Neuroprotective effects of VEGF administration after focal cerebral ischemia/reperfusion: dose response and time window

Administration of vascular endothelial growth factor (VEGF) has been shown to increase cerebral blood flow and reduce neurological damage after experimental ischemic brain injury. The purpose of this study was to examine the optimal dose and time window for the neuroprotective effect of VEGF when administrated after focal ischemia/reperfusion injury in rabbits. Focal cerebral ischemia/reperfusion was induced by the middle cerebral artery occlusion (MCAO) method. In a dose response experiment, low (1.25 ng/μL), middle (2.5 ng/μL) and high (5.0 ng/μL) doses of VEGF were administered 2h after MCAO by the route of perifocal region. The VEGF at a dose of middle (2.5 ng/μL) displayed excellent effects on neuroprotective efficacy for focal cerebral ischemia/reperfusion injury. In another experiment, 2.5 ng/μL VEGF was administered at times varying from 2 to 8h after MCAO. Infarct volume, water content and neurological deficits were significantly reduced when VEGF was given at 2 and 3h after injury. The protective effect was less when the same dose was given at the later times. Thus, the present findings indicated that VEGF reduced ischemic neuronal danger with a therapeutic time window within the first 3h of transient MCAO and may be useful in the treatment of acute ischemic stroke in humans.     

Oxidative stress and neuronal death/survival signaling in cerebral ischemia

It has been demonstrated by numerous studies that apoptotic cell death pathways are implicated in ischemic cerebral injury in ischemia models in vivo. Experimental ischemia and reperfusion models, such as transient focal/global ischemia in rodents, have been thoroughly studied and the numerous reports suggest the involvement of cell survival/death signaling pathways in the pathogenesis of apoptotic cell death in ischemic lesions. In these models, reoxygenation during reperfusion provides oxygen as a substrate for numerous enzymatic oxidation reactions and for mitochondrial oxidative phosphorylation to produce adenosine triphosphate. Oxygen radicals, the products of these biochemical and physiological reactions, are known to damage cellular lipids, proteins, and nucleic acids and to initiate cell signaling pathways after cerebral ischemia. Genetic manipulation of intrinsic antioxidants and factors in the signaling pathways has provided substantial understanding of the mechanisms involved in cell death/survival signaling pathways and the role of oxygen radicals in ischemic cerebral injury. Future studies of these pathways could provide novel therapeutic strategies in clinical stroke.     

Neuroprotection of Chikusetsu saponin V on transient focal cerebral ischemia/reperfusion and the underlying mechanism

BackgroundOxidative stress and frequently unwanted alterations in mitochondrial structure and function are key aspects of the pathological cascade in transient focal cerebral ischemia. Chikusetsu saponin V (CHS V), a major component of saponins from Panax japonicas, can attenuate H₂O₂-induced oxidative stress in SH-SY5Y cells.PurposeThe aim of the present study was to investigate the neuroprotective effects and the possible underlying mechanism of CHS V on transient focal cerebral ischemia/reperfusion.MethodsMice with middle cerebral artery occlusion (MCAO) and cultured cortical neurons exposed to oxygen glucose deprivation (OGD) were used as in vivo and in vitro models of cerebral ischemia, respectively. The neurobehavioral scores, infarction volumes, H&E staining and some antioxidant levels in the brain were evaluated. The occurrence of neuronal death was estimated. Total and mitochondrial reactive oxygen species (ROS) levels, as well as mitochondrial potential were measured using flow cytometry analysis. Mitochondrial structure and respiratory activity were also examined. Protein levels were investigated by western blotting and immunohistochemistry.ResultsCHS V effectively attenuated cerebral ischemia/reperfusion (CI/R) injury, including improving neurological deficits, shrinking infarct volume and reducing the number of apoptotic cells. Furthermore, CHS V treatment remarkably increased antioxidant levels and reduced ROS levels and mitochondrial damage by enhancing the expression and deacetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by activating AMPK and SIRT-1, respectively.ConclusionOur data demonstrated that CHS V prevented CI/R injury by suppressing oxidative stress and mitochondrial damage through the modulation of PGC-1α with AMPK and SIRT-1.     

Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death

Ischemia/reperfusion (I/R) is a pivotal mechanism of liver damage after liver transplantation or hepatic surgery. We have investigated the effects of cannabidiol (CBD), the nonpsychotropic constituent of marijuana, in a mouse model of hepatic I/R injury. I/R triggered time-dependent increases/changes in markers of liver injury (serum transaminases), hepatic oxidative/nitrative stress (4-hydroxy-2-nonenal, nitrotyrosine content/staining, and gp91phox and inducible nitric oxide synthase mRNA), mitochondrial dysfunction (decreased complex I activity), inflammation (tumor necrosis factor α (TNF-α), cyclooxygenase 2, macrophage inflammatory protein-1α/2, intercellular adhesion molecule 1 mRNA levels; tissue neutrophil infiltration; nuclear factor κB (NF-κB) activation), stress signaling (p38MAPK and JNK), and cell death (DNA fragmentation, PARP activity, and TUNEL). CBD significantly reduced the extent of liver inflammation, oxidative/nitrative stress, and cell death and also attenuated the bacterial endotoxin-triggered NF-κB activation and TNF-α production in isolated Kupffer cells, likewise the adhesion molecule expression in primary human liver sinusoidal endothelial cells stimulated with TNF-α and attachment of human neutrophils to the activated endothelium. These protective effects were preserved in CB2 knockout mice and were not prevented by CB1/2 antagonists in vitro. Thus, CBD may represent a novel, protective strategy against I/R injury by attenuating key inflammatory pathways and oxidative/nitrative tissue injury, independent of classical CB1/2 receptors.     

产前应激对子代大鼠脑缺血/再灌注后星形胶质细胞的影响

目的：探讨产前应激对雄性子代大鼠大脑中动脉缺血/再灌注后星形胶质细胞的影响。方法：SD孕鼠随机分为有产前应激处理（妊娠第15到21天每日3次限制活动）和无产前应激处理,并对其雄性子代大鼠采用线栓法制备大脑中动脉闭塞（MCAO）模型,共分为产前应激+假手术组、MCAO模型组、产前应激+MCAO组（n=10）,于再灌注后第5天检测脑梗死体积,免疫荧光双标染色检测缺血灶边缘区星形胶质细胞形态及促红细胞生成素肝细胞受体A4（EphA4）和胶质纤维酸性蛋白（GFAP）的共表达情况,并采用Western blot检测EphA4、GFAP和神经蛋白聚糖（Neurocan）蛋白表达。结果：产前应激+MCAO组子代大鼠脑梗死体积百分比、EphA4、GFAP和Neurocan蛋白表达均较MCAO组显著增加（P均<0.05）,且GFAP阳性细胞形态学改变及EphA4/GFAP共表达也较MCAO组明显。结论：产前应激可能改变子代大鼠脑缺血/再灌注后星形胶质细胞上EphA4受体的表达,促进星形胶质细胞活化,产生神经蛋白聚糖。     

microRNA-129 overexpression in endothelial cell-derived extracellular vesicle influences inflammatory response caused by myocardial ischemia/reperfusion injury

Extracellular vesicles (EVs) have the potency to function as modulators in the process of myocardial ischemia/reperfusion (I/R) injury. This investigation was performed to decipher the mechanism of human umbilical vascular endothelial cells (HUVECs)-derived EVs in myocardial I/R injury with the involvement of microRNA-129 (miR-129). HUVECs-secreted EVs were collected and identified. An I/R mouse model was developed, and cardiomyocytes were used for vitro oxygen-glucose deprivation/reperfusion model establishment. Differentially expressed miRNAs in myocardial tissues after EV treatment were assessed using microarray analysis. The target relationship between miR-129 and toll-like receptor 4 (TLR4) was identified using a dual-luciferase assay. Gain- and loss-function studies regarding miR-129 were implemented to figure out its roles in myocardial I/R injury. Meanwhile, the activation of the nuclear factor-kappa-binding (NF-κB) p65 signaling and NOD-like receptor 3 (NLRP3) inflammasome was evaluated. EVs diminished the apoptosis of cardiomyocytes and the secretion of inflammatory factors, and all these trends were reversed by miR-129 reduction. miR-129 bound to the 3′-untranslated region of TLR4 directly. The NF-κB p65 signaling and NLRP3 inflammasome were abnormally activated after I/R injury, whose impairment after EVs was partially restored by miR-129 downregulation. This study illustrated that EVs could carry miR-129 to mitigate myocardial I/R injury via downregulating TLR4 and disrupting the NF-κB signaling and NLRP3 inflammasome.     

参附注射液对大鼠全脑缺血/再灌注损伤的保护作用

目的:探讨参附注射液对大鼠全脑缺血/再灌注损伤的保护作用及其机制。方法:将SD雄性大鼠40只,随机分为4组(n=10):假手术组、模型对照组、尼莫地平组(30 mg/kg)和参附注射液组(10 mg/kg)。采用Pulsinelli’s四动脉阻断法造成全脑缺血/再灌注损伤模型(CI/R),分别于手术前1 d,术前1 h和再灌注前30 min给药,共3次。分别用高效液相色谱法测定脑组织谷氨酸(Glu)、天冬氨酸(Asp)和甘氨酸(Gly)含量,原子吸收分光光度测定Ca2+含量,干湿重法测定脑组织含水量,化学比色法测定脑组织超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量。结果:与假手术组比较,CI/R模型组大鼠脑组织Glu、Ca2+、MDA含量和含水量明显升高(P<0.05,P<0.01),SOD活性明显降低(P<0.05);参附注射液能显著降低脑组织Glu、Ca2+含量和含水量(P<0.05,P<0.01),显著升高SOD活性及SOD/MAD比值(P<0.05)。结论:参附注射液防治脑缺血/再灌注损伤的机制与降低兴奋性氨基酸(EAA)毒性、阻滞Ca2+超载和提高抗氧化能力有关。     

瘦素对小鼠脑缺血/再灌注损伤神经元凋亡的影响

目的：研究Leptin在脑缺血性损伤神经元凋亡中的作用及其机制。方法：将75只雄性昆明小鼠完全随机分成3组,即假手术组、缺血/再灌注模型组、Leptin干预组;通过大脑中动脉栓塞（MCAO）复制小鼠局灶性脑缺血再灌注损伤模型,Leptin干预组在缺血0 min腹腔注射Leptin（1μg/g体重）,TUNEL染色检测神经元凋亡,RT-PCR检测凋亡相关基因bcl-2和caspase-3 mRNA表达,免疫组化凋亡相关基因bcl-2和caspase-3蛋白水平的表达。结果：模型组脑缺血中心区神经元以坏死为主,与假手术组相比,其半影区神经元凋亡数量显著增多、促凋亡基因cas-pase-3和抑凋亡基因bcl-2的mRNA和蛋白表达水平均显著升高（P<0.01）;与模型组比较,Leptin干预组半影区凋亡神经元数量显著减少、caspase-3 mRNA和蛋白表达水平显著降低（P<0.01）,抑凋亡基因bcl-2 mRNA和蛋白表达水平显著升高（P<0.01）。结论：Leptin能够通过上调抑凋亡基因bcl-2表达,下调促凋亡基因caspase-3表达抑制神经元凋亡,在脑缺血性损伤中发挥神经保护作用。     

脑缺血和缺血再灌注大鼠皮层神经元自噬的动态变化

目的：探讨脑缺血和缺血/再灌注不同时间大鼠大脑皮层神经元自噬的变化。方法：健康雄性SD大鼠60只,随机分为：假手术（Sham）组（n=10）,脑缺血和缺血/再灌注模型组（n=50）.模型组分别在缺血30min、2h,缺血2h再灌注1h、6h、24h五个时间点,随机抽取10只大鼠,测定脑梗死体积和脑含水量,同时采用Western印迹法测定各组大鼠大脑皮层中微管相关蛋白轻链3-Ⅱ（LC3-Ⅱ）的水平,透射电镜检测大脑皮层神经细胞自噬情况。结果：脑缺血30min时LC3-Ⅱ/Ⅰ比值未见明显上升,缺血2h时LC3-Ⅱ/Ⅰ比值开始升高,明显高于Sham组（P<0.01）;缺血/再灌注1h、6h时LC3-Ⅱ/Ⅰ比值虽较缺血2h组有所下降,但仍明显高于Sham组（P<0.05）;缺血/再灌注24h时LC3Ⅱ/Ⅰ比值达高峰,明显高于Sham组（P<0.01）。透射电镜观察进一步证实该现象。缺血/再灌注6h和24h时大鼠脑梗死体积明显增加,与Sham组比较有统计学差异（P<0.01）。缺血/再灌注24h大鼠脑组织含水量明显增加,明显高于Sham组（P<0.05）。HE染色显示：仅在缺血/再灌注24h组大鼠皮层见组织水肿、疏松,部分细胞变性、凋亡,海马区见大量神经元细胞核皱缩、深染呈变性凋亡状。结论：局灶性脑缺血和缺血/再灌注模型中大脑皮层缺血2 h神经元自噬即明显激活,缺血/再灌注1 h、6 h自噬均持续增高,缺血/再灌注24 h自噬达高峰。     

Modified two-step model for studying the inflammatory response during myocardial ischemia and reperfusion in mice

Studies of myocardial ischemia-reperfusion (MI-R) in the mouse can be accomplished by use of reversible ligation of the left interventricular branch artery (LIB). To study interactions of coagulation, inflammation, and reperfusion injury, the model should not be influenced by effects of the surgery. In existing closed-thorax mouse models, the release of inflammatory factors attributable to surgical intervention could be separated from the release resulting from induction of MI-R. In these models, the final myocardial injury was induced by reversible closure of the LIB several days after preparative surgery that included median thoracotomy. In an attempt to develop a less invasive procedure to approach the LIB, we replaced median thoracotomy with lateral thoracotomy. After this procedure, body weight was regained within four days, and on days 9 to 11 after the preparative surgery, cytokine values were back to baseline. During one hour of ischemia, mean arterial pressure (MAP) remained at 78 +/- 2 mmHg. After induction of reperfusion, MAP was 67 +/- 4 mmHg, indicating better perfusion pressure of myocardial tissue at the microcirculatory level than that in simple open-thorax models. Electrocardiographic recording revealed transient ST elevation indicating reversible transmural ischemia and reperfusion. Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining visualized the extent of area of infarction (AOI) and area at risk (AAR). The procedure-related mortality was 13%, which compared well with published data from median thoracotomy studies. We conclude that our new model provides stable near-physiologic hemodynamics and allows study of the inflammatory response resulting from MI-R, with low procedure-related mortality.     

Nebivolol regulates eNOS and iNOS expressions and alleviates oxidative stress in cerebral ischemia/reperfusion injury in rats

AimsOxidative stress-induced cell damage is reported to contribute to the pathogenesis of cerebral ischemia/reperfusion injury. This study investigated the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult in rats.Main methodsThe model adopted was that of surgically-induced forebrain ischemia, performed by means of bilateral common carotid artery occlusion for 1 h, followed by reperfusion for 24 h. The effects of 5 and 10 mg/kg nebivolol, treated for 7 days prior to ischemia/reperfusion insult, were investigated by estimating endothelial and inducible nitric oxide synthases (eNOS and iNOS) protein expressions and assessing oxidative stress-related biochemical parameters in the rat forebrain. Also, infarct volume measurement and histopathological study of the forebrain were examined.Key findingsAdministration of nebivolol increased eNOS expression with simultaneous decrease in iNOS expression in a dose dependent manner. Moreover, nebivolol inhibited ischemia/reperfusion-induced depletion of reduced glutathione level and decreased the elevated total nitric oxide end production and malondialdehyde levels, superoxide dismutase and lactate dehydrogenase activities. A notable finding is that catalase activity was not changed in response to either ischemia/reperfusion insult or nebivolol treatment. However, the results confirmed that nebivolol significantly reduced infarct volume and alleviated ischemia/reperfusion-induced histopathological changes.SignificanceThe present study demonstrates the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult. Neuroprotection observed with nebivolol may possibly be explained by regulating eNOS and iNOS expressions and by inhibition of oxidative stress-induced injury. Thus, nebivolol may be considered as a potential candidate for treatment in patients who are prone to stroke.     

FTO inhibits oxidative stress by mediating m6A demethylation of Nrf2 to alleviate cerebral ischemia/reperfusion injury

Journal of Physiology and Biochemistry - Current therapies are of limited efficacy in cerebral ischemia/reperfusion (I/R) injury. Based on the important role of oxidative stress in cerebral I/R...     

Effects of hyperoxia on local and remote microcirculatory inflammatory response after splanchnic ischemia and reperfusion

Splanchnic ischemia-reperfusion (I/R) causes tissue hypoxia that triggers local and systemic microcirculatory inflammatory responses. We evaluated the effects of hyperoxia in I/R induced by 40-min superior mesenteric artery (SMA) occlusion and 120-min reperfusion in four groups of rats: 1) control (anesthesia only), 2) sham operated (all surgical procedures without vascular occlusion; air ventilation), 3) SMA I/R and air, 4) SMA I/R and 100% oxygen ventilation started 10 min before reperfusion. Leukocyte rolling and adhesion in mesenteric microvessels, pulmonary microvascular blood flow velocity (BFV), and macromolecular (FITC-albumin) flux into lungs were monitored by intravital videomicroscopy. We also determined pulmonary leukocyte infiltration. SMA I/R caused marked decreases in mean arterial blood pressure (MABP) and blood flow to the splanchnic and hindquarters vascular beds and pulmonary BFV and shear rates, followed by extensive increase in leukocyte rolling and adhesion and plugging of >50% of the mesenteric microvasculature. SMA I/R also caused marked increase in pulmonary sequestration of leukocytes and macromolecular leak with concomitant decrease in circulating leukocytes. Inhalation of 100% oxygen maintained MABP at significantly higher values (P < 0.001) but did not change regional blood flows. Oxygen therapy attenuated the increase in mesenteric leukocyte rolling and adherence (P < 0.0001) and maintained microvascular patency at values not significantly different from sham-operated animals. Hyperoxia also attenuated the decrease in pulmonary capillary BFV and shear rates, reduced leukocyte infiltration in the lungs (P < 0.001), and prevented the increase in pulmonary macromolecular leak (P < 0.001), maintaining it at values not different from sham-operated animals. The data suggest that beneficial effects of normobaric hyperoxia in splanchnic I/R are mediated by attenuation of both local and remote inflammatory microvascular responses.     

外源性维生素D对小鼠脑缺血/再灌注神经损伤的保护作用*

目的:观察小鼠大脑中动脉闭塞(MCAO)模型制备前5 d 连续补充1,25-二羟维生素D₃(1,25-VitD₃)对缓解小鼠缺血/再灌注(I/R)后脑损伤中的作用。方法:雄性C57BL6小鼠随机分为Sham组、Vehicle组和1,25-VitD₃组,每组10只小鼠;Vehicle组和1,25-VitD₃组小鼠均进行大脑MCAO1 h,再灌注24 h后处死小鼠,1,25-VitD₃组MCAO手术前5 d连续腹腔注射,100 ng/(kg·d);取各组小鼠脑缺血半影区,进行TTC染色、RT-PCR及免疫组化检测,采用神经功能评分评估小鼠功能缺陷。结果:与sham组相比,Vehicle组小鼠脑梗死体积明显增加,小鼠脑组织中促炎介质IL-6、IL-1β和Gp91phox表达均明显增高(P＜0.05);与Vehicle组相比,补充1,25-VitD₃可减少I/R小鼠大约50%梗死体积(P＜0.05), 1,25-VitD₃组小鼠脑组织中IL-6、IL-1β和Gp91phox表达明显降低(P＜0.05),小鼠脑内T调节细胞标志物Foxp3 mRNA表达明显升高(P＜0.05),而转录因子Rorc mRNA表达明显较低(P＜0.05),提示Th17/γδT细胞反应减少,小鼠脑损伤部位中性粒细胞数量明显降低(P＜0.05)。结论:维生素D可以缓解动脉闭塞(MCAO)再灌注脑梗死发展,其机制可能是通过调节小鼠脑I/R中炎症反应。     

Protective effect of olive leaf extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in Mongolian gerbils

The beneficial effects of antioxidant nutrients, as well as complex plant extracts, in cerebral ischemia/reperfusion brain injury are well known. Mediterranean diet, rich in olive products, is associated with lower incidence of cardiovascular disease, cancer, inflammation and stroke. In this study, the possible neuroprotective effect of standardized dry olive leaf extract (OLE) is investigated for the first time. Transient global cerebral ischemia in Mongolian gerbils was used to investigate the OLE effects on different parameters of oxidative stress and neuronal damage in hippocampus. The biochemical measurements took place at different time points (80 min, 2, 4 and 24 h) after reperfusion. The effects of applied OLE were compared with effects of quercetin, a known neuroprotective plant flavonoid. Pretreatment with OLE (100 mg/kg, per os) significantly inhibited production of superoxide and nitric oxide, decreased lipid peroxidation, and increased superoxide dismutase activity in all time points examined. Furthermore, OLE offered histological improvement as seen by decreasing neuronal damage in CA1 region of hippocampus. The effects of applied OLE were significantly higher than effects of quercetin (100 mg/kg, per os). Our results indicate that OLE exerts a potent neuroprotective activity against neuronal damage in hippocampus after transient global cerebral ischemia, which could be attributed to its antioxidative properties.     

川芎嗪对脑缺血/再灌注后所致肺损伤的影响

目的：观察川芎嗪对脑缺血／再灌注后肺损伤的影响。方法：采用Pulsinelli等的方法建立大鼠急性全脑缺血／再灌注模型。将Wistar大鼠随机分为三组,即：对照组（Control）、缺血／再灌注组（I／R）、川芎嗪＋缺血／再灌注组（TEP＋I／R）,分别测定各组肺功能（PaO2、PaCO2）,肺系数（LI％）、血浆和肺组织中与自由基有关物质的含量。结果：川芎嗪可有效改善脑缺血／再灌注后肺功能,减轻肺水肿,减少胞浆酶的漏出,增加自由基清除醇的活性,抑制组织脂质过氧化的发生。结论：川芎嗪对脑缺血／再灌注后肺损伤具有保护作用,其机制可能与其抗氧自由基和膜保护作用有关。     

Bererine induces peripheral lymphocytes immune regulations to realize its neuroprotective effects in the cerebral ischemia/reperfusion mice

Previous studies have shown that Bererine (Ber) has significant neuroprotective effects and the present article aimed to investigate its mechanism from the aspect of peripheral immune system. We evaluated the effects of Ber 24 h after cerebral ischemia/reperfusion (I/R) on histologic injury in BALB/C mice and NOD-SCID (severe combined immunodeficient) mice lacking T and B cells. Infarct volume, neurological scores and brain water content were strikingly reduced by Ber in BALB/C mice versus NOD-SCID mice. Which suggested that Ber induces peripheral immune regulations to realize its neuroprotective effects in the cerebral I/R mice. Then we tested the lymphocytes from BALB/C lymph nodes (LNs) with their survival, activation, proliferation, cell cycle, apoptosis and differentiation induced by cytokine secretion to provide direct evidences that Ber realized its neuroprotective effects by regulating I/R-induced peripheral lymphocytes early immunoactivation and following immunotolerance and to better understand the importance of peripheral immune system following I/R insults.     

Modulation of lung allergic response by renal ischemia and reperfusion injury

The Th1/Th2 balance represents an important factor in the pathogenesis of renal ischemia-reperfusion injury (IRI). In addition, IRI causes a systemic inflammation that can affect other tissues, such as the lungs. To investigate the ability of renal IRI to modulate pulmonary function in a specific model of allergic inflammation, C57Bl/6 mice were immunized with ovalbumin/albumen on days 0 and 7 and challenged with an ovalbumin (OA) aerosol on days 14 and 21. After 24 h of the second antigen challenge, the animals were subjected to 45 minutes of ischemia. After 24 h of reperfusion, the bronchoalveolar lavage (BAL) fluid, blood and lung tissue were collected for analysis. Serum creatinine levels increased in both allergic and non-immunized animals subjected to IRI. However, BAL analysis showed a reduction in the total cells (46%) and neutrophils (58%) compared with control allergic animals not submitted to IRI. In addition, OA challenge induced the phosphorylation of ERK and Akt and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung homogenates. After renal IRI, the phosphorylation of ERK and expression of COX-2 and iNOS were markedly reduced; however, there was no difference in the phosphorylation of Akt between sham and ischemic OA-challenged animals. Mucus production was also reduced in allergic mice after renal IRI. IL-4, IL-5 and IL-13 were markedly down-regulated in immunized/challenged mice subjected to IRI. These results suggest that renal IRI can modulate lung allergic inflammation, probably by altering the Th1/Th2 balance and, at least in part, by changing cellular signal transduction factors.