Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury

Yu-Ting Yen, Horng-Ren Yang, Hung-Chieh Lo, Ya-Ching Hsieh, Shih-Chang Tsai, Chia-Wen Hong, Chi-Hsun Hsieh

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Background: Autophagy plays distinct roles in apoptosis and the inflammatory process. Understanding the role of autophagy in sepsis-induced acute lung injury (ALI) may provide new insights into developing novel therapeutic strategies for this group of patients. The aim of this study was to investigate the regulation of autophagy in the septic lung and to use pharmacologic agents to modulate autophagy to study its functional significance. Methods: Mice were subjected to cecal ligation and puncture (CLP) or a sham operation. At 1 hour after CLP, mice were treated with vehicle, activated protein C (APC), rapamycin, or bafilomycin A1. Mice were humanely killed at 4 or 24 hours after the operation or were observed for ≤7 days. Results: CLP induced a systemic inflammatory response and significantly decreased survival. In lung tissue, increased leukocyte infiltration, inflammation, and apoptosis were observed. In contrast, autophagy was suppressed after CLP such that the expression of LC3II, Atg5, and Rab7 were downregulated. Rapamycin activated autophagy, limited the CLP-induced proinflammatory response, and downregulated apoptotic activity after CLP. The administration of APC after CLP had an effect similar to that of rapamycin. Both medications significantly improved survival 7 days after CLP. Conclusion: The downregulation of autophagy may lead to systemic inflammation and ALI after sepsis. The direct or indirect modification of autophagy using rapamycin or APC, respectively, resulted in improved survival. Enhancing or restoring autophagy early after sepsis seems to be a potential strategy for the treatment of sepsis-induced ALI. © 2013 Mosby, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)689-698
Number of pages10
JournalSurgery (United States)
Volume153
Issue number5
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

Acute Lung Injury
Autophagy
Sirolimus
Protein C
Punctures
Sepsis
Ligation
Down-Regulation
Survival
Inflammation
Lung
Leukocytes
Apoptosis
Therapeutics

Keywords

  • activated protein C
  • autophagy protein 5
  • bafilomycin A1
  • Rab7 protein
  • rapamycin
  • acute lung injury
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • apoptosis
  • article
  • autophagy
  • cell infiltration
  • controlled study
  • dose response
  • down regulation
  • human
  • human cell
  • inflammation
  • leukocyte
  • lung parenchyma
  • male
  • mouse
  • nonhuman
  • priority journal
  • sepsis
  • sham procedure
  • survival rate
  • upregulation
  • Acute Lung Injury
  • Animals
  • Anti-Bacterial Agents
  • Apoptosis
  • Autophagy
  • Biological Markers
  • Blotting, Western
  • Cecum
  • Cells, Cultured
  • Cytokines
  • Humans
  • Immunohistochemistry
  • Ligation
  • Macrolides
  • Male
  • Mice
  • Mice, Inbred C3H
  • Protein C
  • Sepsis
  • Sirolimus

Cite this

Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. / Yen, Yu-Ting; Yang, Horng-Ren; Lo, Hung-Chieh; Hsieh, Ya-Ching; Tsai, Shih-Chang; Hong, Chia-Wen; Hsieh, Chi-Hsun.

In: Surgery (United States), Vol. 153, No. 5, 2013, p. 689-698.

Research output: Contribution to journalArticle

Yen, Yu-Ting ; Yang, Horng-Ren ; Lo, Hung-Chieh ; Hsieh, Ya-Ching ; Tsai, Shih-Chang ; Hong, Chia-Wen ; Hsieh, Chi-Hsun. / Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. In: Surgery (United States). 2013 ; Vol. 153, No. 5. pp. 689-698.
@article{35948bd84f61492e9bfce642b7846561,
title = "Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury",
abstract = "Background: Autophagy plays distinct roles in apoptosis and the inflammatory process. Understanding the role of autophagy in sepsis-induced acute lung injury (ALI) may provide new insights into developing novel therapeutic strategies for this group of patients. The aim of this study was to investigate the regulation of autophagy in the septic lung and to use pharmacologic agents to modulate autophagy to study its functional significance. Methods: Mice were subjected to cecal ligation and puncture (CLP) or a sham operation. At 1 hour after CLP, mice were treated with vehicle, activated protein C (APC), rapamycin, or bafilomycin A1. Mice were humanely killed at 4 or 24 hours after the operation or were observed for ≤7 days. Results: CLP induced a systemic inflammatory response and significantly decreased survival. In lung tissue, increased leukocyte infiltration, inflammation, and apoptosis were observed. In contrast, autophagy was suppressed after CLP such that the expression of LC3II, Atg5, and Rab7 were downregulated. Rapamycin activated autophagy, limited the CLP-induced proinflammatory response, and downregulated apoptotic activity after CLP. The administration of APC after CLP had an effect similar to that of rapamycin. Both medications significantly improved survival 7 days after CLP. Conclusion: The downregulation of autophagy may lead to systemic inflammation and ALI after sepsis. The direct or indirect modification of autophagy using rapamycin or APC, respectively, resulted in improved survival. Enhancing or restoring autophagy early after sepsis seems to be a potential strategy for the treatment of sepsis-induced ALI. {\circledC} 2013 Mosby, Inc. All rights reserved.",
keywords = "activated protein C, autophagy protein 5, bafilomycin A1, Rab7 protein, rapamycin, acute lung injury, animal cell, animal experiment, animal model, animal tissue, apoptosis, article, autophagy, cell infiltration, controlled study, dose response, down regulation, human, human cell, inflammation, leukocyte, lung parenchyma, male, mouse, nonhuman, priority journal, sepsis, sham procedure, survival rate, upregulation, Acute Lung Injury, Animals, Anti-Bacterial Agents, Apoptosis, Autophagy, Biological Markers, Blotting, Western, Cecum, Cells, Cultured, Cytokines, Humans, Immunohistochemistry, Ligation, Macrolides, Male, Mice, Mice, Inbred C3H, Protein C, Sepsis, Sirolimus",
author = "Yu-Ting Yen and Horng-Ren Yang and Hung-Chieh Lo and Ya-Ching Hsieh and Shih-Chang Tsai and Chia-Wen Hong and Chi-Hsun Hsieh",
note = "被引用次數:15 Export Date: 24 March 2016 CODEN: SURGA 通訊地址: Hsieh, C.-H.; Department of Acute Care Surgery, China Medical University, School of Medicine, 2 Yuh-Der Road, Taichung, 404, Taiwan; 電子郵件: hsiehchihsun@yahoo.com.tw 化學物質/CAS: Rab7 protein, 185229-47-4; bafilomycin A1, 88899-55-2; rapamycin, 53123-88-9; Anti-Bacterial Agents; Biological Markers; Cytokines; Macrolides; Protein C; Sirolimus, 53123-88-9; bafilomycin A1, 88899-55-2 製造商: Biovision, United States; LC, United States 參考文獻: Xiao, W., Mindrinos, M.N., Seok, J., A genomic storm in critically injured humans (2011) J Exp Med, 208, pp. 2581-2590; Martin, G.S., Mannino, D.M., Eaton, S., The epidemiology of sepsis in the United States from 1979 through 2000 (2003) N Engl J Med, 348, pp. 1546-1554; Kitamura, Y., Hashimoto, S., Mizuta, N., Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide- induced lung injury in mice (2001) Am J Respir Crit Care Med, 163, pp. 762-769; Guinee, Jr.D., Brambilla, E., Fleming, M., The potential role of BAX and BCL-2 expression in diffuse alveolar damage (1997) Am J Pathol, 151, pp. 999-1007; Matsuda, N., Yamamoto, S., Takano, K., Silencing of fas-associated death domain protects mice from septic lung inflammation and apoptosis (2009) Am J Respir Crit Care Med, 179, pp. 806-815; Abdulrahman, B.A., Khweek, A.A., Akhter, A., Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis (2011) Autophagy, 7, pp. 1359-1370; Saitoh, T., Fujita, N., Jang, M.H., Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production (2008) Nature, 456, pp. 264-268; Hsieh, C.H., Pai, P.Y., Hsueh, H.W., Complete induction of autophagy is essential for cardioprotection in sepsis (2011) Ann Surg, 253, pp. 1190-1200; Takeuchi, H., Kondo, Y., Fujiwara, K., Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors (2005) Cancer Res, 65, pp. 3336-3346; Hamacher-Brady, A., Brady, N.R., Gottlieb, R.A., Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes (2006) J Biol Chem, 281, pp. 29776-29787; Bernard, G.R., Vincent, J.L., Laterre, P.F., Efficacy and safety of recombinant human activated protein C for severe sepsis (2001) N Engl J Med, 344, pp. 699-709; Faust, S.N., Levin, M., Harrison, O.B., Dysfunction of endothelial protein C activation in severe meningococcal sepsis (2001) N Engl J Med, 345, pp. 408-416; Vincent, J.L., Angus, D.C., Artigas, A., Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial (2003) Crit Care Med, 31, pp. 834-840; Kaya, S., Adventure of recombinant human activated protein C in sepsis and new treatment hopes on the horizon (2012) Recent Pat Inflamm Allergy Drug Discov, 6, pp. 159-164; Riedemann, N.C., Guo, R.F., Ward, P.A., The enigma of sepsis (2003) J Clin Invest, 112, pp. 460-467; Hubbard, W.J., Choudhry, M., Schwacha, M.G., Cecal ligation and puncture (2005) Shock, 24 (SUPPL. 1), pp. 52-57; Cao, C., Gao, Y., Li, Y., The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b (2010) J Clin Invest, 120, pp. 1971-1980; Chen, Y., Gibson, S.B., Is mitochondrial generation of reactive oxygen species a trigger for autophagy? (2008) Autophagy, 4, pp. 246-248; Scherz-Shouval, R., Shvets, E., Fass, E., Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4 (2007) EMBO J, 26, pp. 1749-1760; Nakahira, K., Haspel, J.A., Rathinam, V.A., Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome (2011) Nat Immunol, 12, pp. 222-230; Zhou, R., Yazdi, A.S., Menu, P., A role for mitochondria in NLRP3 inflammasome activation (2011) Nature, 469, pp. 221-225; Yang, H.Z., Wang, J.P., Mi, S., TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury (2012) Am J Pathol, 180, pp. 275-292; Lorne, E., Zhao, X., Zmijewski, J.W., Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury (2009) Am J Respir Cell Mol Biol, 41, pp. 237-245; Wang, L., Gui, Y.S., Tian, X.L., Inactivation of mammalian target of rapamycin (mTOR) by rapamycin in a murine model of lipopolysaccharide-induced acute lung injury (2011) Chin Med J (Engl), 124, pp. 3112-3117; Tsai, S.C., Yang, J.S., Peng, S.F., Bufalin increases sensitivity to AKT/mTOR-induced autophagic cell death in SK-HEP-1 human hepatocellular carcinoma cells (2012) Int J Oncol, , [Epub ahead of print]; Ghavami, S., Yeganeh, B., Stelmack, G.L., Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts (2012) Cell Death Dis, 3, p. 330; Lo, S., Yuan, S.S., Hsu, C., Lc3 transgene improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice (2012) Ann Surg, , [Epub ahead of print]; Casserly, B., Gerlach, H., Phillips, G.S., Evaluating the use of recombinant human activated protein C in adult severe sepsis: Results of the Surviving Sepsis Campaign (2012) Crit Care Med, 40, pp. 1417-1426; Della, V.P., Pavani, G., D'Angelo, A., The protein C pathway and sepsis (2012) Thromb Res, 129, pp. 296-300; Bae, J.S., Rezaie, A.R., Activated protein C inhibits high mobility group box 1 signaling in endothelial cells (2011) Blood, 118, pp. 3952-3959; Toltl, L.J., Austin, R.C., Liaw, P.C., Activated protein C modulates inflammation, apoptosis and tissue factor procoagulant activity by regulating endoplasmic reticulum calcium depletion in blood monocytes (2011) J Thromb Haemost, 9, pp. 582-592; Zhang, L., Cardinal, J.S., Pan, P., Splenocyte apoptosis and autophagy is mediated by interferon regulatory factor-1 during murine endotoxemia (2012) Shock, 37, pp. 511-517; Ranieri, V.M., Thompson, B.T., Barie, P.S., Drotrecogin alfa (activated) in adults with septic shock (2012) N Engl J Med, 366, pp. 2055-2064; Levi, M., Van Der Poll, T., Recombinant human activated protein C: Current insights into its mechanism of action (2007) Crit Care, 11 (SUPPL. 5), p. 3",
year = "2013",
doi = "10.1016/j.surg.2012.11.021",
language = "English",
volume = "153",
pages = "689--698",
journal = "Surgery",
issn = "0039-6060",
publisher = "Mosby Inc.",
number = "5",

}

TY - JOUR

T1 - Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury

AU - Yen, Yu-Ting

AU - Yang, Horng-Ren

AU - Lo, Hung-Chieh

AU - Hsieh, Ya-Ching

AU - Tsai, Shih-Chang

AU - Hong, Chia-Wen

AU - Hsieh, Chi-Hsun

N1 - 被引用次數:15 Export Date: 24 March 2016 CODEN: SURGA 通訊地址: Hsieh, C.-H.; Department of Acute Care Surgery, China Medical University, School of Medicine, 2 Yuh-Der Road, Taichung, 404, Taiwan; 電子郵件: hsiehchihsun@yahoo.com.tw 化學物質/CAS: Rab7 protein, 185229-47-4; bafilomycin A1, 88899-55-2; rapamycin, 53123-88-9; Anti-Bacterial Agents; Biological Markers; Cytokines; Macrolides; Protein C; Sirolimus, 53123-88-9; bafilomycin A1, 88899-55-2 製造商: Biovision, United States; LC, United States 參考文獻: Xiao, W., Mindrinos, M.N., Seok, J., A genomic storm in critically injured humans (2011) J Exp Med, 208, pp. 2581-2590; Martin, G.S., Mannino, D.M., Eaton, S., The epidemiology of sepsis in the United States from 1979 through 2000 (2003) N Engl J Med, 348, pp. 1546-1554; Kitamura, Y., Hashimoto, S., Mizuta, N., Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide- induced lung injury in mice (2001) Am J Respir Crit Care Med, 163, pp. 762-769; Guinee, Jr.D., Brambilla, E., Fleming, M., The potential role of BAX and BCL-2 expression in diffuse alveolar damage (1997) Am J Pathol, 151, pp. 999-1007; Matsuda, N., Yamamoto, S., Takano, K., Silencing of fas-associated death domain protects mice from septic lung inflammation and apoptosis (2009) Am J Respir Crit Care Med, 179, pp. 806-815; Abdulrahman, B.A., Khweek, A.A., Akhter, A., Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis (2011) Autophagy, 7, pp. 1359-1370; Saitoh, T., Fujita, N., Jang, M.H., Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production (2008) Nature, 456, pp. 264-268; Hsieh, C.H., Pai, P.Y., Hsueh, H.W., Complete induction of autophagy is essential for cardioprotection in sepsis (2011) Ann Surg, 253, pp. 1190-1200; Takeuchi, H., Kondo, Y., Fujiwara, K., Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors (2005) Cancer Res, 65, pp. 3336-3346; Hamacher-Brady, A., Brady, N.R., Gottlieb, R.A., Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes (2006) J Biol Chem, 281, pp. 29776-29787; Bernard, G.R., Vincent, J.L., Laterre, P.F., Efficacy and safety of recombinant human activated protein C for severe sepsis (2001) N Engl J Med, 344, pp. 699-709; Faust, S.N., Levin, M., Harrison, O.B., Dysfunction of endothelial protein C activation in severe meningococcal sepsis (2001) N Engl J Med, 345, pp. 408-416; Vincent, J.L., Angus, D.C., Artigas, A., Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial (2003) Crit Care Med, 31, pp. 834-840; Kaya, S., Adventure of recombinant human activated protein C in sepsis and new treatment hopes on the horizon (2012) Recent Pat Inflamm Allergy Drug Discov, 6, pp. 159-164; Riedemann, N.C., Guo, R.F., Ward, P.A., The enigma of sepsis (2003) J Clin Invest, 112, pp. 460-467; Hubbard, W.J., Choudhry, M., Schwacha, M.G., Cecal ligation and puncture (2005) Shock, 24 (SUPPL. 1), pp. 52-57; Cao, C., Gao, Y., Li, Y., The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b (2010) J Clin Invest, 120, pp. 1971-1980; Chen, Y., Gibson, S.B., Is mitochondrial generation of reactive oxygen species a trigger for autophagy? (2008) Autophagy, 4, pp. 246-248; Scherz-Shouval, R., Shvets, E., Fass, E., Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4 (2007) EMBO J, 26, pp. 1749-1760; Nakahira, K., Haspel, J.A., Rathinam, V.A., Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome (2011) Nat Immunol, 12, pp. 222-230; Zhou, R., Yazdi, A.S., Menu, P., A role for mitochondria in NLRP3 inflammasome activation (2011) Nature, 469, pp. 221-225; Yang, H.Z., Wang, J.P., Mi, S., TLR4 activity is required in the resolution of pulmonary inflammation and fibrosis after acute and chronic lung injury (2012) Am J Pathol, 180, pp. 275-292; Lorne, E., Zhao, X., Zmijewski, J.W., Participation of mammalian target of rapamycin complex 1 in Toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury (2009) Am J Respir Cell Mol Biol, 41, pp. 237-245; Wang, L., Gui, Y.S., Tian, X.L., Inactivation of mammalian target of rapamycin (mTOR) by rapamycin in a murine model of lipopolysaccharide-induced acute lung injury (2011) Chin Med J (Engl), 124, pp. 3112-3117; Tsai, S.C., Yang, J.S., Peng, S.F., Bufalin increases sensitivity to AKT/mTOR-induced autophagic cell death in SK-HEP-1 human hepatocellular carcinoma cells (2012) Int J Oncol, , [Epub ahead of print]; Ghavami, S., Yeganeh, B., Stelmack, G.L., Apoptosis, autophagy and ER stress in mevalonate cascade inhibition-induced cell death of human atrial fibroblasts (2012) Cell Death Dis, 3, p. 330; Lo, S., Yuan, S.S., Hsu, C., Lc3 transgene improves survival and attenuates lung injury through increasing autophagosomal clearance in septic mice (2012) Ann Surg, , [Epub ahead of print]; Casserly, B., Gerlach, H., Phillips, G.S., Evaluating the use of recombinant human activated protein C in adult severe sepsis: Results of the Surviving Sepsis Campaign (2012) Crit Care Med, 40, pp. 1417-1426; Della, V.P., Pavani, G., D'Angelo, A., The protein C pathway and sepsis (2012) Thromb Res, 129, pp. 296-300; Bae, J.S., Rezaie, A.R., Activated protein C inhibits high mobility group box 1 signaling in endothelial cells (2011) Blood, 118, pp. 3952-3959; Toltl, L.J., Austin, R.C., Liaw, P.C., Activated protein C modulates inflammation, apoptosis and tissue factor procoagulant activity by regulating endoplasmic reticulum calcium depletion in blood monocytes (2011) J Thromb Haemost, 9, pp. 582-592; Zhang, L., Cardinal, J.S., Pan, P., Splenocyte apoptosis and autophagy is mediated by interferon regulatory factor-1 during murine endotoxemia (2012) Shock, 37, pp. 511-517; Ranieri, V.M., Thompson, B.T., Barie, P.S., Drotrecogin alfa (activated) in adults with septic shock (2012) N Engl J Med, 366, pp. 2055-2064; Levi, M., Van Der Poll, T., Recombinant human activated protein C: Current insights into its mechanism of action (2007) Crit Care, 11 (SUPPL. 5), p. 3

PY - 2013

Y1 - 2013

N2 - Background: Autophagy plays distinct roles in apoptosis and the inflammatory process. Understanding the role of autophagy in sepsis-induced acute lung injury (ALI) may provide new insights into developing novel therapeutic strategies for this group of patients. The aim of this study was to investigate the regulation of autophagy in the septic lung and to use pharmacologic agents to modulate autophagy to study its functional significance. Methods: Mice were subjected to cecal ligation and puncture (CLP) or a sham operation. At 1 hour after CLP, mice were treated with vehicle, activated protein C (APC), rapamycin, or bafilomycin A1. Mice were humanely killed at 4 or 24 hours after the operation or were observed for ≤7 days. Results: CLP induced a systemic inflammatory response and significantly decreased survival. In lung tissue, increased leukocyte infiltration, inflammation, and apoptosis were observed. In contrast, autophagy was suppressed after CLP such that the expression of LC3II, Atg5, and Rab7 were downregulated. Rapamycin activated autophagy, limited the CLP-induced proinflammatory response, and downregulated apoptotic activity after CLP. The administration of APC after CLP had an effect similar to that of rapamycin. Both medications significantly improved survival 7 days after CLP. Conclusion: The downregulation of autophagy may lead to systemic inflammation and ALI after sepsis. The direct or indirect modification of autophagy using rapamycin or APC, respectively, resulted in improved survival. Enhancing or restoring autophagy early after sepsis seems to be a potential strategy for the treatment of sepsis-induced ALI. © 2013 Mosby, Inc. All rights reserved.

AB - Background: Autophagy plays distinct roles in apoptosis and the inflammatory process. Understanding the role of autophagy in sepsis-induced acute lung injury (ALI) may provide new insights into developing novel therapeutic strategies for this group of patients. The aim of this study was to investigate the regulation of autophagy in the septic lung and to use pharmacologic agents to modulate autophagy to study its functional significance. Methods: Mice were subjected to cecal ligation and puncture (CLP) or a sham operation. At 1 hour after CLP, mice were treated with vehicle, activated protein C (APC), rapamycin, or bafilomycin A1. Mice were humanely killed at 4 or 24 hours after the operation or were observed for ≤7 days. Results: CLP induced a systemic inflammatory response and significantly decreased survival. In lung tissue, increased leukocyte infiltration, inflammation, and apoptosis were observed. In contrast, autophagy was suppressed after CLP such that the expression of LC3II, Atg5, and Rab7 were downregulated. Rapamycin activated autophagy, limited the CLP-induced proinflammatory response, and downregulated apoptotic activity after CLP. The administration of APC after CLP had an effect similar to that of rapamycin. Both medications significantly improved survival 7 days after CLP. Conclusion: The downregulation of autophagy may lead to systemic inflammation and ALI after sepsis. The direct or indirect modification of autophagy using rapamycin or APC, respectively, resulted in improved survival. Enhancing or restoring autophagy early after sepsis seems to be a potential strategy for the treatment of sepsis-induced ALI. © 2013 Mosby, Inc. All rights reserved.

KW - activated protein C

KW - autophagy protein 5

KW - bafilomycin A1

KW - Rab7 protein

KW - rapamycin

KW - acute lung injury

KW - animal cell

KW - animal experiment

KW - animal model

KW - animal tissue

KW - apoptosis

KW - article

KW - autophagy

KW - cell infiltration

KW - controlled study

KW - dose response

KW - down regulation

KW - human

KW - human cell

KW - inflammation

KW - leukocyte

KW - lung parenchyma

KW - male

KW - mouse

KW - nonhuman

KW - priority journal

KW - sepsis

KW - sham procedure

KW - survival rate

KW - upregulation

KW - Acute Lung Injury

KW - Animals

KW - Anti-Bacterial Agents

KW - Apoptosis

KW - Autophagy

KW - Biological Markers

KW - Blotting, Western

KW - Cecum

KW - Cells, Cultured

KW - Cytokines

KW - Humans

KW - Immunohistochemistry

KW - Ligation

KW - Macrolides

KW - Male

KW - Mice

KW - Mice, Inbred C3H

KW - Protein C

KW - Sepsis

KW - Sirolimus

U2 - 10.1016/j.surg.2012.11.021

DO - 10.1016/j.surg.2012.11.021

M3 - Article

VL - 153

SP - 689

EP - 698

JO - Surgery

JF - Surgery

SN - 0039-6060

IS - 5

ER -