Pre‑ or post‑treatment with ethanol and ethyl pyruvate results in distinct anti‑inflammatory responses of human lung epithelial cells triggered by interleukin‑6

Relja,Borna; Omid,Nina; Schaible,Alexander; Perl,Mario; Meier,Simon; Oppermann,Elsie; Lehnert,Mark; Marzi,Ingo

doi:10.3892/mmr.2015.3764

Pre‑ or post‑treatment with ethanol and ethyl pyruvate results in distinct anti‑inflammatory responses of human lung epithelial cells triggered by interleukin‑6

Authors:
- Borna Relja
- Nina Omid
- Alexander Schaible
- Mario Perl
- Simon Meier
- Elsie Oppermann
- Mark Lehnert
- Ingo Marzi
View Affiliations

Affiliations: Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University, Frankfurt am Main D‑60590, Germany, Department of Trauma Surgery, Trauma Center Murnau, Murnau D‑82418, Germany, Department of General Surgery, University Hospital, Goethe University, Frankfurt am Main D‑60590, Germany
Published online on: May 8, 2015 https://doi.org/10.3892/mmr.2015.3764
Pages: 2991-2998

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Increased local and systemic levels of interleukin (IL)‑6 are associated with inflammatory processes, including neutrophil infiltration of the alveolar space, resulting in lung injury. Our previous study demonstrated the beneficial anti‑inflammatory effects of acute exposure to ethanol (EtOH) in an acute in vivo model of inflammation. However, due to its side‑effects, EtOH is not used clinically. In the present study, the effects of EtOH and ethyl pyruvate (EtP) as an alternative anti‑inflammatory drug prior to and following application of an IL‑6 stimulus on cultured A549 lung epithelial cells were compared, and it was hypothesized that treatment with EtOH and EtP reduces the inflammatory potential of the A549 cells. Time‑ and dose‑dependent release of IL‑8 from the A549 cells was observed following stimulation with IL‑6. The release of IL‑8 from the A549 cells was assessed following treatment with EtP (2.5‑10 mM), sodium pyruvate (NaP; 10 mM) or EtOH (85‑170 mM) for 1, 24 or 72 h, prior to and following IL‑6 stimulation. The adhesion capacities of neutrophils to the treated A549 cells, and the expression levels of cluster of differentiation (CD)54 by the epithelial cells were measured. Treatment of the A549 cells with either EtOH or EtP significantly reduced the IL‑6‑induced release of IL‑8. This effect was observed in the pre‑ and post‑stimulatory conditions, which is of therapeutic importance. Similar data was revealed regarding the IL‑6‑induced neutrophil adhesion to the treated A549 cells, in which pre‑ and post‑treatment with EtOH or EtP decreased the adhesion capacity, however, the results were dependent on the duration of incubation. Incubation durations of 1 and 24 h decreased the adhesion rates of neutrophils to the stimulated A549 cells, however, the reduction was only significant at 72 h post‑treatment. The expression of CD54 was reduced only following treatment for 24 h with either EtOH or EtP, prior to IL‑6 stimulation. Therefore, EtOH and EtP reduced the inflammatory response of lung epithelial cells, and the potential of EtP to mimic EtOH was observed in the pre‑ and post‑treatment conditions.

View Figures

View References

1	Bird MD, Choudhry MA, Molina PE and Kovacs EJ: Alcohol and trauma: a summary of the Satellite Symposium at the 30th Annual Meeting of the Shock Society. Alcohol. 43:247–252. 2009. View Article : Google Scholar : PubMed/NCBI
2	Jurkovich GJ, Rivara FP, Gurney JG, et al: The effect of acute alcohol intoxication and chronic alcohol abuse on outcome from trauma. JAMA. 270:51–56. 1993. View Article : Google Scholar : PubMed/NCBI
3	Johansson AS, Johansson-Haque K, Okret S and Palmblad J: Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF-kappaB pathway. Br J Pharmacol. 154:1318–1326. 2008. View Article : Google Scholar : PubMed/NCBI
4	Relja B, Höhn C, Bormann F, et al: Acute alcohol intoxication reduces mortality, inflammatory responses and hepatic injury after haemorrhage and resuscitation in vivo. Br J Pharmacol. 165(4b): 1188–1199. 2012. View Article : Google Scholar :
5	Cook RT: Alcohol abuse, alcoholism, and damage to the immune system–a review. Alcohol Clin Exp Res. 22:1927–1942. 1998.
6	Mandrekar P, Catalano D, White B and Szabo G: Moderate alcohol intake in humans attenuates monocyte inflammatory responses: inhibition of nuclear regulatory factor kappa B and induction of interleukin 10. Alcohol Clin Exp Res. 30:135–139. 2006. View Article : Google Scholar : PubMed/NCBI
7	Szabo G, Mandrekar P, Girouard L and Catalano D: Regulation of human monocyte functions by acute ethanol treatment: decreased tumor necrosis factor-alpha, interleukin-1 beta and elevated interleukin-10, and transforming growth factor-beta production. Alcohol Clin Exp Res. 20:900–907. 1996. View Article : Google Scholar : PubMed/NCBI
8	Relja B, Omid N, Kontradowitz K, et al: Decreased inflammatory responses of human lung epithelial cells after ethanol exposure are mimicked by ethyl pyruvate. Mediators Inflamm. 2014:7815192014. View Article : Google Scholar : PubMed/NCBI
9	Li G, Keyl PM, Smith GS and Baker SP: Alcohol and injury severity: reappraisal of the continuing controversy. J Trauma. 42:562–569. 1997. View Article : Google Scholar : PubMed/NCBI
10	Rehm J, Room R, Graham K, Monteiro M, Gmel G and Sempos CT: The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: an overview. Addiction. 98:1209–1228. 2003. View Article : Google Scholar : PubMed/NCBI
11	Ruiz M, Ewig S, Torres A, et al: Severe community-acquired pneumonia. Risk factors and follow-up epidemiology. Am J Respir Crit Care Med. 160:923–929. 1999. View Article : Google Scholar : PubMed/NCBI
12	Bagby GJ, Zhang P, Stoltz DA and Nelson S: Suppression of the granulocyte colony-stimulating factor response to Escherichia coli challenge by alcohol intoxication. Alcohol Clin Exp Res. 22:1740–1745. 1998. View Article : Google Scholar : PubMed/NCBI
13	Boé DM, Nelson S, Zhang P and Bagby GJ: Acute ethanol intoxication suppresses lung chemokine production following infection with Streptococcus pneumoniae. J Infect Dis. 184:1134–1142. 2001. View Article : Google Scholar : PubMed/NCBI
14	Boé DM, Nelson S, Zhang P, Quinton L and Bagby GJ: Alcohol-induced suppression of lung chemokine production and the host defense response to Streptococcus pneumoniae. Alcohol Clin Exp Res. 27:1838–1845. 2003. View Article : Google Scholar : PubMed/NCBI
15	Faunce DE, Gregory MS and Kovacs EJ: Effects of acute ethanol exposure on cellular immune responses in a murine model of thermal injury. J Leukoc Biol. 62:733–740. 1997.PubMed/NCBI
16	Messingham KA, Faunce DE and Kovacs EJ: Alcohol, injury, and cellular immunity. Alcohol. 28:137–149. 2002. View Article : Google Scholar
17	Zhang P, Bagby GJ, Boé DM, et al: Acute alcohol intoxication suppresses the CXC chemokine response during endotoxemia. Alcohol Clin Exp Res. 26:65–73. 2002. View Article : Google Scholar : PubMed/NCBI
18	Berger K, Ajani UA, Kase CS, et al: Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians. N Engl J Med. 341:1557–1564. 1999. View Article : Google Scholar : PubMed/NCBI
19	Lustenberger T, Inaba K, Barmparas G, et al: Ethanol intoxication is associated with a lower incidence of admission coagulopathy in severe traumatic brain injury patients. J Neurotrauma. 28:1699–1706. 2011. View Article : Google Scholar : PubMed/NCBI
20	Sesso HD: Alcohol and cardiovascular health: recent findings. Am J Cardiovasc Drugs. 1:167–172. 2001. View Article : Google Scholar
21	Rubini A: Interleukin-6 and lung inflammation: Evidences of a causing role in inducing respiratory system resistance increments. Inflamm Allergy Drug Targets. 12:315–321. 2013. View Article : Google Scholar : PubMed/NCBI
22	Fink MP: Ethyl pyruvate. Curr Opin Anaesthesiol. 21:160–167. 2008. View Article : Google Scholar : PubMed/NCBI
23	Kao KK and Fink MP: The biochemical basis for the anti-inflammatory and cytoprotective actions of ethyl pyruvate and related compounds. Biochem Pharmacol. 80:151–159. 2010. View Article : Google Scholar : PubMed/NCBI
24	Wang Y, Yin P, Huang S, Wang J and Sun R: Ethyl pyruvate protects against lipopolysaccharide-induced white matter injury in the developing rat brain. Int J Dev Neurosci. 31:181–188. 2013. View Article : Google Scholar : PubMed/NCBI
25	Cai B, Brunner M, Wang H, Wang P, Deitch EA and Ulloa L: Ethyl pyruvate improves survival in awake hemorrhage. J Mol Med-Berl. 87:423–433. 2009. View Article : Google Scholar : PubMed/NCBI
26	Jacobs CC, Holcombe SJ, Cook VL, Gandy JC, Hauptman JG and Sordillo LM: Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses. Equine Vet J. 45:333–339. 2013. View Article : Google Scholar
27	Li LF, Kao KC, Yang CT, Huang CC and Liu YY: Ethyl pyruvate reduces ventilation-induced neutrophil infiltration and oxidative stress. Exp Biol Med (Maywood). 237:720–727. 2012. View Article : Google Scholar
28	Holzer K, Schübel F, Konietzny P, Wilhelm K, Bechstein WO and Henrich D: Interleukin 8 mRNA gene expression in peripheral and intra-abdominal neutrophils during human secondary peritonitis. Shock. 23:501–506. 2005.PubMed/NCBI
29	Johansson AS and Palmblad J: Ethyl pyruvate modulates adhesive and secretory reactions in human lung epithelial cells. Life Sci. 84:805–809. 2009. View Article : Google Scholar : PubMed/NCBI
30	Jonsson AS and Palmblad JE: Effects of ethanol on NF-kappaB activation, production of myeloid growth factors, and adhesive events in human endothelial cells. J Infect Dis. 184:761–769. 2001. View Article : Google Scholar : PubMed/NCBI
31	Maiya R, Buck KJ, Harris RA and Mayfield RD: Ethanol-sensitive sites on the human dopamine transporter. J Biol Chem. 277:30724–30729. 2002. View Article : Google Scholar : PubMed/NCBI
32	Famili A, Ammar DA and Kahook MY: Ethyl pyruvate treatment mitigates oxidative stress damage in cultured trabecular meshwork cells. Mol Vis. 19:1304–1309. 2013.PubMed/NCBI
33	Zhang X, Yin P, Di D, et al: IL-6 regulates MMP-10 expression via JAK2/STAT3 signaling pathway in a human lung adenocarcinoma cell line. Anticancer Res. 29:4497–4501. 2009.PubMed/NCBI
34	Ajisaka H, Okajima M, Goto Y, Taniguchi T and Inaba H: Effects of acute low-dose ethanol on inflammatory reactions to endotoxin-induced shock in rats. J Toxicol Sci. 37:649–654. 2012. View Article : Google Scholar : PubMed/NCBI
35	Hubeau C, Kubera JE, Masek-Hammerman K and Williams CM: Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C). Clin Sci (Lond). 125:483–493. 2013. View Article : Google Scholar
36	Relja B, Henrich D, Wetzel G, et al: Effects of acute ethanol gavage on intestinal integrity after hemorrhage/resuscitation. Scand J Gastroenterol. 48:448–458. 2013. View Article : Google Scholar : PubMed/NCBI
37	Smolen JS, Schoels MM, Nishimoto N, et al: Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann Rheum Dis. 72:482–492. 2013. View Article : Google Scholar :
38	Reiss LK, Uhlig U and Uhlig S: Models and mechanisms of acute lung injury caused by direct insults. Eur J Cell Biol. 91:590–601. 2012. View Article : Google Scholar : PubMed/NCBI
39	Karavitis J, Murdoch EL, Gomez CR, Ramirez L and Kovacs EJ: Acute ethanol exposure attenuates pattern recognition receptor activated macrophage functions. J Interferon Cytokine Res. 28:413–422. 2008. View Article : Google Scholar : PubMed/NCBI
40	Bhatty M, Jan BL, Tan W, Pruett SB and Nanduri B: Role of acute ethanol exposure and TLR4 in early events of sepsis in a mouse model. Alcohol. 45:795–803. 2011. View Article : Google Scholar : PubMed/NCBI
41	Bals R and Hiemstra PS: Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur Respir J. 23:327–333. 2004. View Article : Google Scholar : PubMed/NCBI
42	Fogli LK, Sundrud MS, Goel S, et al: T cell-derived IL-17 mediates epithelial changes in the airway and drives pulmonary neutrophilia. J Immunol. 191:3100–3111. 2013. View Article : Google Scholar : PubMed/NCBI
43	Segel GB, Halterman MW and Lichtman MA: The paradox of the neutrophil’s role in tissue injury. J Leukoc Biol. 89:359–372. 2011. View Article : Google Scholar
44	Weckbach S, Hohmann C, Braumueller, et al: Inflammatory and apoptotic alterations in serum and injured tissue after experimental polytrauma in mice: Distinct early response compared with single trauma or “double-hit” injury. J Trauma Acute Care Surg. 74:489–498. 2013. View Article : Google Scholar : PubMed/NCBI
45	Rhee CK, Kang JY, Kim YH, et al: Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies. Crit Care. 13:R1732009. View Article : Google Scholar : PubMed/NCBI