Acute and Critical Care

Original Articles

Infection
The Effects of Flecainide Acetate on Inflammatory-Immune Response in Lipopolysaccharide-Stimulated Neutrophils and on Mortality in Septic Rats: Shi Young Chung, Jinyoung Kim, Hong Bum Bae, Tran Duc Tin, Wan Ju, Sang Hyun Kwak; Acute Crit Care. 2018;33(1):34-41. Published online February 28, 2018; DOI: https://doi.org/10.4266/acc.2017.00577

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Background
Flecainide acetate is a drug used primarily for cardiac arrhythmia. Some studies also imply that flecainide acetate has the potential to regulate inflammatory-immune responses; however, its mechanism of action is contended. We determined the effects of flecainide acetate on lipopolysaccharide (LPS)-stimulated human neutrophils in vitro and on mortality in a septic rat model.
Methods
Neutrophils from human blood were cultured with varying concentrations of flecainide acetate (1 μM, 10 μM, or 100 μM) with or without LPS (100 ng/ml). To assess neutrophil activation, the protein levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and IL-8 were measured after a 4-hour culture period. To assess the intracellular signaling pathways, the levels of phosphorylation of p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) were measured after a 30-minute culture period, and the nuclear translocation of nuclear factor (NF)-κB was measured after a 1-hour culture period. Additionally, the survival rate was investigated in a rat sepsis model.
Results
Flecainide acetate down-regulated the activation of proinflammatory cytokines, including TNF-α and IL-6 and IL-8, and intracellular signaling pathways including ERK 1/2 and NF-κB. Flecainide acetate also improved the survival rate in the rat sepsis model.
Conclusions
Collectively, these findings indicate that flecainide acetate can improve survival in a rat sepsis model by attenuating LPS-induced neutrophil responses. We therefore suggest that flecainide acetate plays an important role in modulating inflammatoryimmune responses.

Citations

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Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis
Andy Y. An, Arjun Baghela, Peter Zhang, Reza Falsafi, Amy H. Lee, Uriel Trahtemberg, Andrew J. Baker, Claudia C. dos Santos, Robert E. W. Hancock
Frontiers in Immunology.2023;[Epub] CrossRef

Rebound Inflammation Associated with Rewarming from Hypothermia in an Endotoxin-Injured Lung: Chae Man Lim; Korean J Crit Care Med. 2013;28(2):80-85.; DOI: https://doi.org/10.4266/kjccm.2013.28.2.80

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Abstract PDF: BACKGROUND
Hypothermia is known to suppress inflammation in various experimental and clinical settings. We wanted to investigate how the suppressed inflammation by hypothermia is affected during rewarming.
METHODS
Mice were being assigned to normothermia (37degrees C) or hypothermia (32degrees C). After 30 minutes at the assigned temperature, lipopolysaccharide was administered intratracheally. The mice were then randomly grouped and subjected to 4 hours of normothermia (N), 24 hours of normothermia (NN), 4 hours of hypothermia (H), or 4 hours of hypothermia followed by normothermia for the next 20 hours (HN). In another experiment, other HN mice were treated with varying doses of anti-TNF-alpha or anti-IL-1beta antibodies (0, 6.25, 12.5, 25, and 50 microg/250 microl) immediately prior to rewarming.
RESULTS
The neutrophil counts of BAL fluid (x104/ml) were 23.0 +/- 13.1 in the N, 6.4 +/- 3.1 in the H (p = 0.002 vs N), 20.4 +/- 10.2 in the NN, and 49.7 +/- 21.0 in the HN (p = 0.005 vs H; p < 0.001 vs NN). Myeloperoxidase activity of the lung (unit/microg) was 6.7 +/- 2.9, 7.9 +/- 1.9, 17.8 +/- 4.0 (p < 0.001 vs N), and 12.9 +/- 5.9 (p = 0.034 vs H, p = 0.028 vs NN), respectively. Compared with control HN, total WBC and neutrophil counts of mice treated with anti-TNF-alpha antibody or anti-IL-1beta antibody prior to rewarming were lower at all tested doses. The combination of both anti-TNF-alpha or anti-IL-1beta antibodies was not increasingly reducing the neutrophilic sequestration.
CONCLUSIONS
Rewarming from induced hypothermia resulted in augmentation of neutrophilic sequestration of endotoxin-injured lung. Treatment with antibodies against TNF-alpha or IL-1beta prevented this rebound of neutrophilic infiltration.

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