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NF-κB inhibition after cecal ligation and puncture reduces sepsis-associated lung injury without altering bacterial host defense.

Li H, Han W, Polosukhin V, Yull FE, Segal BH, Xie CM, Blackwell TS - Mediators Inflamm. (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, China ; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA ; Division of Respiratory Medicine, Nanjing Drum Tower Hospital & the Affiliated Hospital of Nanjing University, Nanjing, Jiangsu 210008, China.

ABSTRACT

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.

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Related in: MedlinePlus

NF-κB inhibition blocks lung injury and reduces apoptosis after CLP. (a) and (b) Histological evaluation of lung injury on H&E stained lung sections at 48 hours after CLP, *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (c) and (d) Lung edema as measured by wet/dry ratio at 24 and 48 hours after CLP, reported as increase above sham laparotomy controls. N = 5 per group; *P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.
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fig4: NF-κB inhibition blocks lung injury and reduces apoptosis after CLP. (a) and (b) Histological evaluation of lung injury on H&E stained lung sections at 48 hours after CLP, *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (c) and (d) Lung edema as measured by wet/dry ratio at 24 and 48 hours after CLP, reported as increase above sham laparotomy controls. N = 5 per group; *P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.

Mentions: Since BMS-345541 inhibited NF-κB activation and downstream proinflammatory cytokine responses, we asked whether BMS-345541 treatment would reduce CLP-induced lung injury. Mice treated with CLP developed characteristic histological changes of lung injury at 48 hours, including inflammatory cell infiltration, vascular congestion, alveolar edema, interalveolar septal thickening, and hemorrhage (Figures 4(a) and 4(b)). In contrast, mice treated with BMS-345541 following CPL showed preserved alveolar architecture with minimal edema and septal thickening. To quantify lung edema, we measured wet-to-dry ratios in lungs following CLP at 24 and 48 hours. The increased wet-to-dry ratio observed in CLP group was significantly attenuated in the CLP+BMS group, consistent with the histological changes observed in the lungs of mice from each treatment group (Figures 4(c) and 4(d)). Together, these studies indicate that pharmacologic NF-κB inhibition initiated 2 hours after CLP reduces lung inflammation and prevents injury.


NF-κB inhibition after cecal ligation and puncture reduces sepsis-associated lung injury without altering bacterial host defense.

Li H, Han W, Polosukhin V, Yull FE, Segal BH, Xie CM, Blackwell TS - Mediators Inflamm. (2013)

NF-κB inhibition blocks lung injury and reduces apoptosis after CLP. (a) and (b) Histological evaluation of lung injury on H&E stained lung sections at 48 hours after CLP, *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (c) and (d) Lung edema as measured by wet/dry ratio at 24 and 48 hours after CLP, reported as increase above sham laparotomy controls. N = 5 per group; *P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3852536&req=5

fig4: NF-κB inhibition blocks lung injury and reduces apoptosis after CLP. (a) and (b) Histological evaluation of lung injury on H&E stained lung sections at 48 hours after CLP, *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (c) and (d) Lung edema as measured by wet/dry ratio at 24 and 48 hours after CLP, reported as increase above sham laparotomy controls. N = 5 per group; *P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.
Mentions: Since BMS-345541 inhibited NF-κB activation and downstream proinflammatory cytokine responses, we asked whether BMS-345541 treatment would reduce CLP-induced lung injury. Mice treated with CLP developed characteristic histological changes of lung injury at 48 hours, including inflammatory cell infiltration, vascular congestion, alveolar edema, interalveolar septal thickening, and hemorrhage (Figures 4(a) and 4(b)). In contrast, mice treated with BMS-345541 following CPL showed preserved alveolar architecture with minimal edema and septal thickening. To quantify lung edema, we measured wet-to-dry ratios in lungs following CLP at 24 and 48 hours. The increased wet-to-dry ratio observed in CLP group was significantly attenuated in the CLP+BMS group, consistent with the histological changes observed in the lungs of mice from each treatment group (Figures 4(c) and 4(d)). Together, these studies indicate that pharmacologic NF-κB inhibition initiated 2 hours after CLP reduces lung inflammation and prevents injury.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Respiratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province 510080, China ; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA ; Division of Respiratory Medicine, Nanjing Drum Tower Hospital & the Affiliated Hospital of Nanjing University, Nanjing, Jiangsu 210008, China.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus