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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 reduces lung inflammation after CLP. (a) Total cells, (b) neutrophils, and (c) KC levels in BAL at 24 hours after surgery in control mice treated with sham laparotomy (Ctrl), mice that underwent CLP followed by vehicle (CLP), and mice treated with CLP followed by BMS-345541 (CLP+BMS). N = 10 per group. *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (d) Serum cytokine levels for KC, MCP-1, and IL-10 at 24 hours after surgery. N = 5 per group. *P < 0.05 for CLP versus Ctrl; #P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.
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fig3: NF-κB inhibition reduces lung inflammation after CLP. (a) Total cells, (b) neutrophils, and (c) KC levels in BAL at 24 hours after surgery in control mice treated with sham laparotomy (Ctrl), mice that underwent CLP followed by vehicle (CLP), and mice treated with CLP followed by BMS-345541 (CLP+BMS). N = 10 per group. *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (d) Serum cytokine levels for KC, MCP-1, and IL-10 at 24 hours after surgery. N = 5 per group. *P < 0.05 for CLP versus Ctrl; #P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.

Mentions: To evaluate the effects of NF-κB inhibition on the course of lung inflammation in this model, we measured total inflammatory cells, neutrophils, cytokines, and chemokines in BAL fluid at 24 h after CLP. We found a significant reduction in the total number of BAL cells, as well as BAL neutrophils, in the CLP+BMS group compared to the CLP group (Figures 3(a) and 3(b)). Total BAL cells and neutrophils were similar between the CLP+BMS group and sham laparotomy controls. At 48 hours after CLP, we found a similar pattern of cells in BAL with a reduction in total cells and neutrophils in the CLP+BMS group compared to the CLP group (data not shown). Consistent with reduced neutrophilic lung inflammation, levels of the NF-κB-dependent neutrophil chemotactic chemokine KC were lower in serum and BAL fluid in the CLP+BMS group compared to the CLP group (Figures 3(c) and 3(d)). Of other cytokines tested, MCP-1 was reduced, while IL-10 was increased in serum from mice treated with BMS-345541 following CLP compared to mice that underwent CLP followed by vehicle (Figures 3(e) and 3(f)). We also found a trend towards decreased IL-6, IL-17, and MIG in serum from mice treated with CLP+BMS compared to mice treated with CLP (+vehicle) (data not shown). In BAL fluid, levels of these cytokines were similar in both groups (CLP+BMS and CLP) at 24 hours after CLP (data not shown).


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 reduces lung inflammation after CLP. (a) Total cells, (b) neutrophils, and (c) KC levels in BAL at 24 hours after surgery in control mice treated with sham laparotomy (Ctrl), mice that underwent CLP followed by vehicle (CLP), and mice treated with CLP followed by BMS-345541 (CLP+BMS). N = 10 per group. *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (d) Serum cytokine levels for KC, MCP-1, and IL-10 at 24 hours after surgery. N = 5 per group. *P < 0.05 for CLP versus Ctrl; #P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: NF-κB inhibition reduces lung inflammation after CLP. (a) Total cells, (b) neutrophils, and (c) KC levels in BAL at 24 hours after surgery in control mice treated with sham laparotomy (Ctrl), mice that underwent CLP followed by vehicle (CLP), and mice treated with CLP followed by BMS-345541 (CLP+BMS). N = 10 per group. *P < 0.05 for CLP versus sham laparotomy controls (Ctrl); #P < 0.05 for CLP+BMS versus CLP. (d) Serum cytokine levels for KC, MCP-1, and IL-10 at 24 hours after surgery. N = 5 per group. *P < 0.05 for CLP versus Ctrl; #P < 0.05 for CLP+BMS versus CLP. Results are presented as mean ± SE.
Mentions: To evaluate the effects of NF-κB inhibition on the course of lung inflammation in this model, we measured total inflammatory cells, neutrophils, cytokines, and chemokines in BAL fluid at 24 h after CLP. We found a significant reduction in the total number of BAL cells, as well as BAL neutrophils, in the CLP+BMS group compared to the CLP group (Figures 3(a) and 3(b)). Total BAL cells and neutrophils were similar between the CLP+BMS group and sham laparotomy controls. At 48 hours after CLP, we found a similar pattern of cells in BAL with a reduction in total cells and neutrophils in the CLP+BMS group compared to the CLP group (data not shown). Consistent with reduced neutrophilic lung inflammation, levels of the NF-κB-dependent neutrophil chemotactic chemokine KC were lower in serum and BAL fluid in the CLP+BMS group compared to the CLP group (Figures 3(c) and 3(d)). Of other cytokines tested, MCP-1 was reduced, while IL-10 was increased in serum from mice treated with BMS-345541 following CLP compared to mice that underwent CLP followed by vehicle (Figures 3(e) and 3(f)). We also found a trend towards decreased IL-6, IL-17, and MIG in serum from mice treated with CLP+BMS compared to mice treated with CLP (+vehicle) (data not shown). In BAL fluid, levels of these cytokines were similar in both groups (CLP+BMS and CLP) at 24 hours after CLP (data not shown).

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