly lower in the FR group than in the control group. CONCLUSIONS: FR167653 administration is effective in decreasing serum TNF-alpha and IL-1beta levels and associated injury to liver and kidney caused by LPS-induced endotoxemia, as well as decreasing mortality.     

Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster

OBJECTIVE: p38 MAP kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) have been implicated in the pathophysiology of heart failure. We investigated the effects of chronic treatment with p38 MAPK and JNK inhibitors on the development of heart failure in dilated cardiomyopathy (DCM) hamster heart. METHODS AND RESULTS: BIO14.6 hamster hearts showed markedly increased p38 MAPK and JNK activities at 6 weeks of age when there was no significant increase in the area of fibrosis, heart weight/body weight, left ventricular (LV) chamber dilation and LV dysfunction. p38 MAPK and JNK activities were attenuated at 26 weeks of age and abolished at 40 weeks of age in BIO14.6 hamster hearts. BIO14.6 hamsters and the control BIOF1B hamsters were chronically treated (i.p.) with the p38 MAPK inhibitors, SB203580 (1 mg/kg/day) and FR167653 (3 mg/kg/day), or the JNK inhibitor, SP600125 (1 mg/kg/day) or vehicle for 20 weeks starting from 6 weeks of age. Treatment of BIO14.6 hamster hearts with SB203580 and FR167653 reduced the number of TUNEL-positive myocytes, the area of fibrosis and heart weight/body weight associated with a significant decrease of LV dimension and an increase in LV ejection fraction and LV contractility compared to the vehicle-treated counterpart. In contrast, treatment with SP600125 increased the number of TUNEL-positive myocytes and the area of interstitial fibrosis associated with aggravation of LV chamber dilation and LV dysfunction. CONCLUSIONS: These results suggest that chronic treatment with p38 MAPK and JNK inhibitors produces opposing effects on the development of heart failure in the DCM hamster heart.     

Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted

A central role for leukocytes in neointimal hyperplasia after arterial injury is suspected. However, the relative importance of neutrophils and monocytes in balloon or stent-induced injury are not well understood, and mechanistic targeting of leukocyte recruitment or function is crude. We determined the temporal and spatial distribution of different leukocytes after balloon and stent-induced injury in primate iliac arteries. Based on these data, we targeted neutrophil and monocyte recruitment selectively after angioplasty or stent implantation and demonstrated that monocyte-specific blockade achieved via blockade of the MCP-1 receptor CCR2, was effective at reducing neointimal hyperplasia after stenting. In contrast, combined neutrophil and monocyte blockade achieved by targeting the leukocyte beta(2)-integrin beta-subunit CD18 was required to reduce neointimal hyperplasia after balloon injury. Distinct patterns of leukocyte infiltration in balloon versus stent-injured arteries predict distinct mechanisms for antiinflammatory strategies targeting neutrophils or monocytes in primates and may assist design of effective clinical strategies for optimizing vascular interventions.     

Prevention of intimal hyperplasia with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin in the porcine coronary artery balloon injury model

OBJECTIVES: The role of P-selectin in the process of restenosis was evaluated using a recombinant immunoglobulin (Ig) chimera form of its ligand, soluble P-selectin glycoprotein ligand-Ig (rPSGL-Ig), as a competitive inhibitor for the natural ligand on leukocytes. BACKGROUND: Inflammation and coagulation activation after vascular injury may be an important factor in the development of restenosis. P-selectin has been shown to mediate leukocyte-endothelium and leukocyte-platelet interaction. These interactions are mediated through binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) located on the surface of leukocytes. METHODS: Balloon injury was induced in the left anterior descending and right coronary arteries of 16 pigs at a balloon/artery diameter ratio of 1.5:1. Either rPSGL-Ig (1 mg/kg) or saline was randomly administered 15 min before balloon injury as an intravenous bolus. Four weeks after injury, morphometric analysis, immunohistochemistry and histological evaluation were performed on injured arterial segments. RESULTS: Increased luminal area was found in the rPSGL-Ig group compared with the placebo group (1.63 +/- 0.57 mm2 vs. 1.26 +/- 0.32 mm2, p = 0.044) owing to significantly reduced neointimal hyperplasia (cross-sectional area, 0.46 +/- 0.45 mm2 vs. 0.13 +/- 0.11 mm2, p = 0.013). Immunohistochemistry and histological evaluation showed a significant decrease in the presence of tumor necrosis factor-alpha, interleukin-1 beta, and infiltration of macrophages in the injured vessel segments in the rPSGL-Ig group. CONCLUSIONS: P-selectin antagonism using rPSGL-Ig decreases neointimal hyperplasia following balloon injury, by inhibiting the inflammatory and thrombotic responses at the site of balloon injury, which appears to play a pivotal role in the pathogenesis of restenosis.     

Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty

OBJECTIVE: Neointimal hyperplasia is a central feature in the pathogenesis of a variety of vascular pathologies. Mitogen-activated protein kinases (MAPK) are involved in the downstream transduction of signals from receptors for many of the molecules known to be instrumental in this process and thus represent a potential target for the modification of the proliferative response. We examined the hypothesis that down-regulation of MAPK would inhibit neointima formation in a porcine coronary injury model. METHODS: Balloon angioplasty was performed on 38 coronary arteries from 23 large white pigs. Antisense oligonucleotides to the p42 and p44 MAPK were locally delivered to the site of injury immediately after balloon injury. At 7 or 21 days, arteries were harvested for morphometry, determination of cell proliferation and assessment of MAPK protein levels. RESULTS: At 7 days, neointima formation was significantly reduced compared to controls (corrected intima/media ratio (IMR) 1.01+/-0.13 vs. 1.61+/-0.07, P<0.01) and this was associated with a 58% and 23% down-regulation of p42 and p44 protein levels, respectively. Intimal and medial proliferation rates were also reduced by 32% and 26%, respectively. At 21 days however, the effect of the treatment on MAPK protein levels was no longer significant and this correlated with a loss of the effects on IMR and cell proliferation. CONCLUSIONS: Down-regulation of MAPK inhibits early smooth muscle cell (SMC) proliferation and neointimal thickening in response to arterial injury, implying that it plays an important role in determining the early vascular response to injury. Inhibitory effects were less apparent at 21 days after a single delivery of oligonucleotide, implying that more sustained local delivery may be required to achieve longer term therapeutic benefit.     

过表达p27基因抑制血管损伤后新生内膜的形成

目的　探讨p2 7基因转染对血管损伤后新生内膜形成的影响。方法　以腺病毒为载体转染p2 7基因 ,用MTT法观察其对血管平滑肌细胞增殖的影响 ,用流式细胞仪检测细胞周期 ;在兔颈总动脉球囊损伤模型上转染p2 7基因 ,采用免疫组织化学法检测p2 7基因的表达 ,检测其对新生内膜形成的影响。结果　p2 7可明显抑制培养的血管平滑肌细胞增殖 ,细胞停滞于G1期。兔颈总动脉球囊损伤后转染p2 7基因可以减少新生内膜的形成达 2 7 4 3%。结论　以腺病毒为载体转染p2 7基因可以有效地抑制血管平滑肌细胞增殖及血管损伤后新生内膜的形成。     

Effect of FR167653 on Small Bowel Ischemia-Reperfusion Injury in Dogs

IL-1 and TNF- are known to be pleiotropiccytokines associated with various inflammatoryconditions such as small intestinal injury afterischemia-reperfusion. FR167653 has been characterized asa potent suppressant of IL-1 and TNF-production. The effect of FR167653 on intestinalreperfusion injury was investigated in a warm ischemiamodel of the canine gut. Sixteen mongrel dogs weredivided into two groups: a control group and a FR groupto which FR167653 was administered. Both the superiormesenteric artery and vein were clamped for 2 hr.Arterial pH, hepatic venous hemoglobin oxygensaturation, intramucosal pH, and the survival rate werewell maintained in the FR group in comparison with thecontrol group after reperfusion. FR167653 inhibited theexpression of IL-1 mRNA. Histologically,ischemia-reperfusion injury was more severe in the control groupthan the FR group. This study suggests that FR167653inhibits proinflammatory cytokines and amelioratesischemia-reperfusion injury of the smallintestine.     

S100B在大鼠颈总动脉损伤后新生内膜中的表达及意义

目的 探讨S100B在大鼠颈总动脉损伤后新生内膜中表达特征及其临床意义。方法 将体质量400~500 g SD大鼠,随机分为假手术组和颈总动脉球囊损伤模型组,于术后1、3、7、14和28 d取损伤的颈总动脉,40 g/L福尔马林固定过夜,切片行HE染色观察新生内膜形成情况,Western blot、qRT-PCR、免疫组化染色检测S100B的表达。检测干预因素对新生内膜影响时,将大鼠随机分为3组,即假手术组、Ad-GFP组、Ad-shS100B组,假手术组不做球囊拉伤,其余两组除球囊拉伤外分别给予200 μl Ad-GFP和Ad-shS100B。结果 颈总动脉损伤后,新生内膜增生随着时间的延长呈现出逐渐增加的趋势,且在14 d时达峰值（P<0.05）,而内膜与中膜面积比值在28 d达到最大。qRT-PCR显示S100B-mRNA在颈总动脉损伤后呈现出第1天升高,第3、7天时有所下降,第14天时上升,而第28天又下降的动态趋势(P<0.05)。Western blot显示颈总动脉损伤后S100B表达逐渐增加,7 d时达到高峰,随后降低（P<0.05）。免疫组化结果显示增加的S100B蛋白主要存在于新生内膜中。给予Ad-shS100B干预后,新生内膜形成及S100B的表达明显受到抑制。结论 颈总动脉损伤后S100B的表达特征与新生内膜的形成有关。     

Relationship between platelets and neutrophil adhesion and neointimal growth after repeated arterial wall injury induced by angioplasty in pigs

Platelet and neutrophil interactions with injured vascular wall may contribute to restenosis. Their importance was mainly examined following balloon injury of intact arteries. However, dilation of diseased arteries is clinically more relevant and may elicit different responses. We investigated the relationship between platelets and neutrophil adhesion, neointima formation and P-selectin expression on damaged arteries after repeated balloon injury. In an acute single-injury model, 8 pigs were subjected to bilateral carotid angioplasty and sacrificed 1 h later. In a chronic model, 19 pigs were subjected to similar procedures and allowed to recover for 4 weeks; then 18 arteries were redilated at the same previously injured sites (double injury) while the remaining arteries were not redilated and used to investigate the extent and the adhesive properties of the neointima. After single injury, (51)Cr-platelet adhesion (x10(6)/cm(2)) increased significantly from 3.8 +/- 0.6 to 45.9 +/- 6.5 (p < 0.05) on mildly and deeply injured segments, respectively, and were statistically similar after double injury. After single injury, (111)In-neutrophil adhesion (x10(3)/cm(2)) increased from 226.6 +/- 45.5 to 512.5 +/- 70.3 (p < 0.05) on mildly and deeply injured segments, and were significantly higher (p < 0.05) after double injury (mild: 1,289.1 +/- 227.9 and deep: 2,411.8 +/- 333.9). As well, the neo-endothelium expresses P-selectin at 4 weeks and platelet and neutrophil adhesion was directly related to neointimal growth. These results, which indicate ongoing proinflammatory processes 1 month post-angioplasty, suggest that neutrophils may participate in the progression of restenosis.