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HOME > Acute Crit Care > Volume 31(3); 2016 > Article
Original Article Flecainide Improve Sepsis Induced Acute Lung Injury by Controlling Inflammatory Response
Jia Song, M.D.1, Young joong Suh, M.D.2, Hyun jung Lee, M.D.1, Eun a Jang, M.D.3, Hong-beom Bae, M.D., Ph.D.3, Sang-Hyun Kwak, M.D., Ph.D.1orcid
Korean Journal of Critical Care Medicine 2016;31(3):194-201.
DOI: https://doi.org/10.4266/kjccm.2016.00157
Published online: August 30, 2016

1Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Korea

2Department of Anesthesiology and Pain Medicine, Gwangju Christian Hospital, Gwangju, Korea

3Department of Anesthesiology and Pain Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea

Correspondence to: Sang-Hyun Kwak, Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Chonnam National University Medical School, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6893, Fax: +82-62-232-6294 E-mail: shkwak@chonnam.ac.kr
• Received: March 4, 2016   • Revised: March 31, 2016   • Accepted: April 11, 2016

Copyright © 2016 The Korean Society of Critical Care Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Background:
    Flecainide is an antiarrhythmic agent that is used primarily in the treatment of cardiac arrhythmias. Some evidences also suggest that flecainide can participate in alveolar fluid clearance and inflammatory responses. This experiment was aimed to evaluate the effects of flecainide on sepsis induced acute lung injury in a rat model.
  • Methods:
    Rats were treated with subcutaneous infusion of saline or flecainide (0.1 or 0.2 mg/kg/hr) by a mini-osmotic pump. Subcutaneous infusion was started 3 hours before and continued until 8 hours after intraperitoneal injection of saline or endotoxin. Animals were sacrificed for analyses of severity of acute lung injury with wet to dry (W/D) ratio and lung injury score (LIS) in lung and inflammatory responses with level of leukocyte, polymorphonuclear neutrophils (PMNs) and inteleukin-8 (IL-8) in bronchoalveolar lavages fluid (BALF).
  • Results:
    Flecainide markedly improved dose dependently sepsis induced acute lung injury as analysed by W/D ratio (from 2.24 ± 0.11 to 1.76 ± 0.09, p < 0.05) and LIS (from 3 to 1, p < 0.05), and inflammatory response as determined by leukocyte (from 443 ± 127 to 229 ± 95, p < 0.05), PMNs (from 41.43 ± 17.63 to 2.43 ± 2.61, p < 0.05) and IL-8 (from 95.00 ± 15.28 to 40.00 ± 10.21, p < 0.05) in BALF.
  • Conclusions:
    Flecanide improve sepsis induced acute lung injury in rats by controlling inflammatory responses.
Acute respiratory distress syndrome (ARDS) is a complex syndrome that characterize as severe pulmonary inflammatory responses with high morbidity and mortality. Although the exact pathogenesis for ARDS is not yet fully defined. But sepsis-induced over-activation of inflammatory cells involving macrophages and neutrophils is one of variable reasons to play critical roles in the development of ARDS.[1] Thus, nontoxic molecules that regulate inflammation may provide an innovative therapeutic strategy.
Flecainide, a strong blocker of sodium channel, has favorable electrophysiologic effects in the management of cardiac arrhythmia. So it has been widely used in clinical practice. In addition, some reports suggest that flecainide can participate to regulate lung fluid homeostasis[2] and neutrophil action.[3] Thereby flecainide might also participate in modulating alveolar fluid clearance (AFC) and cellular recruitment during acute inflammatory processes. Therefore, we proposed the hypothesis that the efficacy of flecainide include not only antiarrhythmic effect but also anti-inflammatory effect in sepsis induced acute lung injury (ALI).
In the present experiments, we evaluated whether flecainide improves sepsis induced acute lung injury as determined by wet to dry (W/D) ratio and lung injury score (LIS) in lung and inflammatory responses involving level of leukocyte, polymorphonuclear neutrophils (PMNs) and inteleukin-8 (IL-8) in bronchoalveolar lavages fluid (BALF) in a rat model.
1) Materials and animals
Flecainide was obtained from Hana pharm (Seoul, Korea). Sevoflurane was obtained from Abbott Laboratories (Chicago, IL, USA). Escherichia coli 0111:B4 endotoxin was bought from Sigma-Aldrich (St. Louis, MO, USA). Immunoreactive IL-8 were quantified using commercially available enzyme-linked immunosorbent assay kits (R & D Systems, Minneapolis, MN, USA), in accordance with manufacturer’s instructions and as described previously. [4] Male SD rats, 8–12 weeks of age, were purchased from Damul science (Daejeon, Korea). The animals were kept on a 12hours light/dark cycle with free access to water and food. All experiments were conducted according to institutional review board approved protocols.
2) Animal model of endotoxin-induced acute lung injury
Animals were randomly attached to one of five groups involving rats receiving subcutaneous (SC) saline and intraperitoneal (IP) saline (S-S group, n = 14), those receiving SC saline and IP endotoxin (25 mg/kg) (S-E group, n = 14), those receiving SC flecainide (0.2 mg/kg/h) and IP saline (F-S group, n = 14), those receiving SC flecainide (0.1 mg/kg/h) and IP endotoxin (F 0.1-E group, n =14), those receiving SC flecainide (0.2 mg/kg/h) and IP endotoxin (F 0.2-E group, n = 14). Animals were initially anesthetized with sevoflurane. After the swabbing on the interscapular area, a mini-osmotic pump (model 2001; Alzet, Alza, Palp Alto, CA, USA) was implanted to administer saline or flecainide at a rate of 0.1 or 0.2 mg/kg/h for a period of 11 hours totally. SC infusion of saline or flecainide using by a mini-osmotic pump was started 3 hours before and continued until 8 hours after injection of saline or endotoxin when all animals were killed. ALI was induced by IP injection of 25 mg/kg Escherichia coli 0111:B4 endotoxin into animals. With this model, ALI, as characterized by neutrophil infiltration into the lung interstitium, progress of interstitial edema, and increment of proinflammatory cytokine occurs after injection of endotoxin, with the greatest accumulation of neutrophils into the airways and histopathologic injury being present 8 hours after endotoxin exposure.[5-7] Animals were assigned to 14 rats per each group for the assessment of W/D ratio and histopathologic examination of the lung (n = 7) and analysis of BALF (n = 7), respectively. Animals were euthanized to collect BALF and lung tissues at 8 hours after the IP saline or endotoxin. At this time point, the number of white blood cell, percentages of PMNs and the concentration of IL-8 in BALF, W/D ratio and histopathologic examination were evaluated.
3) W/D ratio
All animals used for W/D ratios were of identical ages. The left lobes were excised, rinsed briefly in phosphate buffered saline, blotted, then weighed to acquire the wet weight. Next, lungs were dried in an oven at 70°C for 7 days to acquire the dry weight.
4) Histopathologic examination
The right lobes were fixed by instillation of 10% glutaraldehyde solution through the right main bronchus at 20cmH2O. The lungs were embedded in paraffin, and the sections were stained with hematoxylin and eosin. Lung injury was scored as follows by a pathologist (who was unaware of the nature of the experiment) under light microscopy as previously described[8]—0 (no reaction in alveolar walls), 1 (diffuse reaction in alveolar walls, primarily neutrophilic, no thickening of alveolar walls), 2 (diffuse presence of inflammatory cells [neutrophilic and mononuclear] in alveolar walls and slight thickening), 3 (distinct thickening [two or three times] of the alveolar walls due to the presence of inflammatory cells), 4 (alveolar wall thickening with up to 25% of the lung consolidated), 5 (alveolar wall thickening with more than 50% of the lung consolidated). To count the number of neutrophils in the airspace, five randomly selected fields per slide were read at ×400 magnification by the pathologist. Fields containing large vessels or bronchi were excluded. The number of neutrophils per field was normalized to alveoli per field to control for inflation of the lung.
5) BALF
Bronchoalveolar lavages were obtained by cannulating the trachea with a blunt 16-gauge needle and then lavaging the lungs three times with 10 mL of iced phosphate buffered saline. The BALF was analyzed for cell count and cell differentiation. For cell differentiation, a cytocentrifuged spin preparation (CF-RD, Sakura, Tokyo, Japan) of the BALF was stained with Wright. Using a cell counter (XE2100, Sysmex, Kobe, Japan), the numbers of leukocytes in BALF were counted. The fluid was centrifuged at 250 g at 4ºC for 20 min to remove the cells. The cell-free supernatant was divided into several aliquots and stored at -80ºC for measurements of IL-8.
6) Statistical analysis
SPSS (Windows ver. 21.0, SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. Data are presented as mean ± standard error of the mean except the lung injury score which is given as a median for each experimental group. Data from three or more groups were compared using one-way analysis of variance followed by the Scheffé multiple comparison test. Pairwise comparisons were made with the Student’s t test. A value of p < 0.05 was considered significant.
1) W/D ratios
W/D ratio was increased in S-E group compared with in S-S group. Flecainide reduced the degree of increase in these ratio (Table 1, Fig. 1).
2) Histopathologic grading
Endotoxin caused edema and hemorrhage of lung, thickening of the alveolar wall, and invasion of inflammatory cells into alveolar air spaces. However, flecainide prevented these changes (Fig. 2A-C). Histopathologic assessment of the LIS demonstrated that flecainide successfully attenuated the severity of the lung injury. (Table 1, Fig. 2D).
3) Analysis of BALF
The ratio of BALFs collected from the animals was 77 to 85%. This range of ratio indicates a similar dilution among the groups. Obviously more leukocytes in BALF were collected in groups receiving endotoxin compared than in groups receiving saline, meaning that the neutrophils had invaded into the alveolar air spaces from the pulmonary capillary endothelium. And flecainide slightly prevented the increase in leukocyte counts in BALF (Table 1, Fig. 3A). Leukocytes of BALF in groups receiving saline were mostly macrophages. However, the ratio of PMNs in BALF markedly increased in groups receiving endotoxin in which the mean ratio of PMNs was as high as 41%. Flecainide significantly prevented the increase in these ratios (Table 1, Fig. 3B). The levels of IL-8 in BALF were increased in groups receiving endotoxin compared with in groups receiving saline. Flecainide prevented the increment in these concentrations (Table 1, Fig. 4).
The main results in this experiment were that flecainide improved sepsis induced acute lung injury as analysed by W/D ratio and LIS, and inflammatory response as determined by leukocyte, PMNs and IL-8 in BALF. ARDS is a complex syndrome that characterize as severe pulmonary inflammatory responses with interstitial edema, damage of epithelial integrity, leukocyte infiltration and leakage of protein into alveolar air space and induce alterations in gas exchange.[9] Lipopolysaccharide (LPS) is induced in the host on infection with bacteria and it provokes inflammatory process which activate leukocyte, multiple kinases and proinflammatory cytokines involved with the expression of Toll-like receptors (TLR) 4 in alveolar epithelial cells.[10-12] The inflammatory event was a main cause of alterations in the processes which control lung fluid homeostasis. And eventually the alterations induce lung disease such as ARDS. In this experiment, flecainide decreased the degree of change of lung W/D ratio, histopathologic finding. Also it attenuated concentrations of leukocyte, PMNs and IL-8 in BALF. These findings are very important because these parameters are representative indexes of lung injury induced by disruption of cell integrity. Also in patients with sepsis and ALI, increased levels of leukocyte, PMNs and IL-8 correlate to a poor outcome.[13,14] Although a classically described role for flecainide is antiarrythmic action mediated by sodium channel blocker, we suggested that flecainide particularly appears to participate to regulate lung fluid homeostasis and neutrophil mediated inflammatory processes.
In other words, we proposed the hypothesis that the efficacy of flecainide was extend to decrease pulmonary edema and anti-inflammatory effects related with neutrophil activation. O’Brodovich[15] reported that LPS treated alveolar macrophages could attenuate total and amiloride sensitive sodium channel current in primary cultures of distal pulmonary epithelial cells. And Baines et al.[16] reported that LPS reduce epithelial sodium channel (ENaC) transcription and activity via extracellular signal regulated kinases (ERK) pathways. The alveolar ENaCs acts to resolve pulmonary edema via AFC.[2] Concept of AFC has emerged to explain lung fluid balance under both normal and pathologic conditions. Pathophysiologically, uncontrolled inflammation develop pulmonary edema and it provoke impairment of gas exchange and oxygenation in ALI and ARDS.[17] The failure of reabsorption of excess alveolar fluid to resolve this edema increase mortality in an intensive care unit.[18,19] In the concrete, through apical amiloride sensitive sodium channels, sodium ion enters the alveolar epithelial cells and it is actively transported across the basolateral membrane by the sodium-potassium-adenosine triphosphatase.[20] This vectorial transport of sodium is the main driving force for removal of edema from the air spaces. In some animal studies, it was reported that transgenic expression of ENaC mice (knock out mice) showed an exaggerated increase of the W/D ratio and more severe pulmonary edema on histological examination. These results are coincidence with our data for histopathologic finding that the pulmonary edema and hemorrhage of lung, thickening of the alveolar wall, and invasion of inflammatory cells were more prominent in rats receiving endotoxin. In view of above evidences about transepithelial Na+ transport, there are strong relations the ENaC with the pulmonary edema obviously. [21] Neutrophils, exposured to LPS, induce activation of multiple kinases which is involved in proinflammatory cytokine expression. Also oxygen radicals, protease, leukotrienes, and inflammatory cytokines, such as IL-1β, IL-8, TNF-α were released by activated neutrophils.[22] So, pathways inducing phosphorylation and activation of mitogen-activated protein kinases (MAPKs) such as p38, ERK 1/2 and c-Jun N-terminal kinase act to be critical to treat lung injury. Because LPS induced cytokine production by neutrophils is decreased by inhibition of activation of MAPKs.[23,24] A series of expression mediated with TLR-2 and 4 pathway are partially connected to the epithelial transport of sodium ion. In general, sodium ion shift in epithelial cell via regulation of several factors which is the regulation of the open probability, membrane expression and internalization of the ENaC and membrane expression and turnover of the sodium-potassium pump.[25] The sodium channel activity is not fully known in epithelium, but proinflammatory cytokine, serine protease, the thickness and osmolarity of the airway surface liquid contribute to regulate ENaC, partially. Especially, many of these factors, which are mediated with expression of TLR-2 and 4 pathway, including TNF-α,[26] IL-1,[27] IL-4, and nitric oxide, control the rate of airway epithelial sodium ion transport. Also activation of MAPK pathways, NF-κB and phosphorylation of ERK1/2 have been shown to modulate and interact the transcription and activity of ENaC in pulmonary epithelial cells.[28] Thus, In addition to its electrophysiologic effects, we propose that flecainide has major roles in attenuating of LPS induced neutrophil activation. However, the pathway and the specific roles of flecainide on inflammatory responses remain to be defined. So additional in vitro study should be performed to clarify these anti-inflammatory effects of flecainide acetate.
In conclusion, as showing in the present results, flecainide improve sepsis-induced lung injury in rats by controlling inflammatory response.

No potential conflict of interest relevant to this article was reported.

This study was financially supported by Chonnam National University, 2014.
Fig. 1.
Effects of flecainide acetate on endotoxin-induced changes in the wet-to-dry lung weight ratio (W/D ratio). Lung lobe was collected at 8 hour after the start of saline or endotoxin injection. W/D ratio was determined as described in Methods. Each values represent mean ± standard error of the mean from seven animals. *p < 0.05 vs. S-S group. p < 0.05 vs. group S-E.
kjccm-2016-00157f1.gif
Fig. 2.
Effects of flecainide acetate on lung tissue damage at 8 hour after the start of saline or endotoxin injection. Representive photomicrographies showing hematoxylin and eosin staining samples with median values in group S-S (A), group S-E (B), and group F-E (C). Original print magnifications x 400. (D) Lung injury score: lung injure was scored from 0 (no damage) to 4+ (maximal damage) according to the criteria described in Methods. Bars represent median from seven animals. *p < 0.05 vs. group S-S. p < 0.05 vs. group S-E.
kjccm-2016-00157f2.gif
Fig. 3.
Effects of flecainide acetate on endotoxin-induced changes in the leukocyte count (A) and percentage of polymorphonuclear neutrophils (PMNs) (B) in bronchoalveolar lavage fluids (BALF). BALF was collected at 8 hour after the start of saline or endotoxin injection. The leukocyte counts and percentage of PMNs in BALF were determined as described in Methods. The values represent mean ± standard error of the mean from seven animals. *p < 0.05 vs. S-S group. p < 0.05 vs. group S-E.
kjccm-2016-00157f3.gif
Fig. 4.
Effects of flecainide acetate on endotoxin-induced changes in the concentration of Interleukin-8 (IL-8) in bronchoalveolar lavage fluids (BALF). BALF was collected at 8 hour after the start of saline or endotoxin injection. Concentration of IL-8 in BALF was determined as described in Methods. The values represent mean ± standard error of the mean from seven animals. *p < 0.05 vs. S-S group. p < 0.05 vs. group S-E.
kjccm-2016-00157f4.gif
Table 1.
Changes in BALF chemistry, W/D ratio, LIS in endotoxin and flecainide treated rats
Variables S-S F-S S-E F0.1-E F0.2-E
BALF
Leukocyte (×102/mm3) 271 ± 49 243 ± 53 443 ± 127* 229 ± 111 229 ± 95
PMN/Total cells (%) 0.39 ± 0.17 0.36 ± 0.34 41.43 ± 17.63* 19.5 ± 17.19* 2.43 ± 2.61*
IL-8 (ng/mL) 8.60 ± 2.25 8.30 ± 2.20 95.00 ± 15.28* 80.37 ± 7.71* 40.00 ± 10.21*
W/D ratio 1.63 ± 0.04 1.67 ± 0.06 2.24 ± 0.11* 1.86 ± 0.14* 1.76 ± 0.09
LIS (median [range]) 0 (0-1) 1 (0-1) 3 (2-4)* 1 (0-2)* 1 (0-2)*

BALF chemistry, W/D ratio and LIS are from fourteen rats in each group. Values are mean ± SEM except LIS (median [range]).

S-S: subcutaneous saline-intraperitoneal saline; F-S: SC flecainide-IP saline; S-E: SC saline-IP endotoxin; F0.1-E: SC flecainide 0.1 mg/kg/h-IP endotoxin; F0.2-E: SC flecainide 0.2 mg/kg/h-IP endotoxin; BALF: bronchoalveolar lavage fluids; W/D: wet to dry weight; LIS: lung injury score; PMNL: polymorphoneuclear leukocyte; IL-8: Interleukin-8; SEM: standard error of the mean.

* p < 0.05 vs. group S-S.

p < 0.05 vs. group S-E.

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