NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense
Introduction. Since the NF-κB pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF-κB would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF-κB inhibition during a defined time period aft...
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| Format: | Article |
| Language: | English |
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Wiley
2013-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2013/503213 |
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| author | Hui Li Wei Han Vasilly Polosukhin Fiona E. Yull Brahm H. Segal Can-Mao Xie Timothy S. Blackwell |
| author_facet | Hui Li Wei Han Vasilly Polosukhin Fiona E. Yull Brahm H. Segal Can-Mao Xie Timothy S. Blackwell |
| author_sort | Hui Li |
| collection | DOAJ |
| description | Introduction. Since the NF-κB pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF-κB would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF-κB inhibition during a defined time period after the onset of sepsis would reduce acute lung injury without compromising bacterial host defense. Methods. Mice underwent cecal ligation and puncture (CLP). An NF-κB inhibitor, BMS-345541 (50 µg/g mice), was administered by peroral gavage beginning 2 hours after CLP and repeated at 6 hour intervals for 2 additional doses. Results. Mice treated with BMS-345541 after CLP showed reduced neutrophilic alveolitis and lower levels of KC in bronchoalveolar lavage fluid compared to mice treated with CLP+vehicle. In addition, mice treated with CLP+BMS had minimal histological evidence of lung injury and normal wet-dry ratios, indicating protection from acute lung injury. Treatment with the NF-κB inhibitor did not affect the ability of cultured macrophages to phagocytose bacteria and did not alter bacterial colony counts in blood, lung tissue, or peritoneal fluid at 24 hours after CLP. While BMS-345541 treatment did not alter mortality after CLP, our results showed a trend towards improved survival. Conclusion. Transiently blocking NF-κB activity after the onset of CLP-induced sepsis can effectively reduce acute lung injury in mice without compromising bacterial host defense or survival after CLP. |
| format | Article |
| id | doaj-art-4450ed477dc5413aa19175d0e8f955df |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
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| series | Mediators of Inflammation |
| spelling | doaj-art-4450ed477dc5413aa19175d0e8f955df2025-02-03T05:58:51ZengWileyMediators of Inflammation0962-93511466-18612013-01-01201310.1155/2013/503213503213NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host DefenseHui Li0Wei Han1Vasilly Polosukhin2Fiona E. Yull3Brahm H. Segal4Can-Mao Xie5Timothy S. Blackwell6Division of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, ChinaDepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartments of Medicine and Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USADivision of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, ChinaDepartment of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USAIntroduction. Since the NF-κB pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF-κB would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF-κB inhibition during a defined time period after the onset of sepsis would reduce acute lung injury without compromising bacterial host defense. Methods. Mice underwent cecal ligation and puncture (CLP). An NF-κB inhibitor, BMS-345541 (50 µg/g mice), was administered by peroral gavage beginning 2 hours after CLP and repeated at 6 hour intervals for 2 additional doses. Results. Mice treated with BMS-345541 after CLP showed reduced neutrophilic alveolitis and lower levels of KC in bronchoalveolar lavage fluid compared to mice treated with CLP+vehicle. In addition, mice treated with CLP+BMS had minimal histological evidence of lung injury and normal wet-dry ratios, indicating protection from acute lung injury. Treatment with the NF-κB inhibitor did not affect the ability of cultured macrophages to phagocytose bacteria and did not alter bacterial colony counts in blood, lung tissue, or peritoneal fluid at 24 hours after CLP. While BMS-345541 treatment did not alter mortality after CLP, our results showed a trend towards improved survival. Conclusion. Transiently blocking NF-κB activity after the onset of CLP-induced sepsis can effectively reduce acute lung injury in mice without compromising bacterial host defense or survival after CLP.http://dx.doi.org/10.1155/2013/503213 |
| spellingShingle | Hui Li Wei Han Vasilly Polosukhin Fiona E. Yull Brahm H. Segal Can-Mao Xie Timothy S. Blackwell NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense Mediators of Inflammation |
| title | NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense |
| title_full | NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense |
| title_fullStr | NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense |
| title_full_unstemmed | NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense |
| title_short | NF-κB Inhibition after Cecal Ligation and Puncture Reduces Sepsis-Associated Lung Injury without Altering Bacterial Host Defense |
| title_sort | nf κb inhibition after cecal ligation and puncture reduces sepsis associated lung injury without altering bacterial host defense |
| url | http://dx.doi.org/10.1155/2013/503213 |
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