Enhanced anti-cancer efficacy on lymph node metastasis using peplomycin adsorbed on small activated carbon particles.

A new dosage form (PEP-CH) of peplomycin was tested for therapeutic efficacy against lymph node metastasis in mice. PEP-CH is a suspension comprising 4 mg/ml of activated carbon, 2 mg/ml of peplomycin and 1.6 mg/ml of polyvinylpyrrolidone in saline. Mice were subcutaneously inoculated with 3 x 10(5) MH134 tumor cells into the left hind paw. Drugs were given on day 10 when cancer had been metastasized in the left popliteal lymph node. Mice were killed on day 17 and the left popliteal lymph node and the left deep inguinal lymph node were extirpated. Since the degree of the metastatic lesion and the lymph node weight correlated with a statistically high probability with each other, the degree of metastatic lesion was evaluated through comparison of lymph node weight. The left popliteal lymph node and the deep inguinal lymph node were 10.5 mg and 4.5 mg in average weight, respectively, in the mice given PEP-CH containing 0.1 mg of peplomycin subcutaneously into the left hind foot-pad. The weights were significantly smaller than those in the mice given an identical dose of peplomycin aqueous solution subcutaneously into the left hind foot-pad or intraperitoneally.     

Immunological involvement in pulmonary fibrosis induced by peplomycin

Pulmonary fibrosis in mice induced by peplomycin (PEP) was suppressed by administration of anti-inflammatory agents such as prednisolone and D-penicillamine during or after the administration of PEP. Pulmonary fibrosis was also suppressed by administration of cyclophosphamide, an immunosuppressive antitumor agent before, during or after the administration of PEP. The pulmonary fibrosis in athymic nude mice induced by PEP was less than that in normal mice. The low response in the nude mice was enhanced by transfer of thymocytes to the same level as that in the normal mice. This suggests that the immune system, especially thymus-dependent immunity, is involved in the pulmonary fibrosis induced by PEP.     

口服、肌注与鼻腔内给咪达唑仑对小儿七氟烷麻醉恢复期躁动的影响

目的 对口服、肌注与鼻腔内给咪达唑仑对小儿七氟烷麻醉恢复期躁动的影响进行分析.方法 选取在本院行扁桃体联合腺样体切除术治疗的患儿76例,按照随机数字表法将本批患者分为4组,分别为对照组(C组)、肌内注射咪达唑仑组(IM组)、鼻腔内给予咪达唑组(IN组)以及口服咪达唑仑组(0组),每组19例.C组在麻醉前30 min口服10％葡萄糖溶液10 ml,lM组、O组、IN组咪达唑仑剂量分别为0.15、0.45、0.25 mg·kg-1,利用七氟烷进行相应的麻醉诱导,并在静脉注射相应的瑞芬太尼以及七氟烷对其麻醉效果给与维持.对脱离父母的难易程度以及父母的满意度进行评分,EA发生情况采用患儿麻醉恢复期躁动表化评分表(PAED)进行评估.结果 C组(1分:17例;2分:2例;3分:0例;4分:0例)与O组(1分:0例;2分:15例;3分:4例;4分:0例)、IN组(1分:0例;2分:6例;3分:13例;4分:0例)以及IM组(1分:0例;2分:7例;3分:12例;4分:0例)相比,其在脱离父母难易程度、父母满意度所获评分提升,其相应的PAED评分及EA的发生率均降低(均P＜ 0.05);与0组相比,其相应的脱离父母难易程度上的评分明显升高,在父母的满意度方面的评分降低(均P＜ 0.05),其在EA发生率以及PAED的评分上差异均无统计学意义(均P＞0.05).结论 通过口服、肌注与鼻腔内给相应的咪达唑仑,对于预防小儿七氟烷EA的发生在效果上具有相似之处,并且通过口服的方式用药更容易被接受.     

The Effect of Vitamin E and Selenium on Doxorubicin (Adriamycin®) Induced Delayed Toxicity in Mice

Abstract: The antagonistic action of repeated administration of vitamin E and selenium on the lethality caused by a single intraperitoneal injection of doxorubicin 15 to 20 mg/kg has been investigated in mice. Mice were treated with vitamin E, 20 to 4100 mg/kg intraperitoneally/intramuscularly daily or once a week and/or selenium 27 μg/kg orally daily for 6 to 7 weeks, i.e. one or two weeks before and five weeks after doxorubicin administration. 30 mg/kg of doxorubicin intraperitoneally caused 100% lethality within 4 days, whereas 15 mg/kg caused no deaths within a week, but resulted in a delayed toxicity with a cumulative lethality of 80% at the end of the observation period of 6 months. Vitamin E protected the mice from the lethal effect of doxorubicin, 15 mg/kg during the administration, but the mice began to die when the vitamin E administration was discontinued. Selenium only protected the mice for two weeks in spite of the continuous administration of selenium. The combined administration of vitamin E and selenium had no protective effect on the lethality caused by doxorubicin, 20 mg/kg. The pathogenesis of the delayed lethality of a single doxorubicin administration in mice is discussed. It is concluded that vitamin E and/or selenium have no significant protective action against doxorubicin induced delayed lethality in mice.     

The effect of vitamin E and selenium on doxorubicin (Adriamycin) induced delayed toxicity in mice

The antagonistic action of repeated administration of vitamin E and selenium on the lethality caused by a single intraperitoneal injection of doxorubicin 15 to 20 mg/kg has been investigated in mice. Mice were treated with vitamin E, 20 to 4100 mg/kg intraperitoneally/intramuscularly daily or once a week and/or selenium 27 micrograms/kg orally daily for 6 to 7 weeks, i.e. one or two weeks before and five weeks after doxorubicin administration. 30 mg/kg of doxorubicin intraperitoneally caused 100% lethality within 4 days, whereas 15 mg/kg caused no deaths within a week, but resulted in a delayed toxicity with a cumulative lethality of 80% at the end of the observation period of 6 months. Vitamin E protected the mice from the lethal effect of doxorubicin, 15 mg/kg during the administration, but the mice began to die when the vitamin E administration was discontinued. Selenium only protected the mice for two weeks in spite of the continuous administration of selenium. The combined administration of vitamin E and selenium had no protective effect on the lethality caused by doxorubicin, 20 mg/kg. The pathogenesis of the delayed lethality of a single doxorubicin administration in mice is discussed. It is concluded that vitamin E and/or selenium have no significant protective action against doxorubicin induced delayed lethality in mice.     

β-连环蛋白在肺纤维化小鼠肺组织中的表达

目的观察β-连环蛋白在肺纤维化模型小鼠肺组织中的表达。方法昆明小鼠40只随机均分成实验组和对照组,气管内分别一次性注入博来霉素5mg/kg(0.04ml)和生理盐水0.04ml。给药后第3、7、14、28天,每组处死小鼠5只,取肺组织做病理切片和HE染色;用碱水解法检测肺组织羟脯氨酸含量,免疫组化法及Western blot检测肺组织中β-连环蛋白表达。结果实验组肺泡炎和肺纤维化程度均明显高于对照组(P<0.05),羟脯氨酸的含量在第7-28天明显高于对照组(P<0.01)。实验组在各时间点肺组织中的β-连环蛋白表达高于对照组(P<0.05);其表达高峰在第14天。结论β-连环蛋白在模型小鼠肺纤维化发生过程中存在高表达。     

来氟米特是否诱导大鼠发生肺纤维化

目的:研究来氟米特是否诱导大鼠发生肺纤维化。方法:SD大鼠90只,随机分5组,每组18只。分别单次气管内给予生理盐水1.25 mL·kg~(-1)、来氟米特(2mg·kg~(-1),15mg·kg~(-1))、来氟米特杂质(0.02mg·kg~(-1))和博来霉素(5mg·kg~(-1)),给药后2和4wk收集出肺血液,检测其中丙二醛(MDA)和NO_2~-/NO_3~-的含量;给药后1、2和4wk,肺称重计算肺系数,用Masson三重染色和天狼猩红特殊染色,光镜和电镜检查肺组织的病理变化;免疫组织化学法检测肺组织中TGF-β1表达。结果:单次气管内给药后,与生理盐水组相比,来氟米特低、高剂量组出肺血液中MDA和NO_2~-/NO_3~-的含量无明显变化,而博来霉素组显著升高(均P<0.01)。与生理盐水组相比,来氟米特低、高剂量组大鼠肺系数无明显变化,而博来霉素组显著增大(P<0.01)。来氟米特给药组大鼠未发生肺纤维化毒性反应病理变化,而阳性对照博来霉素组出现典型的早期肺炎和后期肺纤维化的病理变化。结论:来氟米特未诱导大鼠发生肺纤维化的不良反应。     

microRNA-21对肺成纤维细胞增殖和分化的影响

摘要： 目的 探讨小鼠肺成纤维化细胞模型中 microRNA（miR） -21 对肺成纤维细胞增殖和分化的影响。方法 24 只 SPF 级 C57BL/6 小鼠随机分为假手术组和肺纤维化模型组, 各 12 只。经气管内注入博莱霉素建立小鼠肺纤维 化模型, 采用荧光定量 PCR 检测各组肺组织 miR-21 的表达。提取小鼠成纤维细胞, 胰酶消化, 接种于 6 孔板, 使细 胞浓度达到 30%~50%。设随机对照组、 空白对照组和 miR-21 mimic 组。各组分别在 50 μL Opti-MEM 加入 2.5 μL PBS、 阴性对照储存液和 miR-21 mimic 储存液（20 μmol/L）。采用细胞计数试剂盒-8(CCK-8)法检测细胞增殖活性, 蛋白质印迹法检测成纤维细胞含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶(ADAMTS-1)和转化生长因子 （TGF） -β1的表达。结果 与假手术组比较, 肺纤维化模型组小鼠肺组织中 miR-21 的表达量明显上调。与随机对 照组和空白对照组比较, miR-21 mimic 组成纤维细胞 miR-21 基因表达显著上调, 成纤维细胞增殖率增加, ADAMTS-1 蛋白表达明显下降, 而 TGF-β1表达显著上调; 空白对照组与随机对照组 ADAMTS-1 及 TGF-β1蛋白表达无明显差 异。结论 在小鼠肺成纤维化细胞模型中上调的 miR-21 可通过ADAMTS-1/TGF-β1信号通路促进肺纤维化。     

Acrylic microspheres in vivo VI: antitumor effect of microparticles with immobilized L-asparaginase against 6C3HED lymphoma

The antitumor effect of immobilized L-asparaginase was tested against lymphoid leukemia in mice with concomitant scanning of the L-asparagine level in serum. L-Asparaginase was immobilized in microspheres of polyacrylamide or polyacryldextran. These particles were used in C3H mice bearing the L-asparagine-dependent lymphoma (6C3HED). The tumor was maintained as an ascites tumor, 1 X 10(6) cells were injected intraperitoneally and on day 4 after inoculation, L-asparaginase was injected intramuscularly or intraperitoneally in microparticles. After injection of 5.0 IU ip of L-asparaginase in microparticles, partial remission was induced, generally, however, the cancer relapsed and killed the mice within 2-3 weeks. To obtain complete regression, it was necessary to inject 20 IU of L-asparaginase in microparticles intraperitoneally. The best therapeutic effect was obtained when the particles were administered intramuscularly. After injection of 5 IU the survival time was prolonged, but complete regression was not achieved. The best effect was obtained when the particles were given intramuscularly in two small doses (2.5 IU) at a 3-day interval. Such treatment induced complete regression; 10 out of 12 treated mice were completely cured and lived for several months. It is concluded that the L-asparagine level in serum has to be depressed to less than 20% of the normal level for at least 6-7 days to obtain complete regression of the tumor.     

S-Allylmercaptocysteine attenuates Bleomycin-induced pulmonary fibrosis in mice via suppressing TGF-β1/Smad and oxidative stress pathways

Pulmonary fibrosis (PF) is a disease characterized by diffusing alveolar inflammation and alveolar structural disorders that ultimately lead to pulmonary interstitial fibrosis. S-allylmercaptocysteine (SAMC) as a water-soluble organosulfur garlic derivative exhibits efficient anti-inflammatory and anti-oxidative activities. In this study, we attempted to explore the function of SAMC in inhibiting bleomycin (BLM)-induced pulmonary fibrosis in mice. 0.035 U/g of BLM was intraperitoneally injected into mice twice per week for 4 weeks to induce fibrosis. SAMC (25 and 50 mg/kg) and N-acetylcysteine (NAC, 600 mg/kg) were given to mice for 28 days. The results indicate that SAMC could significantly ameliorate the pathological structure, and decrease inflammatory cell infiltration and pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) in BLM-induced pulmonary fibrosis mice. SAMC showed an anti-fibrosis effect by increasing anti-oxidants like HO-1, GSH and SOD as well as decreasing hydroxyproline (HYP) in BLM-induced mice. Mechanistic studies suggested that SAMC alleviated oxidative stress probably by impacting the Nox4/Nrf2 pathways, and played an anti-fibrosis role with decreasing the expression of α-SMA, collagen III, collagen I by suppressing the TGF-β1/Smad pathway. These findings indicate that SAMC may be partially responsible for the therapeutic effect on PF patients.     

Phenylbutyric acid inhibits epithelial-mesenchymal transition during bleomycin-induced lung fibrosis

A recent report showed that unfolded protein response (UPR) signaling was activated during bleomycin (BLM)-induced pulmonary fibrosis. Phenylbutyric acid (PBA) is an endoplasmic reticulum (ER) chemical chaperone that inhibits the UPR signaling. The present study investigated the effects of PBA on BLM-induced epithelial-mesenchymal transition (EMT) and pulmonary fibrosis. For induction of pulmonary fibrosis, all mice except controls were intratracheally injected with a single dose of BLM (3.0 mg/kg). In PBA + BLM group, mice were intraperitoneally injected with PBA (150 mg/kg) daily. Three weeks after BLM injection, EMT was measured and pulmonary fibrosis was evaluated. BLM-induced pulmonary UPR activation was inhibited by PBA. Moreover, BLM-induced pulmonary nuclear factor kappa B (NF-κB) p65 activation was blocked by PBA. In addition, BLM-induced up-regulation of pulmonary inflammatory cytokines was repressed by PBA. Further analysis showed that BLM-induced α-smooth muscle actin (α-SMA), a marker for EMT, was significantly attenuated by PBA. Moreover, BLM-induced pulmonary collagen (Col1α1 and Col1α2) was obviously inhibited by PBA. Importantly, BLM-induced pulmonary fibrosis, as determined using Sirius red staining, was obviously alleviated by PBA. Taken together, these results suggest that PBA alleviates ER stress-mediated EMT in the pathogenesis of BLM-induced pulmonary fibrosis.     

The effect of indomethacin, prednisolone and Cis-4-hydroxyproline on pulmonary fibrosis produced by butylated hydroxytoluene and oxygen

The purpose of this study was to examine whether development of pulmonary fibrosis in mice could be influenced by indomethacin, prednisolone or a proline analog. Pulmonary fibrosis was produced in mice treated with butylated hydroxytoluene (BHT) 400 mg/kg and immediately exposed to 80% oxygen for 3 days. This treatment regimen resulted in 47% mortality. Surviving mice exhibited significant accumulations of pulmonary collagen as evidenced by increases in total lung hydroxyproline levels. The administration of indomethacin (4 mg/kg/day) on days 1–6 after BHT decreased mortality to 14% and diminished the accumulation of collagen in lung tissue. Indomethacin also enhanced survival when administered on days 1–3 after BHT/O₂ but had no effect on lung collagen levels. Treatment with indomethacin on days 4–6 after BHT had no beneficial effect. The administration of prednisolone (60 mg/kg/day) on days 1–3, 1–6 or 4–6 after BHT decreased mortality but had no effect on accumulation of lung collagen. Cis-4-hydroxyproline (400 mg/kg/day) also had no effect on pulmonary fibrosis but did enhance survival when given on days 1–3 after BHT. Administering prednisolone (60 mg/kg/day) on days 1–6 after BHT to mice left in room air produced significantly more pulmonary fibrosis than in BHT-treated mice given saline. These data support the use of the BHT/O₂ model of pulmonary fibrosis for screening potential antifibrotic agents. The possibility that corticosteroid treatment may enhance pulmonary fibrosis in a damaged lung is also demonstrated.     

Bio‐distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice

Cerium oxide nanoparticles have oxygen defects in their lattice structure that enables them to act as a regenerative free radical scavenger in a physiological environment. We performed a comprehensive in vivo analysis of the biological distribution and antioxidant capabilities of nanoceria administered to mice perorally (PO), intravenously (IV), or intraperitoneally (IP) by dosing animals weekly for 2 or 5 weeks with 0.5 mg kg^?1 nanoceria. Next, we examined if nanoceria administration would decrease ROS production in mice treated with carbon tetrachloride (CCl₄). Our results showed that the most extensive and cumulative nano‐deposition was via IV and IP administered while PO administration showed mice excreted greater than 95% of their nanoceria within 24 h. Organ deposition for IV and IP mice was greatest in the spleen followed by the liver, lungs, and kidneys. Elimination for all administration routes was through feces. Nanoceria administration showed no overt toxicity, however, WBC counts were elevated with IV and IP administration. Our in vivo studies show that nanoceria administration to mice with induced liver toxicity (by CCl₄) showed similar findings to mice treated with N‐acetyl cystine (NAC), a common therapeutic to reduce oxidative stress. Taken together, our studies show that nanoceria remains deposited in tissues and may decrease ROS, thereby suggesting that cerium oxide nanoparticles may be a useful antioxidant treatment for oxidative stress. © 2011 Wiley Periodicals, Inc. Environ Toxicol 2013.     

辅助性T细胞17活化在百草枯致小鼠肺纤维化模型中的作用

目的 观察辅助性T细胞17(Th17)活化在百草枯致小鼠肺纤维化模型中的作用.方法 将30只C57BL/6小鼠随机分为对照组(10只)和百草枯中毒组(20只).百草枯中毒组经腹腔注射百草枯35 mg/kg建立小鼠中毒模型;对照组经腹腔注入等体积生理盐水.观察2组小鼠肺脏组织病理变化情况及肺纤维化评分,检测外周血Th17细胞、肺组织中维甲酸相关核孤儿受体γt(RORγt)基因及蛋白的表达情况.结果 百草枯中毒组肺平均内衬间隔、肺泡腔与肺总面积比高于对照组,平均肺泡数低于对照组,外周血Th17细胞阳性率高于对照组,肺组织中ROR-γtmRNA和蛋白表达水平高于对照组(P＜0.01).结论 百草枯致小鼠肺纤维化模型外周血及肺组织中Th17细胞明显活化,提示Th17细胞活化在百草枯致肺纤维化过程中起着重要作用.     

Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats

1.?Weekly intramuscular injections of (250?mg/week) of 17-hydroxyprogesterone caproate (17-OHPC) are the only treatment option for prevention of preterm birth in women with a prior history of preterm delivery.

2.?The objective of the current study was to evaluate the use of an alternate formulation and the feasibility of an alternate route of administration of this agent. 17-OHPC was administered to adult female SD rats, as marketed oily formulation intramuscularly, or as a solution IV, IM, or PO.

3.?Plasma concentrations of 17-OHPC were measured by LC-MS-MS and pharmacokinetic parameters were calculated by non-compartmental analysis, using WinNonLin (Certara, St. Louis, MO).

4.?After IV or IM administration as a solution, the mean half-life of 17-OHPC was around 11?h. The bioavailability was nearly 100% after IM administration, but was very low (<3%) after PO administration of a solution dosage form.

5.?Intramuscular injection of the oily formulation resulted in low levels of 17-OHPC that were sustained for a prolonged time period with a projected bioavailability close to 100%.

6.?The pharmacokinetics of 17-OHPC is dependent on the formulation and the route of administration.

7.?The low bioavailability after oral administration indicates that oral administration of 17-OHPC may not be feasible with simple formulations of this drug.     

Hemolytic streptococcus preparation OK-432; beneficial adjuvant therapy in recurrent gastric carcinoma

The administration of a hemolytic streptococcus preparation, OK-432, is thought to be of therapeutic value in the treatment of cancer patients through a stimulatory effect on the immune system. In order to evaluate any beneficial effect of such an administration, a group of patients with recurrent gastric cancer was studied. This group was randomly subdivided into 3 groups: 1) Intradermal group (ID Group), 42 patients given an intradermal injections of OK-432. 2) Intramuscular group (IM Group), 40 patients given an intramuscular injections of OK-432. 3) Control group (C Group), 39 patients not given injections. Each group was studied in regards to the length of survival, the host immune response and the incidence of side effects. When compared to the IM and C Groups, the ID Group showed improved survival. Accompanying this improved survival, the ID Group also had greater white cell and lymphocyte counts, a greater number of T cells, and a more dramatic skin reaction to the extracted cell wall polysaccharide of hemolytic streptococcus Su-strain (Su-PS). The ID Group, following OK-432 injection, had a 4.8% incidence of fever and a 52.4% incidence of local abscess formation at the injection site. 90% of the IM Group developed fever but abscess formation was absent in all patients. From these results, it was concluded that in the patients tested, intradermal injection of OK-432 appears to be clinically superior to intramuscular injection.     

The effect of ofloxacin and ciprofloxacin on pentylenetetrazol-induced convulsions in mice.

There have been several reports that convulsions, although rare, occur in patients who received fluoroquinolones. In this study, conducted for the evaluation of the convulsant action of fluoroquinolones, the effect of ofloxacin and ciprofloxacin on pentylenetetrazol-induced convulsions were investigated in mice. Mice were pretreated intraperitoneally (IP) with saline, ofloxacin (20 or 80 mg/kg) or ciprofloxacin (20 or 80 mg/kg) 30 minutes before subcutaneous (SC) administration of pentylenetetrazol (40 or 60 mg/kg). In another experiment, diazepam (5 mg/kg) was injected (IP) in mice alone or in combination with ofloxacin (80 mg/kg) 30 minutes before pentylenetetrazol (40 mg/kg) administration (SC). In each experiment mice were observed over the following hour for the incidence and onset of clonic convulsions. Results showed that both doses of ofloxacin increased the incidence of clonic convulsions induced by 40 mg/kg pentylenetetrazol. This effect, however was only significant in the higher dose and inhibited by diazepam. On the other hand, a similar proconvulsant effect by ciprofloxacin could not be demonstrated.     

Effect of Antioxidants, Anti-inflammatory Drugs, and Histamine Antagonists on Sparfloxacin-Induced Phototoxicity in Mice

We examined the effects of antioxidants, anti-inflammatory drugs,and histamine antagonists on auricular inflammation and retinaldegeneration induced by the phototoxicity of sparfloxacin (SPFX),a quinolone antibacterial agent. Catalase (CAT), dimethyl sulfoxide(DMSO), dexamethasone (DM), indomethacin (IM), phenidone (PD),AA-861 (AA), pyrilamine maleate (PY), or cimetidine (CM) wascontinuously administered to female Balb/c mice using microosmoticpumps for 72 hr and intraperitoneally once before SPFX administration.The mice were given a single oral administration of 50 or 100mg/kg SPFX and irradiated with ultraviolet-A (UVA) light at1.5 mW/cm² for 4 hr. SPFX administration plus UVA irradiationinduced thickening and inflammation of the auricular skin andretinal degeneration in the eye. CAT and DMSO significantlyinhibited the auricular thickening only 4 hr after SPFX administration.DM, IM, and PD also inhibited this toxicity from 4 to 48 or72 hr. On the other hand, PY and CM showed no effect on thischange. With regard to the eye, CAT and DMSO completely inhibitedthe occurrence of retinal degeneration and IM and PD tendedto decrease its incidence, whereas DM, AA, PY, and CM showedno or an exacerbating effect. These results suggest that reactiveoxygen species contribute to the initiation of auricular inflammationand retinal degeneration and that cyclooxygenase products arealso involved in the initiation and later progression of auricularinflammation. They also show that histamine and 5-lipoxygenaseproducts are not involved in either phototoxic lesion.     

大鼠肺间质纤维化造模的2种方法比较研究

目的探讨气管和腹腔注射2种给药方式复制特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)大鼠模型的差异。方法240~260g雄性SD大鼠24只,按照随机数字表法分为气管对照组(QC组)、气管给药组(Q组)、腹腔对照组(FC组)和腹腔给药组(F组),每组6只。分别经气管一次性注射生理盐水0.2mL或博莱霉素(BLM)5mg·kg~(-1)·d~(-1);腹腔注射生理盐水0.2mL或博莱霉素15mg·kg~(-1)·d~(-1),连续10d。28d后处死。观察每组小鼠生存率、体质量、肺脏外观、病理改变及肺组织羟脯氨酸含量。结果 Q组生存率为66.7%;F组生存率为83.3%,二者比较差异有统计学意义(P<0.05)。2种方法给药组大鼠体质量均减轻,F组动物体质量在1~7d内下降,第8天起开始恢复;Q组动物体质量在前15d内持续下降,第16d起开始恢复。2种方法给药组的肺脏外观基本相同,没有显著差别。病理检查证实,Q组的胶原纤维沉积主要分布在气管周围,而F组的胶原沉积则分布在胸膜和肺间质。2种方法复制的模型组肺组织羟脯氨酸含量均显著高于对照组,差异有统计学意义(P<0.05);模型组间差异无统计学意义。结论气管给药与腹腔给药对于复制大鼠IPF无明显差别,但气管给药法更方便、经济和可靠。     

VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice

ObjectiveAbnormal angiogenesis is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. It has been shown that vascular endothelial growth factor (VEGF) is one of the critical angiogenic factors in angiogenesis. The aim of the present study was to assess whether disruption of VEGF pathway would attenuate bleomycin-induced pulmonary fibrosis.MethodsBleomycin-induced pulmonary fibrosis mice were treated intraperitoneally with VEGF receptor tyrosine kinase inhibitor SU5416 at different phases after bleomycin infusion. We measured angiogenesis and inflammatory response in both bleomycin-treated and control mice, and correlated these levels with pulmonary fibrosis.ResultsThe increased expressions of VEGF/VEGFR (Flk-1) were correlated to a larger number of microvessels and a higher score of pulmonary fibrosis. Early administration of SU5416 inhibited pulmonary collagen deposition, histopathologic fibroplasias and the activation of TGF-β1/Smad3 signaling pathway in bleomycin-stimulated lung. These were also paralleled by a reduction of VEGF/VEGFR-2 (Flk-1) expression and microvessel numbers in lung. Furthermore, SU5416 inhibited inflammatory cell numbers and LDH activity in BALF and IL-13 expression in lung tissue at early inflammatory phase of bleomycin-induced pulmonary fibrosis.ConclusionThese results suggest that the VEGFR-2 inhibitor, SU5416, attenuates histopathologic fibroplasias and collagen deposition by regulating angiogenesis and inflammation in the lung.