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The alpha-lipoic acid derivative DHLHZn: a new therapeutic agent for acute lung injury in vivo

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Abstract

Objective and design

An animal experiment was performed to demonstrate the anti-inflammatory effects of an alpha-lipoic acid (ALA) derivative, dihydrolipoyl histidinate zinc complex (DHLHZn) for acute lung injury (ALI) and to investigate the mechanism of action.

Material

Rats were randomly divided into three experimental groups: control group (n = 17), DHLHZn(−) group (n = 11, ALI model rats), and DHLHZn(+) group (n = 12, ALI model rats treated by DHLHZn).

Treatment

Lipopolysaccharides (LPS, 10 mg/kg) were administered intratracheally in the DHLHZn(−) group and the DHLHZn(+) group. For the DHLHZn(+) group, DHLHZn (100 mg/kg) was administered intraperitoneally 2 h prior to LPS administration.

Methods

Four hours after LPS administration, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The findings were analyzed using the Mann–Whitney U test.

Results

Total number of cells, number of neutrophils and lymphocytes, levels of various inflammatory cytokines, and NF-kB p65 concentration of BALF were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.05). ALI pathology scores were significantly lower in the DHLHZn(+) group than in the DHLHZn(−) group (p < 0.001).

Conclusions

Anti-inflammatory effects of DHLHZn for ALI were demonstrated by BALF and histopathological findings. The mechanism of action of DHLHZn was considered to be via inhibition of the NF-kB signaling pathway. DHLHZn is thus suggested to be a new prophylactic agent for ALI.

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References

  1. Wheeler AP. Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 2007;369:1553–64.

    Article  PubMed  Google Scholar 

  2. Wyncoll DL. Acute respiratory distress syndrome. Lancet. 1999;354:497–501.

    Article  CAS  PubMed  Google Scholar 

  3. Lehr HA. Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy? J Pathol. 2000;190:373–86.

    Article  CAS  PubMed  Google Scholar 

  4. Riedemann NC. The enigma of sepsis. J Clin Invest. 2003;112:460–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Munford RS. Sensing gram-negative bacterial lipopolysaccharides: a human disease determinant? Infect Immun. 2008;76:454–65.

    Article  CAS  PubMed  Google Scholar 

  6. Davis MR. Purification and visualization of lipopolysaccharide from Gram-negative bacteria by hot aqueous-phenol extraction. J Vis Exp. 2012;63:e3916.

    Google Scholar 

  7. Liu F. Lipopolysaccharide-induced acute lung injury in rats: comparative assessment of intratracheal instillation and aerosol inhalation. Toxicology. 2013;304:158–66.

    Article  CAS  PubMed  Google Scholar 

  8. Ishii K. Attenuation of lipopolysaccharide-induced acute lung injury after (pro)renin receptor blockade. Exp Lung Res. 2015;41:199–207.

    Article  CAS  PubMed  Google Scholar 

  9. Reed LJ. Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase. Science. 1951;114:93–4.

    Article  CAS  PubMed  Google Scholar 

  10. Jordan SW. A new metabolic link. The acyl carrier protein of lipid synthesis donates lipoic acid to the pyruvate dehydrogenase complex in Escherichia coli and mitochondria. J Biol Chem. 1997;272:17903–6.

    Article  CAS  PubMed  Google Scholar 

  11. Machado RS. Construction and properties of pyruvate dehydrogenase complexes with up to nine lipoyl domains per lipoate acetyltransferase chain. FEMS Microbiol Lett. 1992;79:243–8.

    Article  Google Scholar 

  12. Masuda T. Dihydrolipoyl histidinate zinc complex, a new antioxidant, attenuates hepatic ischemia-reperfusion injury in rats. J Gastroenterol Hepatol. 2011;26:1652–8.

    Article  CAS  PubMed  Google Scholar 

  13. Hagiwara S. New lipoic acid derivative drug sodium zinc dihydrolipoylhistidinate prevents cardiac dysfunction in an isolated perfused rat heart model. Crit Care Med. 2011;39:506–11.

    Article  CAS  PubMed  Google Scholar 

  14. Kono Y. Antiproliferative effects of a new α-lipoic acid derivative, DHL-HisZnNa, in HT29 human colon cancer cells in vitro. Expert Opin Ther Targets. 2012;16(Suppl 1):S103–9.

    Article  CAS  PubMed  Google Scholar 

  15. Morakinyo AO. Effects of alpha lipoic acid on blood lipids, renal indices, antioxidant enzymes, insulin and glucose level in streptozotocin-diabetic rats. Biology and Medicine. 2013;5:26–33.

    Google Scholar 

  16. Carrier B. Anti-obesity and lipid-lowering properties of alpha-lipoic acid. J Hum Nutr Food Sci. 2013;1:1002.

    Google Scholar 

  17. Han T. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012;167:465–71.

    Article  CAS  PubMed  Google Scholar 

  18. Xu Q. Meta-analysis of methylcobalamin alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. Diabetes Res Clin Pract. 2013;101:99–105.

    Article  CAS  PubMed  Google Scholar 

  19. Suh SH. Alpha-lipoic acid attenuates lipopolysaccharide-induced kidney injury. Clin Exp Nephrol. 2014;19:82–91.

    Article  PubMed  Google Scholar 

  20. Li G. Alpha-lipoic acid exerts anti-inflammatory effects on lipopolysaccharide-stimulated rat mesangial cells via inhibition of nuclear factor kappa B (NF-κB) signaling pathway. Inflammation. 2014;38:510–19.

    Article  Google Scholar 

  21. Ogata, K. WO World Intellectual Property Organisation Patent, WO 2004/024139 A1, 2004.  

  22. Chen J. Docosahexaenoic acid (DHA) attenuated paraquat induced lung damage in mice. Inhal Toxicol. 2013;25:9–16.

    Article  CAS  PubMed  Google Scholar 

  23. Liu MW. Protective effect of Xuebijing injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats. BMC Complement Altern Med. 2014;14:498.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sato N. Randomized study of the benefits of preoperative corticosteroid administration on the postoperative morbidity and cytokine response in patients undergoing surgery for esophageal cancer. Ann Surg. 2002;236:184–90.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ono S. Effects of neutrophil elastase inhibitor on progression of acute lung injury following esophagectomy. World J Surg. 2007;31:1996–2001.

    Article  PubMed  Google Scholar 

  26. Suda K. Neutrophil elastase inhibitor improves postoperative clinical courses after thoracic esophagectomy. Dis Esophagus. 2007;20:478–86.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang WJ. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J. 2001;15:2423–32.

    Article  CAS  PubMed  Google Scholar 

  28. Watanabe K. Rat CINC, a member of the interleukin-8 family, is a neutrophil-specific chemoattractant in vivo. Exp Mol Pathol. 1991;55:30–7.

    Article  CAS  PubMed  Google Scholar 

  29. Himi T. Production and gene expression of IL-8-like cytokine GRO/CINC-1 in rat nasal mucosa. Acta Otolaryngol. 1997;117:123–7.

    Article  CAS  PubMed  Google Scholar 

  30. Moine P. NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome. Shock. 2000;13:85–91.

    Article  CAS  PubMed  Google Scholar 

  31. Bachofen M. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis. 1977;116:589–615.

    Article  CAS  PubMed  Google Scholar 

  32. Matthay MA. The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol. 2011;6:147–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rittirsch D. Acute lung injury induced by lipopolysaccharide is independent of complement activation. J Immunol. 2008;180:7664–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hilary C. The role of MAPK in drug-induced kidney injury. J Signal Transduct. 2012;2012:463617.

    Google Scholar 

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Acknowledgements

The authors are grateful to Seigo Kitano, MD, PhD, FACS, the president of Oita University, for assisting in the study and its publication.

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Authors and Affiliations

  1. Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan

    Yoshiaki Shoji, Hiroya Takeuchi, Kazumasa Fukuda, Rieko Nakamura, Tsunehiro Takahashi, Norihito Wada, Hirofumi Kawakubo & Yuko Kitagawa

  2. Department of Surgery, School of Medicine, Hamamatsu University, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192, Japan

    Hiroya Takeuchi

  3. Division of Pulmonary Medicine, Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan

    Koichi Fukunaga & Tomoko Betsuyaku

  4. Department of Veterinary Science, School of Veterinary Medicine, Rakuno Gakuen University, 582, Bunkyo-dai, Midori-machi, Ebetsu, Hokkaido, 069-8501, Japan

    Taku Miyasho

  5. Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University, 1-1, Idaigaoka, Hazama-cho, Yufu-Shi, Oita Prefecture, 879-5593, Japan

    Takahiro Hiratsuka & Masafumi Inomata

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  1. Yoshiaki Shoji
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  2. Hiroya Takeuchi
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  9. Taku Miyasho
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  10. Takahiro Hiratsuka
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  11. Masafumi Inomata
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  12. Tomoko Betsuyaku
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  13. Yuko Kitagawa
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Corresponding author

Correspondence to Hiroya Takeuchi.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with The Keio University Institutional Animal Care and Use Committee (Approval Number: 08073).

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Responsible Editor: Yoshiya Tanaka.

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Shoji, Y., Takeuchi, H., Fukuda, K. et al. The alpha-lipoic acid derivative DHLHZn: a new therapeutic agent for acute lung injury in vivo. Inflamm. Res. 66, 803–811 (2017). https://doi.org/10.1007/s00011-017-1059-x

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  • DOI: https://doi.org/10.1007/s00011-017-1059-x

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