Advertisement

Molecular Medicine

, Volume 20, Issue 1, pp 676–683 | Cite as

AICAR Attenuates Organ Injury and Inflammatory Response after Intestinal Ischemia and Reperfusion

  • Juan-Pablo Idrovo
  • Weng-Lang Yang
  • Asha Jacob
  • Monowar Aziz
  • Jeffrey Nicastro
  • Gene F. Coppa
  • Ping Wang
Research Article

Abstract

Intestinal ischemia and reperfusion (I/R) is encountered in various clinical conditions and contributes to multiorgan failure and mortality as high as 60% to 80%. Intestinal I/R not only injures the intestine, but affects remote organs such as the lung leading to acute lung injury. The development of novel and effective therapies for intestinal I/R are critical for the improvement of patient outcome. AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) is a cell-permeable compound that has been shown to possess antiinflammatory effects. The objective is to determine that treatment with AICAR attenuates intestinal I/R injury and subsequent acute lung injury (ALI). Male Sprague Dawley rats (275 to 325 g) underwent intestinal I/R injury with blockage of the superior mesenteric artery for 90 min and subsequent reperfusion. At the initiation of reperfusion, vehicle or AICAR (30 mg/kg BW) was given intravenously (IV) for 30 min. At 4 h after reperfusion, blood and tissues were collected for further analyses. Treatment with AICAR significantly decreased the gut damage score and the water content, indicating improvement in histological integrity. The treatment also attenuated tissue injury and proinflammatory cytokines, and reduced bacterial translocation to the gut. AICAR administration after intestinal I/R maintained lung integrity, attenuated neutrophil chemotaxis and infiltration to the lungs and decreased lung levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6. Inflammatory mediators, lung-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, were decreased in the lungs and lung apoptosis was significantly reduced after AICAR treatment. These data indicate that AICAR could be developed as an effective and novel therapeutic for intestinal I/R and subsequent ALI.

Notes

Acknowledgments

This study was supported by the National Institutes of Health grants, R01 HL076179, R01 GM057468, and R01 GM053008 (to P Wang).

References

  1. 1.
    Tendler DA. (2003) Acute intestinal ischemia and infarction. Semin. Gastrointest. Dis. 14:66–76.PubMedGoogle Scholar
  2. 2.
    Yasuhara H. (2005) Acute mesenteric ischemia: the challenge of gastroenterology. Surg. Today. 35:185–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Carden DL, Granger DN. (2000) Pathophysiology of ischaemia-reperfusion injury. J. Pathol. 190:255–66.CrossRefPubMedGoogle Scholar
  4. 4.
    Granger DN, Korthuis RJ. (1995) Physiologic mechanisms of postischemic tissue injury. Annu. Rev. Physiol. 57:311–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Hassoun HT, et al. (2001) Post-injury multiple organ failure: the role of the gut. Shock 15:1–10.CrossRefPubMedGoogle Scholar
  6. 6.
    Kalia M, Sullivan JM. (1982) Brainstem projections of sensory and motor components of the vagus nerve in the rat. J. Comp. Neurol. 211:248–65.CrossRefPubMedGoogle Scholar
  7. 7.
    Kozar RA, et al. (2004) Superior mesenteric artery occlusion models shock-induced gut ischemiareperfusion. J. Surg. Res. 116:145–50.CrossRefPubMedGoogle Scholar
  8. 8.
    Mallick IH, Yang W, Winslet MC, Seifalian AM. (2004) Ischemia-reperfusion injury of the intestine and protective strategies against injury. Dig. Dis. Sci. 49:1359–77.CrossRefPubMedGoogle Scholar
  9. 9.
    Oldenburg WA, Lau LL, Rodenberg TJ, Edmonds HJ, Burger CD. (2004) Acute mesenteric ischemia: a clinical review. Arch. Intern. Med. 164:1054–62.CrossRefPubMedGoogle Scholar
  10. 10.
    Pierro A, Eaton S. (2004) Intestinal ischemia reperfusion injury and multisystem organ failure. Semin. Pediatr. Surg. 13:11–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Stallion A, et al. (2005) Ischemia/reperfusion: a clinically relevant model of intestinal injury yielding systemic inflammation. J. Pediatr. Surg. 40:470–7.CrossRefGoogle Scholar
  12. 12.
    Chen GY, Nunez G. (2010) Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10:826–37.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Eltzschig HK, Carmeliet P. (2011) Hypoxia and inflammation. N. Engl. J. Med. 364:656–65.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. (2009) Cell death. N. Engl. J. Med. 361:1570–83.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bamboat ZM, et al. (2010) Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion. J. Clin. Invest. 120:559–69.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Swirski FK, et al. (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 325:612–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Giri S, et al. (2004) 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J. Neurosci. 24:479–87.CrossRefPubMedGoogle Scholar
  18. 18.
    Jhun BS, et al. (2004) 5-Aminoimidazole-4-carboxamide riboside suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of phosphatidylinositol 3-kinase/Akt activation in RAW 264.7 murine macrophages. Biochem. Biophys. Res. Commun. 318:372–80.CrossRefPubMedGoogle Scholar
  19. 19.
    Bai A, et al. (2010) Novel anti-inflammatory action of 5-aminoimidazole-4-carboxamide ribonucleoside with protective effect in dextran sulfate sodium-induced acute and chronic colitis. J. Pharmacol. Exp. Ther. 333:717–25.CrossRefPubMedGoogle Scholar
  20. 20.
    Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press.Google Scholar
  21. 21.
    Dwivedi AJ, et al. (2007) Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion. J. Am. Coll. Surg. 205:284–93.CrossRefGoogle Scholar
  22. 22.
    Bachofen M, Weibel ER. (1982) Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin. Chest Med. 3:35–56.PubMedGoogle Scholar
  23. 23.
    Koike K, et al. (1994) Gut ischemia/reperfusion produces lung injury independent of endotoxin. Crit. Care Med. 22:1438–44.CrossRefPubMedGoogle Scholar
  24. 24.
    Berg RD, Garlington AW. (1979) Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect. Immun. 23:403–11.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Ware LB, Matthay MA. (2000) The acute respiratory distress syndrome. N. Engl. J. Med. 342:1334–49.CrossRefPubMedGoogle Scholar
  26. 26.
    Swank GM, Deitch EA. (1996) Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J. Surg. 20:411–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Ammori BJ, et al. (1999) Early increase in intestinal permeability in patients with severe acute pancreatitis: correlation with endotoxemia, organ failure, and mortality. J. Gastrointest. Surg. 3:252–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Faries PL, Simon RJ, Martella AT, Lee MJ, Machiedo GW. (1998) Intestinal permeability correlates with severity of injury in trauma patients. J. Trauma. 44:1031–5; discussion 1035–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Doig CJ, et al. (1998) Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients. Am. J. Respir. Crit. Care Med. 158:444–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Simpson R, et al. (1993) Neutrophil and nonneutrophil-mediated injury in intestinal ischemiareperfusion. Ann. Surg. 218:444–53; discussion 453–4.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gerkin TM, et al. (1992) Pulmonary endothelial cell ATP depletion following intestinal ischemia. J. Surg. Res. 52:642–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Schmeling DJ, Caty MG, Oldham KT, Guice KS, Hinshaw DB. (1989) Evidence for neutrophilrelated acute lung injury after intestinal ischemia-reperfusion. Surgery. 106:195–201; discussion 201–2.PubMedGoogle Scholar
  33. 33.
    Welbourn CR, et al. (1991) Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br. J. Surg. 78:651–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Davis KA, et al. (2001) Combination therapy that targets secondary pulmonary changes after abdominal trauma. Shock. 15:479–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Strassheim D, et al. (2004) Phosphoinositide 3-kinase and Akt occupy central roles in inflammatory responses of Toll-like receptor 2-stimulated neutrophils. J. Immunol. 172:5727–33.CrossRefPubMedGoogle Scholar
  36. 36.
    Asehnoune K, Strassheim D, Mitra S, Kim JY, Abraham E. (2004) Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J. Immunol. 172:2522–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Abraham E. (2003) Neutrophils and acute lung injury. Crit. Care Med. 31: S195–9.CrossRefGoogle Scholar
  38. 38.
    Abraham E, Carmody A, Shenkar R, Arcaroli J. (2000) Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 279: L1137–45.CrossRefPubMedGoogle Scholar
  39. 39.
    Hollingsworth JW, et al. (2005) The critical role of hematopoietic cells in lipopolysaccharide-induced airway inflammation. Am. J. Respir. Crit. Care Med. 171:806–13.CrossRefPubMedGoogle Scholar
  40. 40.
    Savov JD, Gavett SH, Brass DM, Costa DL, Schwartz DA. (2002) Neutrophils play a critical role in development of LPS-induced airway disease. Am. J. Physiol. LungCell. Mol. Physiol. 283:L952–62.CrossRefPubMedGoogle Scholar
  41. 41.
    Zhang F, Wu R, Zhou M, Blau SA, Wang P. (2009) Human adrenomedullin combined with human adrenomedullin binding protein-1 is protective in gut ischemia and reperfusion injury in the rat. Regul. Pept. 152:82–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Kim TB, et al. (2007) Five-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside attenuates poly (I:C)-induced airway inflammation in a murine model of asthma. Clin. Exp. Allergy. 37:1709–19.CrossRefPubMedGoogle Scholar
  43. 43.
    Nath N, et al. (2005) 5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J. Immunol. 175:566–74.CrossRefPubMedGoogle Scholar
  44. 44.
    Zhao X, et al. (2008) Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 295:L497–504.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Matthay MA, et al. (2003) Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. Am. J. Respir. Crit. Care Med. 167:1027–35.CrossRefPubMedGoogle Scholar
  46. 46.
    Perl M, et al. (2007) Fas-induced pulmonary apoptosis and inflammation during indirect acute lung injury. Am. J. Respir. Crit. Care Med. 176:591–601.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Huynh ML, Fadok VA, Henson PM. (2002) Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J. Clin. Invest. 109:41–50.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Suzuki J, et al. (2011) Inhibitory effect of aminoimidazole carboxamide ribonucleotide (AICAR) on endotoxin-induced uveitis in rats. Invest. Ophthalmol. Vis. Sci. 52:6565–71.CrossRefPubMedGoogle Scholar
  49. 49.
    Sag D, Carling D, Stout RD, Suttles J. (2008) Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181:8633–41.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sullivan JE, et al. (1994) Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 353:33–6.CrossRefGoogle Scholar
  51. 51.
    Kuo CL, Ho FM, Chang MY, Prakash E, Lin WW. (2008) Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase and cyclooxygenase-2 gene expression by 5-aminoimidazole-4-carboxamide riboside is independent of AMP-activated protein kinase. J. Cell. Biochem. 103:931–40.CrossRefPubMedGoogle Scholar
  52. 52.
    Labuzek K, Liber S, Gabryel B, Okopien B. (2010) AICAR (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside) increases the production of toxic molecules and affects the profile of cytokines release in LPS-stimulated rat primary microglial cultures. Neurotoxicology. 31:134–46.CrossRefPubMedGoogle Scholar
  53. 53.
    Qin S, Ni M, De Vries GW. (2008) Implication of S-adenosylhomocysteine hydrolase in inhibition of TNF-alpha- and IL-1beta-induced expression of inflammatory mediators by AICAR in RPE cells. Invest. Ophthalmol. Vis. Sci. 49:1274–81.CrossRefPubMedGoogle Scholar
  54. 54.
    Xing J, et al. (2013) Inhibition of AMP-activated protein kinase accentuates lipopolysaccharide-induced lung endothelial barrier dysfunction and lung injury in vivo. Am. J. Pathol. 182:1021–30.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Liu C, Liang B, Wang Q, Wu J, Zou MH. (2010) Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. J. Biol. Chem. 285:15346–55.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hallows KR, et al. (2006) Up-regulation of AMP-activated kinase by dysfunctional cystic fibrosis transmembrane conductance regulator in cystic fibrosis airway epithelial cells mitigates excessive inflammation. J. Biol. Chem. 281:4231–41.CrossRefPubMedGoogle Scholar
  57. 57.
    Li H, et al. (2010) Regulation of the creatine transporter by AMP-activated protein kinase in kidney epithelial cells. Am. J. Physiol. Renal Physiol. 299:F167–77.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Park DW, et al. (2013) Activation of AMPK enhances neutrophil chemotaxis and bacterial killing. Mol. Med. 19:387–98.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Juan-Pablo Idrovo
    • 1
  • Weng-Lang Yang
    • 1
    • 2
  • Asha Jacob
    • 1
    • 2
  • Monowar Aziz
    • 1
    • 2
  • Jeffrey Nicastro
    • 1
  • Gene F. Coppa
    • 1
  • Ping Wang
    • 1
    • 2
  1. 1.Department of SurgeryHofstra North Shore-LIJ School of MedicineHempsteadUSA
  2. 2.Center for Translational ResearchThe Feinstein Institute for Medical ResearchManhassetUSA

Personalised recommendations