自噬反应在百草枯致急性呼吸窘迫综合征和肺泡上皮细胞死亡过程中的作用及其机制研究
|
摘要
目的
百草枯是一种广泛运用于农业生产中的除草剂。百草枯经口误服或自服中毒后急性起病,无特效解毒剂,救治成功率低,病死率高。我国百草枯中毒致死患者呈逐年急剧递增趋势。国内外研究发现,百草枯能在肺组织中被肺泡I型上皮细胞、Ⅱ型上皮细胞和Clara细胞主动摄取,因此在肺内异常高浓度聚集,肺中浓度可达血浆浓度的6-10倍,该聚集机制与多胺转运系统相关。百草枯吸收后可导致急性呼吸窘迫综合征,并发展为急性呼吸衰竭,后期形成肺纤维化。目前,百草枯致急性呼吸窘迫综合征机制仍不清,且动物模型多采用腹腔注射百草枯建立,与人体经口摄入而中毒的途径不符。
氯喹是一种广泛运用于临床的抗疟药,因其免疫调节作用,也被用于治疗免疫系统疾病、恶性肿瘤、病毒感染等疾病中。目前尚无相关研究,探索氯喹是否能用于百草枯中毒的解救。氯喹的治疗作用被认为可能与抑制细胞自噬反应相关。
本实验研究采用人肺泡Ⅱ型上皮细胞A549细胞建立百草枯中毒细胞模型,并模拟临床中毒途径,通过百草枯灌胃建立稳定的急性呼吸窘迫综合征小鼠模型。同时,通过体外实验研究氯喹对百草枯攻毒后A549细胞存活率、蛋白表达情况的影响,分析百草枯致急性呼吸窘迫综合征可能的分子生物学机制,探讨自噬反应在百草枯中毒所致肺损伤过程中的作用及其机制。
方法
(一)百草枯灌胃致小鼠急性呼吸窘迫综合征模型的建立及其致病机制探讨
采用不同浓度百草枯(3、10、30、100、150、300mg/kg)灌胃建立小鼠急性呼吸窘迫综合征模型。根据小鼠临床表现,确定建立稳定模型的百草枯浓度。采用该浓度百草枯灌胃建立小鼠模型后,在1d、2d、3d、4d时观察小鼠临床表现、测量肺湿/干比、行HE病理染色以进行研究分析。使用western-blot检测LC-3蛋白表达情况。
(二)百草枯攻毒并氯喹解救百草枯攻毒A549细胞模型的建立和分子生物学机制探讨
1、采用MTS法检测不同浓度百草枯(0.1、0.3、1、3、10、30、100、300、1000μmol/L)对A549细胞生存率的影响情况,确定能建立稳定细胞模型的百草枯浓度。
2、使用不同浓度CQ(O.3、1、3、10、30μmol/L)、3-MA(0.3、1、3、5mmol/L)、 LY294002(0.3、1、3、10μmol/L)、 wortmannin (3、10、30、50、100μmol/L)、 necrostatin-1(0.1、0.3、1、3、10μmol/L)、 rolipram(1、3、10、30、100μmol/L)干预PQ100μmol/L浓度攻毒A549细胞,分别于攻毒后12h、24h、48h使用MTS法检测细胞存活率情况。
3、采用不同浓度氯喹(0.3、1、3、10、30μmol/L)在PQ100μmol/L浓度攻毒0h、1h、3h、6h后对其进行干预,分别于攻毒后12h、24h、48h使用MTS法检测细胞存活率情况,并使用western-blot检测LC-3、LAMP-1、LAMP-2等蛋白表达情况,并与PQ攻毒组进行对比。
结果
(一)成功建立百草枯灌胃致小鼠急性呼吸窘迫综合征模型
一次性使用百草枯灌胃可以建立小鼠急性呼吸窘迫综合征模型,建立稳定模型的百草枯浓度为300mg/kg。灌胃后,小鼠表现为体重下降,毛发蓬松无光泽,进食水差,呼吸困难,活动困难。肺湿／干比明显升高。肺组织充血出血水肿,广泛炎症细胞浸润、肺泡间隔增宽、肺泡结构破坏表现。PQ攻毒组小鼠LC-3表达含量较对照组有先升高后降低的趋势。
(二)成功建立百草枯致A549细胞死亡模型,成功建立氯喹解救百草枯所致的A549细胞死亡模型
百草枯能导致A549细胞发生时间、剂量依赖性细胞死亡。能建立稳定细胞模型、且使用药物解救可能有效的百草枯浓度为100μmol/L。
经过不同浓度氯喹解救后,百草枯攻毒A549细胞存活率明显升高。各浓度3-MA、 LY294002、wortmannin、necrostatin-1、rolipram处理后细胞存活率无改善。PQ攻毒后A549细胞LC-3表达先下调后上调,LAMP-1、LAMP-2表达量有上调趋势,CQ解救组LC-3、LAMP-1、LAMP-2表达均上调。
结论
1.百草枯能导致肺泡Ⅱ型上皮细胞死亡和小鼠急性呼吸窘迫综合征。
2.百草枯致急性呼吸窘迫综合征过程可能存在自噬反应的参与。
3.氯喹能解救百草枯攻毒所致的肺泡Ⅱ型上皮细胞死亡。
4.氯喹解救百草枯攻毒所致的肺泡Ⅱ型上皮细胞死亡可能并非经过阻断或抑制自噬反应途径、细胞坏死途径或通过抑制磷酸二酯酶-4(PDE-4)诱导的炎症反应途径而发挥作用,而是通过上调自噬反应或稳定溶酶体膜发生。
Purpose
Paraquat (PQ) is an organic heterocyclic herbicides which is widely used in agriculture. Nearly all paraquat poisonings resulted from intentional or accidental oral administration. With no specific anti-toxification drug, PQ has a reputation of high mortality. The prevalence of paraquat poisonings has increased dramatically in the recent two decades in China. Uptake by the polyamine uptake system in the alveolar type Ⅱ cells, the Clara cells, and very probably the alveolar type Ⅰ cells, PQ ends to accumulate in the lung tissue and the pulmonary concentration can be6to10times higher than that in the plasma. During the early phase of intoxication, clinical manifestations of the respiratory system mainly include acute respiratory distress syndrome(ARDS), followed by progressive pulmonary fibrosis after acute phase. Nowadays, the exact toxic mechanism remains unclear. What's more, the establishment of PQ-induced ARDS animal models mostly by intraperitoneal injection, which is not accompanied with oral administration in clinical situations.
Chloroquine (CQ), is widely used not only in the prophylactic treatment of malaria, but also in the treatment of rheumatic diseases, carcinomas, inflammations and viral infective diseases. Its therapeutic effect may be related to its inhibition effect to autophagy.
In this study, we used A549type Ⅱ-like alveolar epithelial cells to establish cell model, and established PQ-induced ARDS mice model by gavage. Then we evaluated the potential role of CQ in reducing the cytotoxic effect of PQ in the A549cell line, and pursue the molecular mechanisms of PQ-induced ARDS.
Methods
1. ARDS mice models establishment by PQ gavage
Mice poisoning models were established by PQ gavage with varies doses of3、10、30、100.150.300mg/kg respectively. The clinical manifestations, lung wet/dry (W/D), pathological manifestations by HE staining were observed and analyzed on1d.2d、3d and4d. Western-blot was used to detect proteins of LC-3.
2. PQ-induced A549cells death model establishment
A549cell viability after exposed to different concentration of PQ (0.1.0.3.1.3.10.30、100.300、1000μmol/L) was measured by MTS assay.
3. The rescuing effect of CQ to PQ-treated A549cells models and investigation of its molecular mechanisms.
After0h,1h,3h,6h exposed to100μmol/L PQ, A549cells were treated by different concentrations of CQ (0.3,1,3,10,30μmol/L). After12h,24h,48h exposed to100μmol/L PQ, A549cell viability was measured by MTS assay. Western-blot was used to detect proteins of LC-3, LAMP-1, LAMP-2. Then we tried different concentrations of3-MA (0.3,1,3,5mmol/L), LY294002(0.3,1,3,10μmol/L), wortmannin (3,10,30,50,100μmol/L), necrostatin-1(0.1,0.3,1,3,10μmol/L), rolipram (1,3,10,30,100μmol/L) when0h exposed to100μmol/L PQ, after12h,24h,48h exposed to100μmol/L PQ, A549cell viability was measured by MTS assay.
Results
1. Successfully established ARDS mice models by PQ gavage
The stable ALI mice models can be successfully established by single dose of PQ gavage, with the concentration of300mg/kg. Clinical manifestations included weight loss, poor water and food ingestion, difficulty in breathing, limitation of motion. Lung W/D was increased dramatically. Congestion, edema, hemorrhage, alveolar structure damage, inflammation cells infiltration of lung tissue were observed. There is a slightly increasing trend followed by downward tendency of LC-3expression in lung tissue.
2. Successfully established PQ-induced A549cells death model
When the concentration is≥100μmol/L, PQ causes A549cell death, with both concentration-dependence and time-dependence.
3. Successfully established CQ rescue PQ-induced A549cells death model
CQ can ameliorate PQ induced cell death in a dose-dependent manner.3-MA, wortmannin, LY294002, necrostatin-1and rolipram were not able to ameliorate A549cells death caused by PQ at all concentration levels. The LC-3expression increased after an initial decline, while both of LAMP-1and LAMP-2showed upward trend in PQ-treated cell line. Three mentioned proteins expression elevated after rescued by CQ.
Conclusions
1. PQ can induce A549cell death and ARDS to mice.
2. Autophagy may play a role in PQ-induced ARDS.
3. CQ can ameliorate PQ induced cell death.
4. CQ ameliorated PQ-induced A549cells death not though inhibition of autophagy, necrosis or phosphodiesterase-4(PDE-4) induced inflammation, but through activation of autophagy, protection of lysosome membrane or some unknown molecular mechanisms.
百草枯是一种广泛运用于农业生产中的除草剂。百草枯经口误服或自服中毒后急性起病,无特效解毒剂,救治成功率低,病死率高。我国百草枯中毒致死患者呈逐年急剧递增趋势。国内外研究发现,百草枯能在肺组织中被肺泡I型上皮细胞、Ⅱ型上皮细胞和Clara细胞主动摄取,因此在肺内异常高浓度聚集,肺中浓度可达血浆浓度的6-10倍,该聚集机制与多胺转运系统相关。百草枯吸收后可导致急性呼吸窘迫综合征,并发展为急性呼吸衰竭,后期形成肺纤维化。目前,百草枯致急性呼吸窘迫综合征机制仍不清,且动物模型多采用腹腔注射百草枯建立,与人体经口摄入而中毒的途径不符。
氯喹是一种广泛运用于临床的抗疟药,因其免疫调节作用,也被用于治疗免疫系统疾病、恶性肿瘤、病毒感染等疾病中。目前尚无相关研究,探索氯喹是否能用于百草枯中毒的解救。氯喹的治疗作用被认为可能与抑制细胞自噬反应相关。
本实验研究采用人肺泡Ⅱ型上皮细胞A549细胞建立百草枯中毒细胞模型,并模拟临床中毒途径,通过百草枯灌胃建立稳定的急性呼吸窘迫综合征小鼠模型。同时,通过体外实验研究氯喹对百草枯攻毒后A549细胞存活率、蛋白表达情况的影响,分析百草枯致急性呼吸窘迫综合征可能的分子生物学机制,探讨自噬反应在百草枯中毒所致肺损伤过程中的作用及其机制。
方法
(一)百草枯灌胃致小鼠急性呼吸窘迫综合征模型的建立及其致病机制探讨
采用不同浓度百草枯(3、10、30、100、150、300mg/kg)灌胃建立小鼠急性呼吸窘迫综合征模型。根据小鼠临床表现,确定建立稳定模型的百草枯浓度。采用该浓度百草枯灌胃建立小鼠模型后,在1d、2d、3d、4d时观察小鼠临床表现、测量肺湿/干比、行HE病理染色以进行研究分析。使用western-blot检测LC-3蛋白表达情况。
(二)百草枯攻毒并氯喹解救百草枯攻毒A549细胞模型的建立和分子生物学机制探讨
1、采用MTS法检测不同浓度百草枯(0.1、0.3、1、3、10、30、100、300、1000μmol/L)对A549细胞生存率的影响情况,确定能建立稳定细胞模型的百草枯浓度。
2、使用不同浓度CQ(O.3、1、3、10、30μmol/L)、3-MA(0.3、1、3、5mmol/L)、 LY294002(0.3、1、3、10μmol/L)、 wortmannin (3、10、30、50、100μmol/L)、 necrostatin-1(0.1、0.3、1、3、10μmol/L)、 rolipram(1、3、10、30、100μmol/L)干预PQ100μmol/L浓度攻毒A549细胞,分别于攻毒后12h、24h、48h使用MTS法检测细胞存活率情况。
3、采用不同浓度氯喹(0.3、1、3、10、30μmol/L)在PQ100μmol/L浓度攻毒0h、1h、3h、6h后对其进行干预,分别于攻毒后12h、24h、48h使用MTS法检测细胞存活率情况,并使用western-blot检测LC-3、LAMP-1、LAMP-2等蛋白表达情况,并与PQ攻毒组进行对比。
结果
(一)成功建立百草枯灌胃致小鼠急性呼吸窘迫综合征模型
一次性使用百草枯灌胃可以建立小鼠急性呼吸窘迫综合征模型,建立稳定模型的百草枯浓度为300mg/kg。灌胃后,小鼠表现为体重下降,毛发蓬松无光泽,进食水差,呼吸困难,活动困难。肺湿／干比明显升高。肺组织充血出血水肿,广泛炎症细胞浸润、肺泡间隔增宽、肺泡结构破坏表现。PQ攻毒组小鼠LC-3表达含量较对照组有先升高后降低的趋势。
(二)成功建立百草枯致A549细胞死亡模型,成功建立氯喹解救百草枯所致的A549细胞死亡模型
百草枯能导致A549细胞发生时间、剂量依赖性细胞死亡。能建立稳定细胞模型、且使用药物解救可能有效的百草枯浓度为100μmol/L。
经过不同浓度氯喹解救后,百草枯攻毒A549细胞存活率明显升高。各浓度3-MA、 LY294002、wortmannin、necrostatin-1、rolipram处理后细胞存活率无改善。PQ攻毒后A549细胞LC-3表达先下调后上调,LAMP-1、LAMP-2表达量有上调趋势,CQ解救组LC-3、LAMP-1、LAMP-2表达均上调。
结论
1.百草枯能导致肺泡Ⅱ型上皮细胞死亡和小鼠急性呼吸窘迫综合征。
2.百草枯致急性呼吸窘迫综合征过程可能存在自噬反应的参与。
3.氯喹能解救百草枯攻毒所致的肺泡Ⅱ型上皮细胞死亡。
4.氯喹解救百草枯攻毒所致的肺泡Ⅱ型上皮细胞死亡可能并非经过阻断或抑制自噬反应途径、细胞坏死途径或通过抑制磷酸二酯酶-4(PDE-4)诱导的炎症反应途径而发挥作用,而是通过上调自噬反应或稳定溶酶体膜发生。
Purpose
Paraquat (PQ) is an organic heterocyclic herbicides which is widely used in agriculture. Nearly all paraquat poisonings resulted from intentional or accidental oral administration. With no specific anti-toxification drug, PQ has a reputation of high mortality. The prevalence of paraquat poisonings has increased dramatically in the recent two decades in China. Uptake by the polyamine uptake system in the alveolar type Ⅱ cells, the Clara cells, and very probably the alveolar type Ⅰ cells, PQ ends to accumulate in the lung tissue and the pulmonary concentration can be6to10times higher than that in the plasma. During the early phase of intoxication, clinical manifestations of the respiratory system mainly include acute respiratory distress syndrome(ARDS), followed by progressive pulmonary fibrosis after acute phase. Nowadays, the exact toxic mechanism remains unclear. What's more, the establishment of PQ-induced ARDS animal models mostly by intraperitoneal injection, which is not accompanied with oral administration in clinical situations.
Chloroquine (CQ), is widely used not only in the prophylactic treatment of malaria, but also in the treatment of rheumatic diseases, carcinomas, inflammations and viral infective diseases. Its therapeutic effect may be related to its inhibition effect to autophagy.
In this study, we used A549type Ⅱ-like alveolar epithelial cells to establish cell model, and established PQ-induced ARDS mice model by gavage. Then we evaluated the potential role of CQ in reducing the cytotoxic effect of PQ in the A549cell line, and pursue the molecular mechanisms of PQ-induced ARDS.
Methods
1. ARDS mice models establishment by PQ gavage
Mice poisoning models were established by PQ gavage with varies doses of3、10、30、100.150.300mg/kg respectively. The clinical manifestations, lung wet/dry (W/D), pathological manifestations by HE staining were observed and analyzed on1d.2d、3d and4d. Western-blot was used to detect proteins of LC-3.
2. PQ-induced A549cells death model establishment
A549cell viability after exposed to different concentration of PQ (0.1.0.3.1.3.10.30、100.300、1000μmol/L) was measured by MTS assay.
3. The rescuing effect of CQ to PQ-treated A549cells models and investigation of its molecular mechanisms.
After0h,1h,3h,6h exposed to100μmol/L PQ, A549cells were treated by different concentrations of CQ (0.3,1,3,10,30μmol/L). After12h,24h,48h exposed to100μmol/L PQ, A549cell viability was measured by MTS assay. Western-blot was used to detect proteins of LC-3, LAMP-1, LAMP-2. Then we tried different concentrations of3-MA (0.3,1,3,5mmol/L), LY294002(0.3,1,3,10μmol/L), wortmannin (3,10,30,50,100μmol/L), necrostatin-1(0.1,0.3,1,3,10μmol/L), rolipram (1,3,10,30,100μmol/L) when0h exposed to100μmol/L PQ, after12h,24h,48h exposed to100μmol/L PQ, A549cell viability was measured by MTS assay.
Results
1. Successfully established ARDS mice models by PQ gavage
The stable ALI mice models can be successfully established by single dose of PQ gavage, with the concentration of300mg/kg. Clinical manifestations included weight loss, poor water and food ingestion, difficulty in breathing, limitation of motion. Lung W/D was increased dramatically. Congestion, edema, hemorrhage, alveolar structure damage, inflammation cells infiltration of lung tissue were observed. There is a slightly increasing trend followed by downward tendency of LC-3expression in lung tissue.
2. Successfully established PQ-induced A549cells death model
When the concentration is≥100μmol/L, PQ causes A549cell death, with both concentration-dependence and time-dependence.
3. Successfully established CQ rescue PQ-induced A549cells death model
CQ can ameliorate PQ induced cell death in a dose-dependent manner.3-MA, wortmannin, LY294002, necrostatin-1and rolipram were not able to ameliorate A549cells death caused by PQ at all concentration levels. The LC-3expression increased after an initial decline, while both of LAMP-1and LAMP-2showed upward trend in PQ-treated cell line. Three mentioned proteins expression elevated after rescued by CQ.
Conclusions
1. PQ can induce A549cell death and ARDS to mice.
2. Autophagy may play a role in PQ-induced ARDS.
3. CQ can ameliorate PQ induced cell death.
4. CQ ameliorated PQ-induced A549cells death not though inhibition of autophagy, necrosis or phosphodiesterase-4(PDE-4) induced inflammation, but through activation of autophagy, protection of lysosome membrane or some unknown molecular mechanisms.
引文
[1]Hawksworth GM, Bennett PN, Davies DS. Kinetics of paraquat elimination in the dog [J]. Toxicol Appl Pharmacol,1981,57(2):139-45.
[2]Bismuth C, Scherrmann JM, Garnier R, et al. Elimination of paraquat [J]. Hum Toxicol.1987,6(1):63-7.
[3]Houze P, Baud FJ, Mony R, et al. Toxicokinetics of paraquat in human [J]. Hum Exp Toxicol,1990,9(1):5-12.
[4]Dinis-Oliveira RJ, Duarte JA, Sanchez-Navarro A, et al. Paraquat poisonings:mechanisms of lung toxicity, clinical features, and treatment [J]. Crit Rev Toxicol.2008,38(1):13-71.
[5]Smith LL, Lewis CP, Wyatt I, et al. The Importance of Epithelial Uptake Systems in Lung Toxicity [J]. Environ Health Perspect,1990,85:25-30.
[6]Zhang BL, Yao L, Ou Y. Literature analysis of paraquat poisoning in China (1991-2008) [J]. Chin J Crit Care Med,2010,30,139-141.
[7]Yu HJ, and Fang Q. Clinical data analysis of severe acute paraquat poisoning [J]. Chin J Hyg Occup Dis,2010,28,786-787.
[8]Smith, LL. The identification of an accumulation system for diamines and polyamines into the lung and its relevance to paraquat toxicity [J]. Arch. Toxicol.1982,5 (Suppl.):1-14
[9]Tang PS, Mura M, Seth R, Liu M. Acute lung injury and cell death:how many ways can cells die [J]? Am J Physiol Lung Cell Mol Physiol.2008, 294(4):L632-41.
[10]Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy [J]. Nat Rev Drug Discov.2007, 6(4):304-12.
[11]Sun Y, Li C, Shu Y, et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection [J]. Sci Signal.2012, 5(212):ra16. doi:10.1126/scisignal.2001931.
[12]Mikawa K, Nishina K, Takao Y, and Obara H.ONO-1714, a nitric oxide synthase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits [J]. Anesth Analg.2003,97(6):1751-5.
[13]Houze P, Baud FJ, Mony R, et al. Toxicokinetics of paraquat in human [J]. Hum Exp Toxicol,1990,9(1):5-12.
[14]Rose MS, Smith LL, and Wyatt I. Evidence for energy dependent accumulation of paraquat into rat lung [J]. Nature 1974,252:314-315.
[15]Tkachenko AG. Mechanisms of protective functions of Escherichia coli polyamines against toxic effect of paraquat, which causes superoxide stress [J]. Biochemistry.2004,69(2):188-94.
[16]Agostinelli E, Marques MP, Calheiros R, et al. Polyamines:fundamental characters in chemistry and biology [J]. Amino Acids.2010,38(2):393-403.
[17]Smith LL, and Wyatt I. The accumulation of putrescine into slices of rat lung and brain and its relationship into the accumulation of paraquat [J]. Biochem. Pharmacol.1981,30:1053-1058.
[18]Smith LL, Wyatt I, and Cohen GM. The accumulation of diamines and polyamines into rat lung slices [J]. Biochem. Pharmacol.1982,31:3029-3033.
[19]Bayoumi AE, Perez-Pertejo Y, Ordonez C, Reguera RM, Cubria JC, Balana-Fouce R, Ordonez D. Alterations on polyamine content and glutathione metabolism induced by different concentrations of paraquat in CHO-K1 cells [J]. Toxicol In Vitro.2000,14,211-217.
[20]Fujita M, Fujita Y, Iuchi S, et al. Natural variation in a polyamine transporter determines paraquat tolerance in Arabidopsis[J]. Proc Natl Acad Sci U.S.A.2012,109,6343-6347.
[21]Uemura T, Tachihara K, Tomitori H, Kashiwagi K, Igarashi K. Characteristics of the polyamine transporter TPO1 and regulation of its activity and cellular localization by phosphorylation [J]. J Biol Chem.2005, 280,9646-9652.
[22]Kashiwagi K, Igarashi K. Identification and assays of polyamine transport systems in Escherichia coli and Saccharomyces cerevisiae[J]. Methods Mol Biol.2011,720,295-308.
[23]Seidenfeld JJ, Wycoff D, Zavala DC, Richerson HB. Paraquat lung injury in rabbits [J]. Br J Ind Med.1978,35(3):245-57.
[24]Delaval PM, Gillespie DJ. Pulmonary dysfunction during paraquat-induced lung injury:a model of acute alveolar injury [J]. Crit Care Med.1985, 13(12):1056-60.
[25]Shibamoto T, Parker JC. Fructose 1,6-diphosphate augments paraquat injury in isolated dog lungs [J]. J Appl Physiol (1985).1991,71 (5):1830-5.
[26]Block ER, Schoen FJ. Depression of serotonin uptake by rat lungs exposed to paraquat [J]. J Pharmacol Exp Ther.1982,221(1):254-60.
[27]Thompson WD, Patrick RS. Collagen stimulating factors from lung in experimental paraquat poisoning demonstrated in vitro and in vivo [J]. J Clin Pathol.1984,37(5):537-41.
[28]Parkins CS, Fowler JF. A cautionary note on the resolution of paraquat lung damage after radiotherapy [J]. Br J Radiol.1985,58(695):1137-40.
[29]Sun S, Wang H, Zhao G, et al. Complement inhibition alleviates paraquat-induced acute lung injury [J]. Am J Respir Cell Mol Biol.2011, 45(4):834-42. doi:10.1165/rcmb.2010-04440C.
[30]Liu S, Liu K, Sun Q, et al. Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats [J]. J Biomed Biotechnol.2011, 2011:305086. doi:10.1155/2011/305086.
[31]Yang H, Wen Y, Bin J, Hou-You Y, Yu-Tong W. Protection of bone marrow mesenchymal stem cells from acute lung injury induced by paraquat poisoning [J]. Clin Toxicol (Phila).2011,49(4):298-302. doi: 10.3109/15563650.2011.566882.
[32]Tsai HL, Chang JW, Yang HW, et al. Amelioration of paraquat-induced pulmonary injury by mesenchymal stem cells [J]. Cell Transplant. 2013,22(9):1667-81. doi:10.3727/096368912X657765.
[33]Sun Y, Zhang J, Yan Y, et al. The protective effect of C-phycocyanin on paraquat-induced acute lung injury in rats [J], Environ Toxicol Pharmacol. 2011,32(2):168-74. doi:10.1016/j. etap.2011.04.008.
[34]Tomita M, Okuyama T, Katsuyama H, et al. Mouse model of paraquat-poisoned lungs and its gene expression profile [J]. Toxicology. 2007,231(2-3):200-9.
[35]Chen J, Zeng T, Bi Y, et al. Docosahexaenoic acid (DHA) attenuated paraquat induced lung damage in mice [J]. Inhal Toxicol.2013,25(1):9-16. doi:10.3109/08958378.2012.750405.
[36]Xiangdong Jian, Ming Li, Yijing Zhang, et al. Role of growth factors in acute lung injury induced by paraquat in a rat model [J]. Hum Exp Toxicol. 2011,30(6):460-9. doi:10.1177/0960327110372648.
[37]Jones AL, Elton R, Flanagan R. Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning [J]. QJM.1999,92(10):573-8.
[38]付晶,王雷,施阳,等.438例急性百草枯中毒病例流行病学特点分析[J].西部医学,2011,23(2)：340-341.
[39]姜凯丽,张锡刚,江云.百草枯中毒患者预后早期判断指标的研究[J].中国急救复苏与灾害医学杂志,2010,5(7)：617-619.
[40]Wu F, Liu Y, Lv X, et al. Small interference RNA targeting TLR4 gene effectively attenuates pulmonary inflammation in a rat model [J]. J Biomed Biotechnol.2012,2012:406435. doi:10.1155/2012/406435.
[41]Novaes RD, Goncalves RV, Cupertino MC, et al. Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats [J]. Int J Exp Pathol.2012,93(3):225-33. doi:10.1111/j.1365-2613.2012.00808. x.
[42]Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury [J]. Nat Med.2005, 11(8):875-9.
[43]Kim KS, Suh GJ, Kwon WY, et al. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats [J]. Clin Toxicol (Phila).2012, 50(8):749-53. doi:10.3109/15563650.2012.708418.
[44]Smith P, Heath D. Paraquat lung:a reappraisal [J]. Thorax,1974, 29:643-653.
[45]Seidenfeld JJ, Wycoff D, Zavala DC, et al. Paraquat lung injury in rabbits. Br J Ind Med,1978,35:245-257.
[46]Dinis-Oliveira RJ, de Pinho PG, Santos L, et al. Postmortem analyses unveil the poor efficacy of decontamination, anti-inflammatory and immunosuppressive therapies in paraquat human intoxications [J]. PLoS One. 2009,4(9):e7149. doi:10.1371/journal.pone.0007149.
[47]Levine B, Klionsky DJ. Development by self-digestion:molecular mechanisms and biological functions of autophagy [J]. Dev Cell.2004, 6(4):463-77.
[48]Levine B, Kroemer G. Autophagy in the pathogenesis of disease [J]. Cell. 2008,132(1):27-42. doi:10.1016/j. cell.2007.12.018.
[49]Ryter SW, Choi AM. Autophagy in the lung [J]. Proc Am Thorac Soc.2010, 7(1):13-21. doi:10.1513/pats.200909-101JS.
[50]Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease [J]. PLoS One. 2008,3(10):e3316. doi:10.1371/journal. pone.0003316.
[51]Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing [J]. EMBO J.2000,19(21):5720-8.
[52]Liu QP, Zhou DX, Lin P, et al. Participation of autophagy in acute lung injury induced by seawater [J]. Exp Lung Res.2013,39(10):441-52. doi: 10.3109/01902148.2013.845626.
[53]Komiya K, Uchida T, Ueno T, et al. Free fatty acids stimulate autophagy in pancreatic β-cells via JNK pathway [J]. Biochem Biophys Res Commun.2010, 401 (4):561-7. doi:10.1016/j. bbrc.2010.09.101.
[54]Li C, Liu H, Sun Y, et al. PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway [J]. J Mol Cell Biol.2009,1(1):37-45. doi:10.1093/jmcb/mjp002.
[55]Lee SJ, Smith A, Guo L, et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension [J]. Am J Respir Crit Care Med.2011,183(5):649-58. doi:10.1164/rccm.201005-07460C.
[56]Pandit L, Bonilla DL, Eissa NT. Autophagy:a new frontier in research in lung diseases [J]. Am J Respir Crit Care Med.2011,183(5):566-8. doi: 10.1164/rccm.201011-1848ED.
[57]Lo S, Yuan SS, Hsu C, et al. Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice [J]. Ann Surg.2013,257(2):352-63. doi: 10.1097/SLA.0b013e318269d0e2.
[58]Yan Y, Zou Z, Sun Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model [J]. Cell Res.2013,23(2):300-2. doi:10.1038/cr.2012.165.
[59]Gonzalez-Polo RA, Niso-Santano M, Ortiz-Ortiz MA, et al. Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells [J]. Toxicol Sci.2007,97(2):448-58.
[60]Niso-Santano M, Bravo-San Pedro JM, G6mez-Sanchez R, et al. ASK1 overexpression accelerates paraquat-induced autophagy via endoplasmic reticulum stress [J]. Toxicol Sci.2011,119(1):156-68.
[61]Omura T, Asari M, Yamamoto J, et al. Sodium tauroursodeoxycholate prevents paraquat-induced cell death by suppressing endoplasmic reticulum stress responses in human lung epithelial A549 cells [J]. Biochem Biophys Res Commun.2013,432(4):689-94. doi:10.1016/j. bbrc.2013.01.131.
[62]Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest,2007,131:554-62.
[63]Bismuth C, Garnier R, Dally S, Fournier PE, Scherrmann JM. Prognosis and treatment of paraquat poisoning:a review of 28 cases [J]. J Toxicol Clin Toxicol.1982,19(5):461-74.
[64]Pond SM. Manifestations and management of paraquat poisoning [J]. Med J Aust.1990,152(5):256-9.
[65]Kimbrough RD. Toxic effects of the herbicide paraquat [J]. Chest.1974, 65:Suppl:65S-67S.
[66]Galani V, Tatsaki E, Bai M, et al. The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS):an up-to-date cell-specific review [J]. Pathol Res Pr act.2010,206 (3):145-50. doi:10.1016/j.prp.2009.12.002.
[67]Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EL. Double-blind, random-ized, controlled clinical trial of clofazimine compared with chloroquinein patients with systemic lupus erythematosus [J]. Arthritis and Rheumatism.2005,52:3073-8.
[68]Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: frommalaria to autoimmunity [J]. Clinical Reviews in Allergy & Immunology. 2012,42:145-53.
[69]Chiang G, Sassaroli M, Louie M, et al. Inhibition of HIV-1 replication by hydroxychloroquine:mechanism of action and comparison with zidovudine [J]. Clinical Therapeutics 1996,18:1080-92.
[70]Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patientsinfected with human immunodeficiency virus type 1 [J]. Clinical Therapeutics,1997,19:913-23.
[71]周红,丁国富.老药新用——氯喹治疗SIRS的作用研究进展[J].四川生理科学杂志,2003,25(4)：165-166.
[72]Harrison FE, Best JL, Meredith ME, et al. Increased expression of SVCT2 in a new mouse model raises ascorbic acid in tissues and protects against paraquat-induced oxidative damage in lung [J].PLoS One.2012,7(4):e35623. doi:10.1371/journal.pone.0035623.
[73]Yu Q, Wang T, Zhou X, et al. Wld(S) reduces paraquat-induced cytotoxicity via SIRT1 in non-neuronal cells by attenuating the depletion of NAD [J].PLoS One.2011,6(7):e21770. doi:10.1371/journal.pone.0021770.
[74]Yeh ST, Guo HR, Su YS, et al. Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells [J]. Toxicology.2006,223(3):181-90.
[75]Kim KS, Suh GJ, Kwon WY, et al. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats [J]. Clin Toxicol (Phila).2012, 50(8):749-53.
[76]Huang WD, Wang JZ, Lu YQ, et al. Lysine acetylsalicylate ameliorates lung injury in rats acutely exposed to paraquat [J]. Chin Med J (Engl).2011,
124(16):2496-501. [77] Janda E, Parafati M, Aprigliano S, et al. The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo [J]. Br J Pharmacol.2013,168(1):46-59.
[78]Djukic MM, Jovanovic MD, Ninkovic M, et al. Protective role of glutathione reductase in paraquat induced neurotoxicity [J]. Chem Biol Interact.2012,199(2):74-86.
[79]Novaes RD, Gonpalves RV, Cupertino MC, et al. Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats [J]. Int J Exp Pathol.2012,93(3):225-33. doi:10.1111/j.1365-2613.2012.00808. x.
[80]Ryter SW, Nakahira K, Haspel JA, Choi AM. Autophagy in pulmonary diseases [J]. Annu Rev Physiol.2012,74:377-401. doi: 10.1146/annurev-physiol-020911-153348.
[81]Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling [J]. Biochem J.2012,441(2):523-40. doi: 10.1042/BJ20111451.
[82]Mitsopoulos P, Suntres ZE. Cytotoxicity and gene array analysis of alveolar epithelial A549 cells exposed to paraquat [J]. Chem Biol Interact. 2010,188(3):427-36. doi:10.1016/j. cbi.2010.09.022.
[83]Zerin T, Kim YS, Hong SY, Song HY. Protective effect of methylprednisolone on paraquat-induced A549 cell cytotoxicity via induction of efflux transporter, P-glycoprotein expression [J]. Toxicol Lett.2012, 208(2):101-7. doi:10.1016/j. toxlet.2011.10.019.
[84]Podder B, Kim YS, Zerin T, Song HY. Antioxidant effect of silymarin on paraquat-induced human lung adenocarcinoma A549 cell line [J]. Food Chem Toxicol.2012,50(9):3206-14. doi:10.1016/j. fct.2012.06.007.
[85]Cappelletti G, Maggioni MG, Maci R. Apoptosis in human lung epithelial cells:triggering by paraquat and modulation by antioxidants [J]. Cell Biol Int.1998,22(9-10):671-8.
[86]Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease[J]. Toxicology.2011,283(2-3):65-87. doi:10.1016/j. tox.2011.03.001
[87]Chargui A, Zekri S, Jacquillet G, et al. Cadmium-induced autophagy in rat kidney:an early biomarker of subtoxic exposure [J]. Toxicol Sci.2011, 121(1):31-42. doi:10.1093/toxsci/kfr031.
[88]Duarte FV, Teodoro JS, Rolo AP, Palmeira CM. Exposure to dibenzofuran triggers autophagy in lung cells [J]. Toxicol Lett.2012,209(1):35-42. doi: 10.1016/j. toxlet.2011.11.029.
[89]Xiong N, Jia M, Chen C, et al. Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y [J]. Neuroscience.2011,199:292-302. doi:10.1016/j. neuroscience.2011.10.031.
[90]Gonzalez-Polo RA, Niso-Santano M, Ortiz-Ortiz MA, et al. Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells [J]. Toxicol Sci.2007,97(2):448-58.
[91]Pasquali L, Lazzeri G, Isidoro C, et al. Role of autophagy during methamphetamine neurotoxicity [J]. Ann N Y Acad Sci.2008,1139:191-6. doi: 10.1196/annals.1432.016.
[92]Slater AF. Chloroquine:mechanism of drug action and resistance in Plasmodium falciparum [J]. Pharmacol Ther.1993,57(2-3):203-35.
[93]Sundelin SP, Terman A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells [J]. APMIS.2002,110(6):481-9.
[94]Mares V, Schultze B, Maurer W. Stability of DNA in Purkinje cell nuclei of the mouse. An autoradiographic study [J]. J Cell Biol.1974,63(2 Pt 1):665-74.
[95]Leung KK, Shilton BH. Chloroquine binding reveals flavin redox switch function of quinone reductase 2 [J]. J Biol Chem.2013,288(16):11242-51. doi:10.1074/jbc. M113.457002.
[96]Yoon YH, Cho KS, Hwang JJ, et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells [J]. Invest Ophthalmol Vis Sci.2010,51(11):6030-7. doi: 10.1167/iovs.10-5278.
[97]Demachi-Okamura A, Torikai H, Akatsuka Y, et al. Autophagy creates a CTL epitope that mimics tumor-associated antigens [J]. PLoS One.2012, 7(10):e47126. doi:10.1371/journal.pone.0047126.
[98]Jeong JY, Choi JW, Jeon KI, Jue DM. Chloroquine decreases cell-surface expression of tumour necrosis factor receptors in human histiocytic U-937 cells [J]. Immunology.2002,105(1):83-91.
[99]Legssyer R, Josse C, Piette J, Ward RJ, Crichton RR. Changes in function of iron-loaded alveolar macrophages after in vivo administration of desferrioxamine and/or chloroquine [J]. J Inorg Biochem.2003, 94(1-2):36-42.
[100]Loehberg CR, Strissel PL, Dittrich R, et al. Akt and p53 are potential mediators of reduced mammary tumor growth by cloroquine and the mTOR inhibitor RAD001 [J]. Biochem Pharmacol.2012,83(4):480-8. doi: 10.1016/j. bcp.2011.
[101]Gonzalez-Polo R, Niso-Santano M, Moran JM, et al. Silencing DJ-1 reveals its contribution in paraquat-induced autophagy [J]. J Neurochem. 2009,109(3):889-98.
[102]Pan H, Zhang Y, Luo Z, et al. Autophagy mediates avian influenza H5N1 pseudotyped particle-induced lung inflammation through NF-κB and p38 MAPK signaling pathways [J]. Am J Physiol Lung Cell Mol Physiol.2014, 306(2):L183-95. doi:10.1152/ajplung.00147.2013.
[103]Ma J, Sun Q, Mi R, Zhang H. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling [J]. J Genet Genomics.2011,38(11):533-7. doi:10.1016/j. jgg.2011.10.002.
[104]Liu QP, Zhou DX, Lin P, et al. Participation of autophagy in acute lung injury induced by seawater [J]. Exp Lung Res.2013,39(10):441-52. doi: 10.3109/01902148.2013.845626.
[105]Wu CL, Lin LY, Yeh HM, et al. Delay of LPS-induced acute lung injury resolution by soluble immune complexes is neutrophil dependent [J]. Shock. 2009,32(3):276-85.
[106]Deng W, Li CY, Tong J, Zhang W, Wang DX. Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury [J]. Respir Res.2012,13:29.doi: 10.1186/1465-9921-13-29.
[107]Jang AS, Concel VJ, Bein K, et al. Endothelial dysfunction and claudin 5 regulation during acrolein-induced lung injury [J]. Am J Respir Cell Mol Biol.2011,44(4):483-90.
[108]Li LF, Liu YY, Yang CT, et al. Improvement of ventilator-induced lung injury by IPS cell-derived conditioned medium via inhibition of PI3K/Akt pathway and IP-10-dependent paracrine regulation [J]. Biomaterials.2013, 34(1):78-91.
[109]Yang SJ, Chen HM, Hsieh CH, et al. Akt pathway is required for oestrogen-mediated attenuation of lung injury in a rodent model of cerulein-induced acute pancreatitis [J]. Injury.2011,42(7):638-42.
[110]Oishi H, Takano K, Tomita K, et al. Olprinone and colforsin daropate alleviate septic lung inflammation and apoptosis through CREB-independent activation of the Akt pathway [J]. Am J Physiol Lung Cell Mol Physiol.2012, 303(2):L130-40.
[111]Chang P, Dong W, Zhang M, et al. Anti-Necroptosis Chemical Necrostatin-1 Can Also Suppress Apoptotic and Autophagic Pathway to Exert Neuroprotective Effect in Mice Intracerebral Hemorrhage Model [J]. J Mol Neurosci.2013 Oct 11. DOI 10.1007/s12031-013-0132-3. [Epub ahead of print]
[112]Zhou Y, Dai W, Lin C, et al. Protective effects of necrostatin-1 against concanavalin A-induced acute hepatic injury in mice [J]. Mediators Inflamm. 2013,2013:706156. doi:10.1155/2013/706156.
[113]Zhang YF, He W, Zhang C, et al. Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice [J]. Toxicol Lett.2014, pii:S0378-4274(14)00015-0. doi:10.1016/j. toxlet.2014.01.005. [Epub ahead of print]
[114]Arslan SC, Scheidereit C. The prevalence of TNFα-induced necrosis over apoptosis is determined by TAK1-RIP1 interplay [J]. PLoS One. 2011,6(10):e26069. doi:10.1371/journal.pone.0026069.
[115]Dondelinger Y, Aguileta MA, Goossens V, et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAPl/2 depletion or TAK1 kinase inhibition [J]. Cell Death Differ.2013, 20(10):1381-92. doi:10.1038/cdd.2013.94.
[116]Obitsu S, Sakata K, Teshima R, Kondo K. Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction [J]. Cell Death Dis.2013,4:e674. doi:10.1038/cddis.2013.188.
[117]Wright LC, Seybold J, Robichaud A, Adcock IM, Barnes PJ. Phosphodiesterase expression in human epithelial cells [J]. Am J Physiol. 1998,275(4 Pt 1):L694-700.
[118]Tang HF, Lu JJ, Tang JF, et al. Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury [J]. Int Immunopharmacol. 2010,10(4):406-11. doi:10.1016/j. int imp.2010.01.003.
[119]Miotla JM, Teixeira MM, Hellewell PG. Suppression of acute lung injury in mice by an inhibitor of phosphodiesterase type 4 [J]. Am J Respir Cell Mol Biol.1998,18(3):411-20.
[120]Hamamoto M, Suga M, Nakatani T, et al. Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model [J]. Eur J Cardiothorac Surg.2004,25(5):833-8.
[121]Chang W, Chen J, Schlueter CF, et al. Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram [J]. Toxicol Appl Pharmacol.2012,263(2):251-8.
[122]Kolosionek E, Savai R, Ghofrani HA, et al. Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition:the role of phosphodiesterase 4 [J]. Mol Biol Cell.2009,20(22):4751-65.
[123]Jager S, Bucci C, Tanida I, et al. Role for Rab7 in maturation of late autophagic vacuoles [J]. J Cell Sci.2004,117(Pt 20):4837-48.
[124]Chen JW, Madamanchi N, Madamanchi NR, Trier TT, Keherly MJ. Lamp-1 is upregulated in human glioblastoma cell lines induced to undergo apoptosis [J]. J Biomed Sci.2001,8(4):365-74.
[125]Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease) [J]. Nature. 2000,406(6798):906-10.
[126]Pereira EM, do Monte SJ, do Nascimento FF, et al. Lysosome-associated protein 1 (LAMP-1) and Lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease [J]. Gene.2014,536(1):118-22. doi: 10.1016/j. gene.2013.11.063.
[127]Wang L, Wang J, Shi Y, et al. Identification of a primary biliary cirrhosis associated protein as lysosome-associated membrane protein-2 [J]. J Proteomics.2013,91:569-79. doi:10.1016/j. jprot.2013.08.019.
[128]Armstrong A, Mattsson N, Appelqvist H, et al. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimer's Disease [J]. Neuromolecular Med.2013 Oct 8. [Epub ahead of print]
[129]Mello AS, Goldim MP, Mezzalira J, et al. LAMP2 as a marker of EBV-mediated B lymphocyte transformation in the study of lysosomal storage diseases [J]. Mol Cell Biochem.2014,385(1-2):1-6. doi: 10.1007/s11010-013-1806-4.
[130]Cohnen A, Chiang SC, Stojanovic A, et al. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage [J]. Blood.2013,122(8):1411-8. doi:10.1182/blood-2012-07-441832.
[131]Suryawan A, Davis TA. Regulation of protein degradation pathways by amino acids and insulin in skeletal muscle of neonatal pigs [J]. J Anim Sci Biotechnol.2014,5(1):8. doi:10.1186/2049-1891-5-8.
[1]Levine B, Kroemer G. Autophagy in the pathogenesis of disease [J]. Cell. 2008,132(1):27-42.
[2]Eskelinen EL, Saftig P. Autophagy:a lysosomal degradation pathway with a central role in health and disease [J]. Biochim Biophys Acta.2009, 1793(4):664-73.
[3]Deretic V, Levine B. Autophagy, immunity, and microbial adaptations [J]. Cell Host Microbe.2009,5(6):527-49.
[4]Mizushima N, Komatsu M. Autophagy:Renovation of cells and tissues [J]. Cell.2011,147:728-741.
[5]Klionsky DJ. Autophagy:from phenomenology to molecular understanding in less than a decade [J]. Nat Rev Mol Cell Biol.2007,8(11):931-7.
[6]Mizushima N, Klionsky DJ. Protein turnover via autophagy:implications for metabolism [J]. Annu Rev Nutr.2007,27:19-40.
[7]Monick MM, Powers LS, Walters K, et al. Identification of an autophagy defect in smokers'alveolar macrophages [J]. J Immunol.2010, 185(9):5425-35.
[8]Chen ZH, Lam HC, Jin Y, et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema [J]. Proc Natl Acad Sci U S A.2010, 107(44):18880-5.
[9]Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease [J]. PLoS One.2008, 3(10):e3316. Doi:10.1371/journal, pone.0003316.
[10]Chen CZ, Ou CY, Wang RH, et al. Association of Egr-1 and autophagy-related gene polymorphism in men with chronic obstructive pulmonary disease [J]. J Formos Med Assoc.2013, pii:S0929-6646(13)00262-3. Doi:10.1016/j. jfma.2013.07.015. [Epub ahead of print]
[11]Zhu L, Barret EC, Xu Y, et al. Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2 [J]. PloS One.2013,8(4):e55695. Doi: 10.1371/journal. pone.0055695.
[12]An CH, Wang XM, Lam HC, et al. TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema [J]. Am J Physiol Lung Cell Mol Physiol.2012,303(9):L748-57.
[13]Fujii S, Hara H, Araya J, et al. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease [J]. Oncoimmunology.2012,1(5):630-641.
[14]Takasaka N, Araya J, Hara H, et al. Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence [J]. J Immunol. 2014,192(3):958-68.
[15]Lam HC, Cloonan SM, Bhashyam AR, et al. Hi stone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction [J]. J Clin Invest.2013,123(12):5212-30.
[16]Guo Y, Gosker HR, Schols AM, et al. Autophagy in locomotor muscles of patients with chronic obstructive pulmonary disease [J]. Am J Respir Crit Care Med.2013,188(11):1313-20.
[17]Lee SJ, Smith A, Guo L, et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension [J]. Am J Respir Crit Care Med.2011,183(5):649-58.
[18]Lin KW, Li J, Finn PW. Emerging pathways in asthma:innate and adaptive interactions [J]. Biochim Biophys Acta.2011,1810(11):1052-8.
[19]Jyothula SS, Eissa NT. Autophagy and role in asthma [J]. Curr Opin Pulm Med.2013,19(1):30-5.
[20]Poon A, Eidelman D, Laprise C, Hamid Q. ATG5, autophagy and lung function in asthma [J]. Autophagy.2012,8(4):694-5.
[21]Martin LJ, Gupta J, Jyothula SS, et al. Functional variant in the autophagy-related 5 gene 92romoter is associated with childhood asthma [J]. PloS One.2012,7(4):e33454. Doi:10.1371/journal. pone.0033454.
[22]Wu Q, van Dyk LF, Jiang D, et al. Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway [J]. Virology.2013,446(1-2):199-206.
[23]Yeganeh B, Rezaei Moghadam A, Tran AT, et al. Asthma and influenza virus infection:focusing on cell death and stress pathways in influenza virus replication [J]. Iran J Allergy Asthma Immunol.2013,12(1):1-17.
[24]Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis:evidence-based guidelines for diagnosis and management [J]. Am J Respir Crit Care Med.2011, 183(6):788-824.
[25]Margaritopoulos GA1, Tsitoura E, Tzanakis N, et al. Self-eating:friend or foe? The emerging role of autophagy in idiopathic pulmonary fibrosis [J]. Biomed Res Int.2013,2013:420497. Doi:10.1155/2013/420497.
[26]Patel AS, Lin L, Geyer A, et al. Autophagy in idiopathic pulmonary fibrosis [J]. PloS One.2012,7(7):e41394. Doi: 10.1371/journal. pone.0041394.
[27]Araya J, Kojima J, Takasaka N, et al. Insufficient autophagy in idiopathic pulmonary fibrosis [J]. Am J Physiol Lung Cell Mol Physiol.2013, 304(1):L56-69.
[28]Mi S1, Li Z, Yang HZ, et al. Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-betal-dependent and-independent mechanisms [J]. J Immunol.2011,187(6):3003-14.
[29]Ricci A, Cherubini E, Scozzi D, et al. Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts [J]. J Cell Physiol.2013,228(7):1516-24.
[30]Minagawa S, Araya J, Numata T, et al. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol.2011,300(3):L391-401.
[31]King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis [J]. Lancet. 2011,378(9807):1949-61.
[32]Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response [J]. PloS Biol.2006,4(12):e423.
[33]Yang HZ, Wang JP, Mi S, TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury [J]. Am J Pathol.2012,180(1):275-92.
[34]Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes [J]. Cell Death Differ.2009, 16(1):87-93.
[35]Vessoni AT, Filippi-Chiela EC, Menck CF, Lenz G. Autophagy and genomic integrity [J]. Cell Death Differ.2013,20(11):1444-54.
[36]Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene [J]. J Clin Invest.2003, 112(12):1809-20.
[37]Kaewpiboon C, Surapinit S, Malilas W, et al. Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells [J]. Int J Oncol.2014,44(4):1233-42.
[38]Mei W, Dong C, Hui C, et al. Gambogenic Acid Kills Lung Cancer Cells through Aberrant Autophagy [J]. PLoS One.2014,9(1):e83604. doi: 10.1371/journal. pone.0083604.
[39]Klarer AC, O'Neal J, Imbert-Fernandez Y, et al. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism [J]. Cancer Metab.2014,2(1):2. doi:10.1186/2049-3002-2-2.
[40]Strohecker AM, White E. Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism [J]. Autophagy.2014, 10(2):384-385.
[41]Rao S, Tortola L, Perlot T, et al. A dual role for autophagy in a murine model of lung cancer [J]. Nat Commun.2014,5:3056. doi:10.1038/ncomms4056.
[42]Rao S, Yang H, Penninger JM, Kroemer G. Autophagy in non-small cell lung carcinogenesis:A positive regulator of antitumor immunosurveillance [J]. Autophagy.2014 Jan 7;10(3). [Epub ahead of print]
[43]Quintavaller C, Costanzo S, Zanca C, et al. Phosphorylation-Regulated Degradation of the Tumor-Suppressor Form of PED by Chaperone-Mediated Autophagy in Lung Cancer Cells [J]. J Cell Physiol.2014 Jan 29. doi: 10.1002/jcp.24569. [Epub ahead of print]
[44]Gannage M, Dormann D, Albrecht R, et al. Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes [J]. Cell Host Microbe. 2009,6(4):367-80.
[45]Ma J, Sun Q, Mi R, Zhang H. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling [J]. J Genet Genomics.2011,38(11):533-7.
[46]Sun Y, Li C, Shu Y, et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection [J]. Sci Signal.2012, 5(212):ra16. doi:10.1126/scisignal.2001931.
[47]Pan H, Zhang Y, Luo Z, et al. Autophagy mediates avian influenza H5N1 pseudotyped particle-induced lung inflammation through NF-κB and p38 MAPK signaling pathways [J]. Am J Physiol Lung Cell Mol Physiol.2014, 306(2):L183-95.
[48]Wu Q, van Dyk LF, Jiang D, et al. Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway [J]. Virology.2013,446(1-2):199-206.
[49]Reed M, Morris SH, Jang S, et al. Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection [J]. J Immunol.2013,191(5):2526-37.
[50]Junkins RD, Shen A, Rosen K, McCormick C, Lin TJ. Autophagy enhances bacterial clearance during P. aeruginosa lung infection [J]. PLoS One.2013, 8(8):e72263. doi:10.1371/journal, pone.0072263.
[51]Choy A1, Dancourt J, Mugo B, et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation [J]. Science.2012, 338(6110):1072-6.
[52]Tung SM, Unal C, Ley A, et al. Loss of Dictyostelium ATG9 results in a pleiotropic phenotype affecting growth, development, phagocytosis and clearance and replication of Legionella pneumophila. Cell Microbiol.2010, 12(6):765-80.
[53]Hoffmann C1, Harrison CF, Hilbi H. The natural alternative:protozoa as cellular models for Legionella infection [J]. Cell Microbiol.2013 Oct 29. doi:10.1111/cmi.12235. [Epub ahead of print]
[54]Abdulrahman BA, Khweek AA, Akhter A, et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis [J]. Autophagy.2011, 7(11):1359-70.
[55]Abdulrahman BA, Khweek AA, Akhter A, et al. Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr △F508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery [J]. J Biol Chem.2013,288(3):2049-58.
[56]Guo XG, Ji TX, Xia Y, Ma YY. Autophagy protects type II alveolar epithelial cells from Mycobacterium tuberculosis infection [J]. Biochem Biophys Res Commun.2013,432(2):308-13.
[57]Renna M, Schaffner C, Brown K, et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection [J]. J Clin Invest.2011,121(9):3554-63.
[58]Parihar SP, Guler R, Khutlang R, et al. Statin Therapy Reduces the Mycobacterium tuberculosis Burden in Human Macrophages and in Mice by Enhancing Autophagy and Phagosome Maturation [J]. J Infect Dis.2014, 209(5):754-63.
[59]Gupta A, Pant G, Mitra K, et al. Inhalable particles containing rapamycin for induction of autophagy in macrophages infected with Mycobacterium tuberculosis [J]. Mol Pharm.2014 Feb 17. [Epub ahead of print]
[60]Xu Y, Fattah EA, Liu XD, et al. Harnessing of TLR-mediated autophagy to combat mycobacteria in macrophages [J]. Tuberculosis (Edinb).2013,93 Suppl:S33-7.
[61]Seto S, Tsujimura K, Horii T, Koide Y. Autophagy adaptor protein p62/SQSTM1 and autophagy-related gene Atg5 mediate autophagosome formation in response to Mycobacterium tuberculosis infection in dendritic cells [J]. PLoS One.2013,8(12):e86017. doi:10.1371/journal. pone.0086017. eCollection 2013.
[62]Seto S, Tsujimura K, Koide Y. Coronin-la inhibits autophagosome formation around Mycobacterium tuberculosis-containing phagosomes and assists mycobacterial survival in macrophages [J]. Cell Microbiol.2012, 14(5):710-27.
[63]Sanjurjo L, Amezaga N, Vilaplana C, et al. The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy [J]. PLoS One.2013,8(11):e79670. doi:10.1371/journal. pone.0079670. eCollection 2013.
[64]Wang J, Yang K, Zhou L, et al. MicroRNA-155 promotes autophagy to eliminate intracellular mycobacteria by targeting Rheb [J]. PLoS Pathog. 2013,9(10):e1003697. doi:10.1371/journal. ppat.1003697.
[65]Biswas D, Qureshi OS, Lee WY, et al. ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages [J]. BMC Immunol.2008,9:35. doi: 10.1186/1471-2172-9-35.
[66]Verway M, Bouttier M, Wang TT, et al. Vitamin D induces interleukin-1β expression:paracrine macrophage epithelial signaling controls M. tuberculosis infection [J]. PLoS Pathog.2013,9(6):e1003407. doi: 10.1371/journal. ppat.1003407.
[67]Sato E, Imafuku S, Ishii K, et al. Vitamin D-dependent cathelicidin inhibits Mycobacterium marinum infection in human monocytic cells [J]. J Dermatol Sci.2013,70(3):166-72.
[68]Bradfute SB, Castillo EF, Arko-Mensah J, et al. Autophagy as an immune effector against tuberculosis [J]. Curr Opin Microbiol.2013,16(3):355-65.
[69]Jo EK. Autophagy as an innate defense against mycobacteria [J]. Pathog Dis.2013,67(2):108-18.
[70]Liu QP, Zhou DX, Lin P, et al. Participation of autophagy in acute lung injury induced by seawater [J]. Exp Lung Res.2013,39(10):441-52.
[71]Laskin DL, Sunil VR, Gardner CR, Laskin JD. Macrophages and tissue injury:agents of defense or destruction [J]? Annu Rev Pharmacol Toxicol. 2011,51:267-88.
[72]Sunil VR, Vayas KN, Massa CB, et al. Ozone-induced injury and oxidative stress in bronchiolar epithelium are associated with altered pulmonary mechanics [J]. Toxicol Sci.2013,133(2):309-19.
[73]Liu HL, Zhang YL, Yang N, et al. A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt-TSC2-mTOR signaling [J]. Cell Death Dis.2011,2:e159. doi: 10.1038/cddis.2011.27.
[74]Lee SM, McLaughlin JN, Frederick DR, et al. Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury [J]. Am J Physiol Lung Cell Mol Physiol.2013,304(5):L350-60.
[75]Weinberger B, Laskin JD, Sunil VR, et al. Sulfur mustard-induced pulmonary injury:therapeutic approaches to mitigating toxicity [J]. Pulm Pharmacol Ther.2011,24(1):92-9.
[76]Lee SJ, Ryter SW, Xu JF, et al. Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation [J]. Am J Respir Cell Mol Biol.2011,45(4):867-73.
[77]Yen YT, Yang HR, Lo HC, et al. Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury [J]. Surgery.2013,153(5):689-98.
[78]Lo S, Yuan SS, Hsu C, et al. Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice [J]. Ann Surg.2013,257(2):352-63.
[2]Bismuth C, Scherrmann JM, Garnier R, et al. Elimination of paraquat [J]. Hum Toxicol.1987,6(1):63-7.
[3]Houze P, Baud FJ, Mony R, et al. Toxicokinetics of paraquat in human [J]. Hum Exp Toxicol,1990,9(1):5-12.
[4]Dinis-Oliveira RJ, Duarte JA, Sanchez-Navarro A, et al. Paraquat poisonings:mechanisms of lung toxicity, clinical features, and treatment [J]. Crit Rev Toxicol.2008,38(1):13-71.
[5]Smith LL, Lewis CP, Wyatt I, et al. The Importance of Epithelial Uptake Systems in Lung Toxicity [J]. Environ Health Perspect,1990,85:25-30.
[6]Zhang BL, Yao L, Ou Y. Literature analysis of paraquat poisoning in China (1991-2008) [J]. Chin J Crit Care Med,2010,30,139-141.
[7]Yu HJ, and Fang Q. Clinical data analysis of severe acute paraquat poisoning [J]. Chin J Hyg Occup Dis,2010,28,786-787.
[8]Smith, LL. The identification of an accumulation system for diamines and polyamines into the lung and its relevance to paraquat toxicity [J]. Arch. Toxicol.1982,5 (Suppl.):1-14
[9]Tang PS, Mura M, Seth R, Liu M. Acute lung injury and cell death:how many ways can cells die [J]? Am J Physiol Lung Cell Mol Physiol.2008, 294(4):L632-41.
[10]Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy [J]. Nat Rev Drug Discov.2007, 6(4):304-12.
[11]Sun Y, Li C, Shu Y, et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection [J]. Sci Signal.2012, 5(212):ra16. doi:10.1126/scisignal.2001931.
[12]Mikawa K, Nishina K, Takao Y, and Obara H.ONO-1714, a nitric oxide synthase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits [J]. Anesth Analg.2003,97(6):1751-5.
[13]Houze P, Baud FJ, Mony R, et al. Toxicokinetics of paraquat in human [J]. Hum Exp Toxicol,1990,9(1):5-12.
[14]Rose MS, Smith LL, and Wyatt I. Evidence for energy dependent accumulation of paraquat into rat lung [J]. Nature 1974,252:314-315.
[15]Tkachenko AG. Mechanisms of protective functions of Escherichia coli polyamines against toxic effect of paraquat, which causes superoxide stress [J]. Biochemistry.2004,69(2):188-94.
[16]Agostinelli E, Marques MP, Calheiros R, et al. Polyamines:fundamental characters in chemistry and biology [J]. Amino Acids.2010,38(2):393-403.
[17]Smith LL, and Wyatt I. The accumulation of putrescine into slices of rat lung and brain and its relationship into the accumulation of paraquat [J]. Biochem. Pharmacol.1981,30:1053-1058.
[18]Smith LL, Wyatt I, and Cohen GM. The accumulation of diamines and polyamines into rat lung slices [J]. Biochem. Pharmacol.1982,31:3029-3033.
[19]Bayoumi AE, Perez-Pertejo Y, Ordonez C, Reguera RM, Cubria JC, Balana-Fouce R, Ordonez D. Alterations on polyamine content and glutathione metabolism induced by different concentrations of paraquat in CHO-K1 cells [J]. Toxicol In Vitro.2000,14,211-217.
[20]Fujita M, Fujita Y, Iuchi S, et al. Natural variation in a polyamine transporter determines paraquat tolerance in Arabidopsis[J]. Proc Natl Acad Sci U.S.A.2012,109,6343-6347.
[21]Uemura T, Tachihara K, Tomitori H, Kashiwagi K, Igarashi K. Characteristics of the polyamine transporter TPO1 and regulation of its activity and cellular localization by phosphorylation [J]. J Biol Chem.2005, 280,9646-9652.
[22]Kashiwagi K, Igarashi K. Identification and assays of polyamine transport systems in Escherichia coli and Saccharomyces cerevisiae[J]. Methods Mol Biol.2011,720,295-308.
[23]Seidenfeld JJ, Wycoff D, Zavala DC, Richerson HB. Paraquat lung injury in rabbits [J]. Br J Ind Med.1978,35(3):245-57.
[24]Delaval PM, Gillespie DJ. Pulmonary dysfunction during paraquat-induced lung injury:a model of acute alveolar injury [J]. Crit Care Med.1985, 13(12):1056-60.
[25]Shibamoto T, Parker JC. Fructose 1,6-diphosphate augments paraquat injury in isolated dog lungs [J]. J Appl Physiol (1985).1991,71 (5):1830-5.
[26]Block ER, Schoen FJ. Depression of serotonin uptake by rat lungs exposed to paraquat [J]. J Pharmacol Exp Ther.1982,221(1):254-60.
[27]Thompson WD, Patrick RS. Collagen stimulating factors from lung in experimental paraquat poisoning demonstrated in vitro and in vivo [J]. J Clin Pathol.1984,37(5):537-41.
[28]Parkins CS, Fowler JF. A cautionary note on the resolution of paraquat lung damage after radiotherapy [J]. Br J Radiol.1985,58(695):1137-40.
[29]Sun S, Wang H, Zhao G, et al. Complement inhibition alleviates paraquat-induced acute lung injury [J]. Am J Respir Cell Mol Biol.2011, 45(4):834-42. doi:10.1165/rcmb.2010-04440C.
[30]Liu S, Liu K, Sun Q, et al. Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats [J]. J Biomed Biotechnol.2011, 2011:305086. doi:10.1155/2011/305086.
[31]Yang H, Wen Y, Bin J, Hou-You Y, Yu-Tong W. Protection of bone marrow mesenchymal stem cells from acute lung injury induced by paraquat poisoning [J]. Clin Toxicol (Phila).2011,49(4):298-302. doi: 10.3109/15563650.2011.566882.
[32]Tsai HL, Chang JW, Yang HW, et al. Amelioration of paraquat-induced pulmonary injury by mesenchymal stem cells [J]. Cell Transplant. 2013,22(9):1667-81. doi:10.3727/096368912X657765.
[33]Sun Y, Zhang J, Yan Y, et al. The protective effect of C-phycocyanin on paraquat-induced acute lung injury in rats [J], Environ Toxicol Pharmacol. 2011,32(2):168-74. doi:10.1016/j. etap.2011.04.008.
[34]Tomita M, Okuyama T, Katsuyama H, et al. Mouse model of paraquat-poisoned lungs and its gene expression profile [J]. Toxicology. 2007,231(2-3):200-9.
[35]Chen J, Zeng T, Bi Y, et al. Docosahexaenoic acid (DHA) attenuated paraquat induced lung damage in mice [J]. Inhal Toxicol.2013,25(1):9-16. doi:10.3109/08958378.2012.750405.
[36]Xiangdong Jian, Ming Li, Yijing Zhang, et al. Role of growth factors in acute lung injury induced by paraquat in a rat model [J]. Hum Exp Toxicol. 2011,30(6):460-9. doi:10.1177/0960327110372648.
[37]Jones AL, Elton R, Flanagan R. Multiple logistic regression analysis of plasma paraquat concentrations as a predictor of outcome in 375 cases of paraquat poisoning [J]. QJM.1999,92(10):573-8.
[38]付晶,王雷,施阳,等.438例急性百草枯中毒病例流行病学特点分析[J].西部医学,2011,23(2)：340-341.
[39]姜凯丽,张锡刚,江云.百草枯中毒患者预后早期判断指标的研究[J].中国急救复苏与灾害医学杂志,2010,5(7)：617-619.
[40]Wu F, Liu Y, Lv X, et al. Small interference RNA targeting TLR4 gene effectively attenuates pulmonary inflammation in a rat model [J]. J Biomed Biotechnol.2012,2012:406435. doi:10.1155/2012/406435.
[41]Novaes RD, Goncalves RV, Cupertino MC, et al. Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats [J]. Int J Exp Pathol.2012,93(3):225-33. doi:10.1111/j.1365-2613.2012.00808. x.
[42]Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury [J]. Nat Med.2005, 11(8):875-9.
[43]Kim KS, Suh GJ, Kwon WY, et al. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats [J]. Clin Toxicol (Phila).2012, 50(8):749-53. doi:10.3109/15563650.2012.708418.
[44]Smith P, Heath D. Paraquat lung:a reappraisal [J]. Thorax,1974, 29:643-653.
[45]Seidenfeld JJ, Wycoff D, Zavala DC, et al. Paraquat lung injury in rabbits. Br J Ind Med,1978,35:245-257.
[46]Dinis-Oliveira RJ, de Pinho PG, Santos L, et al. Postmortem analyses unveil the poor efficacy of decontamination, anti-inflammatory and immunosuppressive therapies in paraquat human intoxications [J]. PLoS One. 2009,4(9):e7149. doi:10.1371/journal.pone.0007149.
[47]Levine B, Klionsky DJ. Development by self-digestion:molecular mechanisms and biological functions of autophagy [J]. Dev Cell.2004, 6(4):463-77.
[48]Levine B, Kroemer G. Autophagy in the pathogenesis of disease [J]. Cell. 2008,132(1):27-42. doi:10.1016/j. cell.2007.12.018.
[49]Ryter SW, Choi AM. Autophagy in the lung [J]. Proc Am Thorac Soc.2010, 7(1):13-21. doi:10.1513/pats.200909-101JS.
[50]Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease [J]. PLoS One. 2008,3(10):e3316. doi:10.1371/journal. pone.0003316.
[51]Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing [J]. EMBO J.2000,19(21):5720-8.
[52]Liu QP, Zhou DX, Lin P, et al. Participation of autophagy in acute lung injury induced by seawater [J]. Exp Lung Res.2013,39(10):441-52. doi: 10.3109/01902148.2013.845626.
[53]Komiya K, Uchida T, Ueno T, et al. Free fatty acids stimulate autophagy in pancreatic β-cells via JNK pathway [J]. Biochem Biophys Res Commun.2010, 401 (4):561-7. doi:10.1016/j. bbrc.2010.09.101.
[54]Li C, Liu H, Sun Y, et al. PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway [J]. J Mol Cell Biol.2009,1(1):37-45. doi:10.1093/jmcb/mjp002.
[55]Lee SJ, Smith A, Guo L, et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension [J]. Am J Respir Crit Care Med.2011,183(5):649-58. doi:10.1164/rccm.201005-07460C.
[56]Pandit L, Bonilla DL, Eissa NT. Autophagy:a new frontier in research in lung diseases [J]. Am J Respir Crit Care Med.2011,183(5):566-8. doi: 10.1164/rccm.201011-1848ED.
[57]Lo S, Yuan SS, Hsu C, et al. Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice [J]. Ann Surg.2013,257(2):352-63. doi: 10.1097/SLA.0b013e318269d0e2.
[58]Yan Y, Zou Z, Sun Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model [J]. Cell Res.2013,23(2):300-2. doi:10.1038/cr.2012.165.
[59]Gonzalez-Polo RA, Niso-Santano M, Ortiz-Ortiz MA, et al. Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells [J]. Toxicol Sci.2007,97(2):448-58.
[60]Niso-Santano M, Bravo-San Pedro JM, G6mez-Sanchez R, et al. ASK1 overexpression accelerates paraquat-induced autophagy via endoplasmic reticulum stress [J]. Toxicol Sci.2011,119(1):156-68.
[61]Omura T, Asari M, Yamamoto J, et al. Sodium tauroursodeoxycholate prevents paraquat-induced cell death by suppressing endoplasmic reticulum stress responses in human lung epithelial A549 cells [J]. Biochem Biophys Res Commun.2013,432(4):689-94. doi:10.1016/j. bbrc.2013.01.131.
[62]Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest,2007,131:554-62.
[63]Bismuth C, Garnier R, Dally S, Fournier PE, Scherrmann JM. Prognosis and treatment of paraquat poisoning:a review of 28 cases [J]. J Toxicol Clin Toxicol.1982,19(5):461-74.
[64]Pond SM. Manifestations and management of paraquat poisoning [J]. Med J Aust.1990,152(5):256-9.
[65]Kimbrough RD. Toxic effects of the herbicide paraquat [J]. Chest.1974, 65:Suppl:65S-67S.
[66]Galani V, Tatsaki E, Bai M, et al. The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS):an up-to-date cell-specific review [J]. Pathol Res Pr act.2010,206 (3):145-50. doi:10.1016/j.prp.2009.12.002.
[67]Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EL. Double-blind, random-ized, controlled clinical trial of clofazimine compared with chloroquinein patients with systemic lupus erythematosus [J]. Arthritis and Rheumatism.2005,52:3073-8.
[68]Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: frommalaria to autoimmunity [J]. Clinical Reviews in Allergy & Immunology. 2012,42:145-53.
[69]Chiang G, Sassaroli M, Louie M, et al. Inhibition of HIV-1 replication by hydroxychloroquine:mechanism of action and comparison with zidovudine [J]. Clinical Therapeutics 1996,18:1080-92.
[70]Sperber K, Chiang G, Chen H, et al. Comparison of hydroxychloroquine with zidovudine in asymptomatic patientsinfected with human immunodeficiency virus type 1 [J]. Clinical Therapeutics,1997,19:913-23.
[71]周红,丁国富.老药新用——氯喹治疗SIRS的作用研究进展[J].四川生理科学杂志,2003,25(4)：165-166.
[72]Harrison FE, Best JL, Meredith ME, et al. Increased expression of SVCT2 in a new mouse model raises ascorbic acid in tissues and protects against paraquat-induced oxidative damage in lung [J].PLoS One.2012,7(4):e35623. doi:10.1371/journal.pone.0035623.
[73]Yu Q, Wang T, Zhou X, et al. Wld(S) reduces paraquat-induced cytotoxicity via SIRT1 in non-neuronal cells by attenuating the depletion of NAD [J].PLoS One.2011,6(7):e21770. doi:10.1371/journal.pone.0021770.
[74]Yeh ST, Guo HR, Su YS, et al. Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells [J]. Toxicology.2006,223(3):181-90.
[75]Kim KS, Suh GJ, Kwon WY, et al. Antioxidant effects of selenium on lung injury in paraquat intoxicated rats [J]. Clin Toxicol (Phila).2012, 50(8):749-53.
[76]Huang WD, Wang JZ, Lu YQ, et al. Lysine acetylsalicylate ameliorates lung injury in rats acutely exposed to paraquat [J]. Chin Med J (Engl).2011,
124(16):2496-501. [77] Janda E, Parafati M, Aprigliano S, et al. The antidote effect of quinone oxidoreductase 2 inhibitor against paraquat-induced toxicity in vitro and in vivo [J]. Br J Pharmacol.2013,168(1):46-59.
[78]Djukic MM, Jovanovic MD, Ninkovic M, et al. Protective role of glutathione reductase in paraquat induced neurotoxicity [J]. Chem Biol Interact.2012,199(2):74-86.
[79]Novaes RD, Gonpalves RV, Cupertino MC, et al. Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats [J]. Int J Exp Pathol.2012,93(3):225-33. doi:10.1111/j.1365-2613.2012.00808. x.
[80]Ryter SW, Nakahira K, Haspel JA, Choi AM. Autophagy in pulmonary diseases [J]. Annu Rev Physiol.2012,74:377-401. doi: 10.1146/annurev-physiol-020911-153348.
[81]Lee J, Giordano S, Zhang J. Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling [J]. Biochem J.2012,441(2):523-40. doi: 10.1042/BJ20111451.
[82]Mitsopoulos P, Suntres ZE. Cytotoxicity and gene array analysis of alveolar epithelial A549 cells exposed to paraquat [J]. Chem Biol Interact. 2010,188(3):427-36. doi:10.1016/j. cbi.2010.09.022.
[83]Zerin T, Kim YS, Hong SY, Song HY. Protective effect of methylprednisolone on paraquat-induced A549 cell cytotoxicity via induction of efflux transporter, P-glycoprotein expression [J]. Toxicol Lett.2012, 208(2):101-7. doi:10.1016/j. toxlet.2011.10.019.
[84]Podder B, Kim YS, Zerin T, Song HY. Antioxidant effect of silymarin on paraquat-induced human lung adenocarcinoma A549 cell line [J]. Food Chem Toxicol.2012,50(9):3206-14. doi:10.1016/j. fct.2012.06.007.
[85]Cappelletti G, Maggioni MG, Maci R. Apoptosis in human lung epithelial cells:triggering by paraquat and modulation by antioxidants [J]. Cell Biol Int.1998,22(9-10):671-8.
[86]Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease[J]. Toxicology.2011,283(2-3):65-87. doi:10.1016/j. tox.2011.03.001
[87]Chargui A, Zekri S, Jacquillet G, et al. Cadmium-induced autophagy in rat kidney:an early biomarker of subtoxic exposure [J]. Toxicol Sci.2011, 121(1):31-42. doi:10.1093/toxsci/kfr031.
[88]Duarte FV, Teodoro JS, Rolo AP, Palmeira CM. Exposure to dibenzofuran triggers autophagy in lung cells [J]. Toxicol Lett.2012,209(1):35-42. doi: 10.1016/j. toxlet.2011.11.029.
[89]Xiong N, Jia M, Chen C, et al. Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y [J]. Neuroscience.2011,199:292-302. doi:10.1016/j. neuroscience.2011.10.031.
[90]Gonzalez-Polo RA, Niso-Santano M, Ortiz-Ortiz MA, et al. Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells [J]. Toxicol Sci.2007,97(2):448-58.
[91]Pasquali L, Lazzeri G, Isidoro C, et al. Role of autophagy during methamphetamine neurotoxicity [J]. Ann N Y Acad Sci.2008,1139:191-6. doi: 10.1196/annals.1432.016.
[92]Slater AF. Chloroquine:mechanism of drug action and resistance in Plasmodium falciparum [J]. Pharmacol Ther.1993,57(2-3):203-35.
[93]Sundelin SP, Terman A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells [J]. APMIS.2002,110(6):481-9.
[94]Mares V, Schultze B, Maurer W. Stability of DNA in Purkinje cell nuclei of the mouse. An autoradiographic study [J]. J Cell Biol.1974,63(2 Pt 1):665-74.
[95]Leung KK, Shilton BH. Chloroquine binding reveals flavin redox switch function of quinone reductase 2 [J]. J Biol Chem.2013,288(16):11242-51. doi:10.1074/jbc. M113.457002.
[96]Yoon YH, Cho KS, Hwang JJ, et al. Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells [J]. Invest Ophthalmol Vis Sci.2010,51(11):6030-7. doi: 10.1167/iovs.10-5278.
[97]Demachi-Okamura A, Torikai H, Akatsuka Y, et al. Autophagy creates a CTL epitope that mimics tumor-associated antigens [J]. PLoS One.2012, 7(10):e47126. doi:10.1371/journal.pone.0047126.
[98]Jeong JY, Choi JW, Jeon KI, Jue DM. Chloroquine decreases cell-surface expression of tumour necrosis factor receptors in human histiocytic U-937 cells [J]. Immunology.2002,105(1):83-91.
[99]Legssyer R, Josse C, Piette J, Ward RJ, Crichton RR. Changes in function of iron-loaded alveolar macrophages after in vivo administration of desferrioxamine and/or chloroquine [J]. J Inorg Biochem.2003, 94(1-2):36-42.
[100]Loehberg CR, Strissel PL, Dittrich R, et al. Akt and p53 are potential mediators of reduced mammary tumor growth by cloroquine and the mTOR inhibitor RAD001 [J]. Biochem Pharmacol.2012,83(4):480-8. doi: 10.1016/j. bcp.2011.
[101]Gonzalez-Polo R, Niso-Santano M, Moran JM, et al. Silencing DJ-1 reveals its contribution in paraquat-induced autophagy [J]. J Neurochem. 2009,109(3):889-98.
[102]Pan H, Zhang Y, Luo Z, et al. Autophagy mediates avian influenza H5N1 pseudotyped particle-induced lung inflammation through NF-κB and p38 MAPK signaling pathways [J]. Am J Physiol Lung Cell Mol Physiol.2014, 306(2):L183-95. doi:10.1152/ajplung.00147.2013.
[103]Ma J, Sun Q, Mi R, Zhang H. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling [J]. J Genet Genomics.2011,38(11):533-7. doi:10.1016/j. jgg.2011.10.002.
[104]Liu QP, Zhou DX, Lin P, et al. Participation of autophagy in acute lung injury induced by seawater [J]. Exp Lung Res.2013,39(10):441-52. doi: 10.3109/01902148.2013.845626.
[105]Wu CL, Lin LY, Yeh HM, et al. Delay of LPS-induced acute lung injury resolution by soluble immune complexes is neutrophil dependent [J]. Shock. 2009,32(3):276-85.
[106]Deng W, Li CY, Tong J, Zhang W, Wang DX. Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury [J]. Respir Res.2012,13:29.doi: 10.1186/1465-9921-13-29.
[107]Jang AS, Concel VJ, Bein K, et al. Endothelial dysfunction and claudin 5 regulation during acrolein-induced lung injury [J]. Am J Respir Cell Mol Biol.2011,44(4):483-90.
[108]Li LF, Liu YY, Yang CT, et al. Improvement of ventilator-induced lung injury by IPS cell-derived conditioned medium via inhibition of PI3K/Akt pathway and IP-10-dependent paracrine regulation [J]. Biomaterials.2013, 34(1):78-91.
[109]Yang SJ, Chen HM, Hsieh CH, et al. Akt pathway is required for oestrogen-mediated attenuation of lung injury in a rodent model of cerulein-induced acute pancreatitis [J]. Injury.2011,42(7):638-42.
[110]Oishi H, Takano K, Tomita K, et al. Olprinone and colforsin daropate alleviate septic lung inflammation and apoptosis through CREB-independent activation of the Akt pathway [J]. Am J Physiol Lung Cell Mol Physiol.2012, 303(2):L130-40.
[111]Chang P, Dong W, Zhang M, et al. Anti-Necroptosis Chemical Necrostatin-1 Can Also Suppress Apoptotic and Autophagic Pathway to Exert Neuroprotective Effect in Mice Intracerebral Hemorrhage Model [J]. J Mol Neurosci.2013 Oct 11. DOI 10.1007/s12031-013-0132-3. [Epub ahead of print]
[112]Zhou Y, Dai W, Lin C, et al. Protective effects of necrostatin-1 against concanavalin A-induced acute hepatic injury in mice [J]. Mediators Inflamm. 2013,2013:706156. doi:10.1155/2013/706156.
[113]Zhang YF, He W, Zhang C, et al. Role of receptor interacting protein (RIP)1 on apoptosis-inducing factor-mediated necroptosis during acetaminophen-evoked acute liver failure in mice [J]. Toxicol Lett.2014, pii:S0378-4274(14)00015-0. doi:10.1016/j. toxlet.2014.01.005. [Epub ahead of print]
[114]Arslan SC, Scheidereit C. The prevalence of TNFα-induced necrosis over apoptosis is determined by TAK1-RIP1 interplay [J]. PLoS One. 2011,6(10):e26069. doi:10.1371/journal.pone.0026069.
[115]Dondelinger Y, Aguileta MA, Goossens V, et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAPl/2 depletion or TAK1 kinase inhibition [J]. Cell Death Differ.2013, 20(10):1381-92. doi:10.1038/cdd.2013.94.
[116]Obitsu S, Sakata K, Teshima R, Kondo K. Eleostearic acid induces RIP1-mediated atypical apoptosis in a kinase-independent manner via ERK phosphorylation, ROS generation and mitochondrial dysfunction [J]. Cell Death Dis.2013,4:e674. doi:10.1038/cddis.2013.188.
[117]Wright LC, Seybold J, Robichaud A, Adcock IM, Barnes PJ. Phosphodiesterase expression in human epithelial cells [J]. Am J Physiol. 1998,275(4 Pt 1):L694-700.
[118]Tang HF, Lu JJ, Tang JF, et al. Action of a Novel PDE4 inhibitor ZL-n-91 on lipopolysaccharide-induced acute lung injury [J]. Int Immunopharmacol. 2010,10(4):406-11. doi:10.1016/j. int imp.2010.01.003.
[119]Miotla JM, Teixeira MM, Hellewell PG. Suppression of acute lung injury in mice by an inhibitor of phosphodiesterase type 4 [J]. Am J Respir Cell Mol Biol.1998,18(3):411-20.
[120]Hamamoto M, Suga M, Nakatani T, et al. Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model [J]. Eur J Cardiothorac Surg.2004,25(5):833-8.
[121]Chang W, Chen J, Schlueter CF, et al. Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram [J]. Toxicol Appl Pharmacol.2012,263(2):251-8.
[122]Kolosionek E, Savai R, Ghofrani HA, et al. Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition:the role of phosphodiesterase 4 [J]. Mol Biol Cell.2009,20(22):4751-65.
[123]Jager S, Bucci C, Tanida I, et al. Role for Rab7 in maturation of late autophagic vacuoles [J]. J Cell Sci.2004,117(Pt 20):4837-48.
[124]Chen JW, Madamanchi N, Madamanchi NR, Trier TT, Keherly MJ. Lamp-1 is upregulated in human glioblastoma cell lines induced to undergo apoptosis [J]. J Biomed Sci.2001,8(4):365-74.
[125]Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease) [J]. Nature. 2000,406(6798):906-10.
[126]Pereira EM, do Monte SJ, do Nascimento FF, et al. Lysosome-associated protein 1 (LAMP-1) and Lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease [J]. Gene.2014,536(1):118-22. doi: 10.1016/j. gene.2013.11.063.
[127]Wang L, Wang J, Shi Y, et al. Identification of a primary biliary cirrhosis associated protein as lysosome-associated membrane protein-2 [J]. J Proteomics.2013,91:569-79. doi:10.1016/j. jprot.2013.08.019.
[128]Armstrong A, Mattsson N, Appelqvist H, et al. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimer's Disease [J]. Neuromolecular Med.2013 Oct 8. [Epub ahead of print]
[129]Mello AS, Goldim MP, Mezzalira J, et al. LAMP2 as a marker of EBV-mediated B lymphocyte transformation in the study of lysosomal storage diseases [J]. Mol Cell Biochem.2014,385(1-2):1-6. doi: 10.1007/s11010-013-1806-4.
[130]Cohnen A, Chiang SC, Stojanovic A, et al. Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage [J]. Blood.2013,122(8):1411-8. doi:10.1182/blood-2012-07-441832.
[131]Suryawan A, Davis TA. Regulation of protein degradation pathways by amino acids and insulin in skeletal muscle of neonatal pigs [J]. J Anim Sci Biotechnol.2014,5(1):8. doi:10.1186/2049-1891-5-8.
[1]Levine B, Kroemer G. Autophagy in the pathogenesis of disease [J]. Cell. 2008,132(1):27-42.
[2]Eskelinen EL, Saftig P. Autophagy:a lysosomal degradation pathway with a central role in health and disease [J]. Biochim Biophys Acta.2009, 1793(4):664-73.
[3]Deretic V, Levine B. Autophagy, immunity, and microbial adaptations [J]. Cell Host Microbe.2009,5(6):527-49.
[4]Mizushima N, Komatsu M. Autophagy:Renovation of cells and tissues [J]. Cell.2011,147:728-741.
[5]Klionsky DJ. Autophagy:from phenomenology to molecular understanding in less than a decade [J]. Nat Rev Mol Cell Biol.2007,8(11):931-7.
[6]Mizushima N, Klionsky DJ. Protein turnover via autophagy:implications for metabolism [J]. Annu Rev Nutr.2007,27:19-40.
[7]Monick MM, Powers LS, Walters K, et al. Identification of an autophagy defect in smokers'alveolar macrophages [J]. J Immunol.2010, 185(9):5425-35.
[8]Chen ZH, Lam HC, Jin Y, et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema [J]. Proc Natl Acad Sci U S A.2010, 107(44):18880-5.
[9]Chen ZH, Kim HP, Sciurba FC, et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease [J]. PLoS One.2008, 3(10):e3316. Doi:10.1371/journal, pone.0003316.
[10]Chen CZ, Ou CY, Wang RH, et al. Association of Egr-1 and autophagy-related gene polymorphism in men with chronic obstructive pulmonary disease [J]. J Formos Med Assoc.2013, pii:S0929-6646(13)00262-3. Doi:10.1016/j. jfma.2013.07.015. [Epub ahead of print]
[11]Zhu L, Barret EC, Xu Y, et al. Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2 [J]. PloS One.2013,8(4):e55695. Doi: 10.1371/journal. pone.0055695.
[12]An CH, Wang XM, Lam HC, et al. TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema [J]. Am J Physiol Lung Cell Mol Physiol.2012,303(9):L748-57.
[13]Fujii S, Hara H, Araya J, et al. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease [J]. Oncoimmunology.2012,1(5):630-641.
[14]Takasaka N, Araya J, Hara H, et al. Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence [J]. J Immunol. 2014,192(3):958-68.
[15]Lam HC, Cloonan SM, Bhashyam AR, et al. Hi stone deacetylase 6-mediated selective autophagy regulates COPD-associated cilia dysfunction [J]. J Clin Invest.2013,123(12):5212-30.
[16]Guo Y, Gosker HR, Schols AM, et al. Autophagy in locomotor muscles of patients with chronic obstructive pulmonary disease [J]. Am J Respir Crit Care Med.2013,188(11):1313-20.
[17]Lee SJ, Smith A, Guo L, et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension [J]. Am J Respir Crit Care Med.2011,183(5):649-58.
[18]Lin KW, Li J, Finn PW. Emerging pathways in asthma:innate and adaptive interactions [J]. Biochim Biophys Acta.2011,1810(11):1052-8.
[19]Jyothula SS, Eissa NT. Autophagy and role in asthma [J]. Curr Opin Pulm Med.2013,19(1):30-5.
[20]Poon A, Eidelman D, Laprise C, Hamid Q. ATG5, autophagy and lung function in asthma [J]. Autophagy.2012,8(4):694-5.
[21]Martin LJ, Gupta J, Jyothula SS, et al. Functional variant in the autophagy-related 5 gene 92romoter is associated with childhood asthma [J]. PloS One.2012,7(4):e33454. Doi:10.1371/journal. pone.0033454.
[22]Wu Q, van Dyk LF, Jiang D, et al. Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway [J]. Virology.2013,446(1-2):199-206.
[23]Yeganeh B, Rezaei Moghadam A, Tran AT, et al. Asthma and influenza virus infection:focusing on cell death and stress pathways in influenza virus replication [J]. Iran J Allergy Asthma Immunol.2013,12(1):1-17.
[24]Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis:evidence-based guidelines for diagnosis and management [J]. Am J Respir Crit Care Med.2011, 183(6):788-824.
[25]Margaritopoulos GA1, Tsitoura E, Tzanakis N, et al. Self-eating:friend or foe? The emerging role of autophagy in idiopathic pulmonary fibrosis [J]. Biomed Res Int.2013,2013:420497. Doi:10.1155/2013/420497.
[26]Patel AS, Lin L, Geyer A, et al. Autophagy in idiopathic pulmonary fibrosis [J]. PloS One.2012,7(7):e41394. Doi: 10.1371/journal. pone.0041394.
[27]Araya J, Kojima J, Takasaka N, et al. Insufficient autophagy in idiopathic pulmonary fibrosis [J]. Am J Physiol Lung Cell Mol Physiol.2013, 304(1):L56-69.
[28]Mi S1, Li Z, Yang HZ, et al. Blocking IL-17A promotes the resolution of pulmonary inflammation and fibrosis via TGF-betal-dependent and-independent mechanisms [J]. J Immunol.2011,187(6):3003-14.
[29]Ricci A, Cherubini E, Scozzi D, et al. Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts [J]. J Cell Physiol.2013,228(7):1516-24.
[30]Minagawa S, Araya J, Numata T, et al. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells [J]. Am J Physiol Lung Cell Mol Physiol.2011,300(3):L391-401.
[31]King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis [J]. Lancet. 2011,378(9807):1949-61.
[32]Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response [J]. PloS Biol.2006,4(12):e423.
[33]Yang HZ, Wang JP, Mi S, TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury [J]. Am J Pathol.2012,180(1):275-92.
[34]Maiuri MC, Tasdemir E, Criollo A, et al. Control of autophagy by oncogenes and tumor suppressor genes [J]. Cell Death Differ.2009, 16(1):87-93.
[35]Vessoni AT, Filippi-Chiela EC, Menck CF, Lenz G. Autophagy and genomic integrity [J]. Cell Death Differ.2013,20(11):1444-54.
[36]Qu X, Yu J, Bhagat G, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene [J]. J Clin Invest.2003, 112(12):1809-20.
[37]Kaewpiboon C, Surapinit S, Malilas W, et al. Feroniellin A-induced autophagy causes apoptosis in multidrug-resistant human A549 lung cancer cells [J]. Int J Oncol.2014,44(4):1233-42.
[38]Mei W, Dong C, Hui C, et al. Gambogenic Acid Kills Lung Cancer Cells through Aberrant Autophagy [J]. PLoS One.2014,9(1):e83604. doi: 10.1371/journal. pone.0083604.
[39]Klarer AC, O'Neal J, Imbert-Fernandez Y, et al. Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism [J]. Cancer Metab.2014,2(1):2. doi:10.1186/2049-3002-2-2.
[40]Strohecker AM, White E. Autophagy promotes BrafV600E-driven lung tumorigenesis by preserving mitochondrial metabolism [J]. Autophagy.2014, 10(2):384-385.
[41]Rao S, Tortola L, Perlot T, et al. A dual role for autophagy in a murine model of lung cancer [J]. Nat Commun.2014,5:3056. doi:10.1038/ncomms4056.
[42]Rao S, Yang H, Penninger JM, Kroemer G. Autophagy in non-small cell lung carcinogenesis:A positive regulator of antitumor immunosurveillance [J]. Autophagy.2014 Jan 7;10(3). [Epub ahead of print]
[43]Quintavaller C, Costanzo S, Zanca C, et al. Phosphorylation-Regulated Degradation of the Tumor-Suppressor Form of PED by Chaperone-Mediated Autophagy in Lung Cancer Cells [J]. J Cell Physiol.2014 Jan 29. doi: 10.1002/jcp.24569. [Epub ahead of print]
[44]Gannage M, Dormann D, Albrecht R, et al. Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes [J]. Cell Host Microbe. 2009,6(4):367-80.
[45]Ma J, Sun Q, Mi R, Zhang H. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling [J]. J Genet Genomics.2011,38(11):533-7.
[46]Sun Y, Li C, Shu Y, et al. Inhibition of autophagy ameliorates acute lung injury caused by avian influenza A H5N1 infection [J]. Sci Signal.2012, 5(212):ra16. doi:10.1126/scisignal.2001931.
[47]Pan H, Zhang Y, Luo Z, et al. Autophagy mediates avian influenza H5N1 pseudotyped particle-induced lung inflammation through NF-κB and p38 MAPK signaling pathways [J]. Am J Physiol Lung Cell Mol Physiol.2014, 306(2):L183-95.
[48]Wu Q, van Dyk LF, Jiang D, et al. Interleukin-1 receptor-associated kinase M (IRAK-M) promotes human rhinovirus infection in lung epithelial cells via the autophagic pathway [J]. Virology.2013,446(1-2):199-206.
[49]Reed M, Morris SH, Jang S, et al. Autophagy-inducing protein beclin-1 in dendritic cells regulates CD4 T cell responses and disease severity during respiratory syncytial virus infection [J]. J Immunol.2013,191(5):2526-37.
[50]Junkins RD, Shen A, Rosen K, McCormick C, Lin TJ. Autophagy enhances bacterial clearance during P. aeruginosa lung infection [J]. PLoS One.2013, 8(8):e72263. doi:10.1371/journal, pone.0072263.
[51]Choy A1, Dancourt J, Mugo B, et al. The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation [J]. Science.2012, 338(6110):1072-6.
[52]Tung SM, Unal C, Ley A, et al. Loss of Dictyostelium ATG9 results in a pleiotropic phenotype affecting growth, development, phagocytosis and clearance and replication of Legionella pneumophila. Cell Microbiol.2010, 12(6):765-80.
[53]Hoffmann C1, Harrison CF, Hilbi H. The natural alternative:protozoa as cellular models for Legionella infection [J]. Cell Microbiol.2013 Oct 29. doi:10.1111/cmi.12235. [Epub ahead of print]
[54]Abdulrahman BA, Khweek AA, Akhter A, et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis [J]. Autophagy.2011, 7(11):1359-70.
[55]Abdulrahman BA, Khweek AA, Akhter A, et al. Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr △F508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery [J]. J Biol Chem.2013,288(3):2049-58.
[56]Guo XG, Ji TX, Xia Y, Ma YY. Autophagy protects type II alveolar epithelial cells from Mycobacterium tuberculosis infection [J]. Biochem Biophys Res Commun.2013,432(2):308-13.
[57]Renna M, Schaffner C, Brown K, et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection [J]. J Clin Invest.2011,121(9):3554-63.
[58]Parihar SP, Guler R, Khutlang R, et al. Statin Therapy Reduces the Mycobacterium tuberculosis Burden in Human Macrophages and in Mice by Enhancing Autophagy and Phagosome Maturation [J]. J Infect Dis.2014, 209(5):754-63.
[59]Gupta A, Pant G, Mitra K, et al. Inhalable particles containing rapamycin for induction of autophagy in macrophages infected with Mycobacterium tuberculosis [J]. Mol Pharm.2014 Feb 17. [Epub ahead of print]
[60]Xu Y, Fattah EA, Liu XD, et al. Harnessing of TLR-mediated autophagy to combat mycobacteria in macrophages [J]. Tuberculosis (Edinb).2013,93 Suppl:S33-7.
[61]Seto S, Tsujimura K, Horii T, Koide Y. Autophagy adaptor protein p62/SQSTM1 and autophagy-related gene Atg5 mediate autophagosome formation in response to Mycobacterium tuberculosis infection in dendritic cells [J]. PLoS One.2013,8(12):e86017. doi:10.1371/journal. pone.0086017. eCollection 2013.
[62]Seto S, Tsujimura K, Koide Y. Coronin-la inhibits autophagosome formation around Mycobacterium tuberculosis-containing phagosomes and assists mycobacterial survival in macrophages [J]. Cell Microbiol.2012, 14(5):710-27.
[63]Sanjurjo L, Amezaga N, Vilaplana C, et al. The scavenger protein apoptosis inhibitor of macrophages (AIM) potentiates the antimicrobial response against Mycobacterium tuberculosis by enhancing autophagy [J]. PLoS One.2013,8(11):e79670. doi:10.1371/journal. pone.0079670. eCollection 2013.
[64]Wang J, Yang K, Zhou L, et al. MicroRNA-155 promotes autophagy to eliminate intracellular mycobacteria by targeting Rheb [J]. PLoS Pathog. 2013,9(10):e1003697. doi:10.1371/journal. ppat.1003697.
[65]Biswas D, Qureshi OS, Lee WY, et al. ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages [J]. BMC Immunol.2008,9:35. doi: 10.1186/1471-2172-9-35.
[66]Verway M, Bouttier M, Wang TT, et al. Vitamin D induces interleukin-1β expression:paracrine macrophage epithelial signaling controls M. tuberculosis infection [J]. PLoS Pathog.2013,9(6):e1003407. doi: 10.1371/journal. ppat.1003407.
[67]Sato E, Imafuku S, Ishii K, et al. Vitamin D-dependent cathelicidin inhibits Mycobacterium marinum infection in human monocytic cells [J]. J Dermatol Sci.2013,70(3):166-72.
[68]Bradfute SB, Castillo EF, Arko-Mensah J, et al. Autophagy as an immune effector against tuberculosis [J]. Curr Opin Microbiol.2013,16(3):355-65.
[69]Jo EK. Autophagy as an innate defense against mycobacteria [J]. Pathog Dis.2013,67(2):108-18.
[70]Liu QP, Zhou DX, Lin P, et al. Participation of autophagy in acute lung injury induced by seawater [J]. Exp Lung Res.2013,39(10):441-52.
[71]Laskin DL, Sunil VR, Gardner CR, Laskin JD. Macrophages and tissue injury:agents of defense or destruction [J]? Annu Rev Pharmacol Toxicol. 2011,51:267-88.
[72]Sunil VR, Vayas KN, Massa CB, et al. Ozone-induced injury and oxidative stress in bronchiolar epithelium are associated with altered pulmonary mechanics [J]. Toxicol Sci.2013,133(2):309-19.
[73]Liu HL, Zhang YL, Yang N, et al. A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt-TSC2-mTOR signaling [J]. Cell Death Dis.2011,2:e159. doi: 10.1038/cddis.2011.27.
[74]Lee SM, McLaughlin JN, Frederick DR, et al. Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury [J]. Am J Physiol Lung Cell Mol Physiol.2013,304(5):L350-60.
[75]Weinberger B, Laskin JD, Sunil VR, et al. Sulfur mustard-induced pulmonary injury:therapeutic approaches to mitigating toxicity [J]. Pulm Pharmacol Ther.2011,24(1):92-9.
[76]Lee SJ, Ryter SW, Xu JF, et al. Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation [J]. Am J Respir Cell Mol Biol.2011,45(4):867-73.
[77]Yen YT, Yang HR, Lo HC, et al. Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury [J]. Surgery.2013,153(5):689-98.
[78]Lo S, Yuan SS, Hsu C, et al. Lc3 over-expression improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice [J]. Ann Surg.2013,257(2):352-63.