Molecular Medicine

, Volume 17, Issue 11–12, pp 1323–1337 | Cite as

Histidine Decarboxylase Is Identified as a Potential Biomarker of Intestinal Mucosal Injury in Patients with Acute Intestinal Obstruction

  • Jian-Jun Yang
  • Yan-Lei Ma
  • Peng Zhang
  • Hong-Qi Chen
  • Zhi-Hua Liu
  • Huan-Long Qin
Research Article


Various biomarkers currently used for the diagnosis of intestinal mucosal injury (IMI) in patients with acute intestinal obstruction have low sensitivity and specificity. In the present study, IMI, as indicated by the impaired expression of tight junction proteins, including zonula occludens-1, occludin and claudin-1, and inflammation were determined in colonic tissues of patients with 45 strangulated intestinal obstruction (STR-IO) and the adjacent “normal” colonic tissues of 35 patients with colon cancers by quantitative real-time polymerase chain reaction (QRT-PCR), Western blotting, immunohistochemistry and histological examination, respectively. Then, two-dimensional fluorescent difference gel electrophoresis coupled with linear trap quadrupole mass spectrometry was used to screen for potential biomarkers of IMI in the serum samples of 10 STR-IO, 10 simple intestinal obstruction (SIM-IO) and 10 normal healthy controls. A total of 35 protein spots were differentially expressed among the serum samples, and six of the proteins were identified as potential biomarkers. Among the six proteins, histidine decarboxylase (HDC) and ceruloplasmin (CP) were elevated significantly in patients with STR-IO, compared with patients with SIM-IO and healthy controls. Thus, HDC and CP were further validated by QRT-PCR, Western blotting, immunohistochemistry and enzyme-linked immunosorbent assay, respectively, in colonic tissues, serum and urine samples. Finally, the receiver operating characteristic curves were used to show the area under the curves of HDC, CP and several established biomarkers, followed by the determination of the appropriate cutoff values and their sensitivities and specificities. It was shown that for serum and urine, HDC levels achieved sensitivities and specificities compatible to or even greater than those of established biomarkers for the diagnosis of IMI in patients with acute intestinal obstruction, although further validation in a larger cohort is required.



We are grateful to the staff in the Research Center for Proteome Analysis, Shanghai Institutes for Biological Sciences, for technical assistance and the staff in the Bioinformatics Center, Shanghai Institutes for Biological Sciences, for bioinformatic analysis. This work was supported by grants from the Shanghai Science and Technology Development Fund (05DJ14010), the Major Basic Research Program of Shanghai (07DZ19505) and the National 973 Basic Research Program of China (2008CB517403), Shanghai Rising-Star Program (No.11QA1404800) and the National Natural Science Foundation of China (No.81001069). We also thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript.

Supplementary material

10020_2011_17111323_MOESM1_ESM.pdf (120 kb)
Supplementary material, approximately 120 KB.


  1. 1.
    Bruewer M, Samarin S, Nusrat A. (2006) Inflammatory bowel disease and the apical junctional complex. Ann. N. Y. Acad. Sci. 1072:242–252.CrossRefGoogle Scholar
  2. 2.
    Gurleyik G, et al. (2003) Prostaglandins E1 and E2 analogues ameliorate mucosal injury secondary to distal colonic obstruction. J. Invest. Surg. 16:283–8.CrossRefGoogle Scholar
  3. 3.
    Chang T, Lu R, Tsai L. (2001) Glutamine ameliorates mechanical obstruction-induced intestinal injury. J. Surg. Res. 95:133–40.CrossRefGoogle Scholar
  4. 4.
    Costantini TW, et al. (2009) Role of p38 MAPK in burn-induced intestinal barrier breakdown. J. Surg. Res. 156:64–69.CrossRefGoogle Scholar
  5. 5.
    de Haan JJ, et al. (2009) Rapid development of intestinal cell damage following severe trauma: a prospective observational cohort study. Crit. Care. 13:R86.CrossRefGoogle Scholar
  6. 6.
    Jin W, et al. (2009) Transcription factor Nrf2 plays a pivotal role in protection against traumatic brain injury-induced acute intestinal mucosal injury in mice. J. Surg. Res. 157:251–60.CrossRefGoogle Scholar
  7. 7.
    Derikx JP, et al. (2008) Rapid reversal of human intestinal ischemia-reperfusion induced damage by shedding of injured enterocytes and reepithelialisation. PLoS One. 3:e3428.CrossRefGoogle Scholar
  8. 8.
    Guan Y, Worrell RT, Pritts TA, Montrose MH. (2009) Intestinal ischemia-reperfusion injury: reversible and irreversible damage imaged in vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 297:G187–96.CrossRefGoogle Scholar
  9. 9.
    Tunc T, et al. (2009) Erdosteine and ebselen as useful agents in intestinal ischemia/reperfusion injury. J. Surg. Res. 155:210–6.CrossRefGoogle Scholar
  10. 10.
    Zhang XP, Zhang J, Song QL, Chen HQ. (2007) Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier. J. Zhejiang Univ. Sci. B. 8:888–95.CrossRefGoogle Scholar
  11. 11.
    Rahman SH, Ammori BJ, Holmfield J, Larvin M, McMahon MJ. (2003) Intestinal hypoperfusion contributes to gut barrier failure in severe acute pancreatitis. J. Gastrointest. Surg. 7:26–36.CrossRefGoogle Scholar
  12. 12.
    Zhang X, et al. (2008) Study of the protective effects of dexamethasone on ileum mucosa injury in rats with severe acute pancreatitis. Pancreas. 37:e74–82.CrossRefGoogle Scholar
  13. 13.
    Grotz MR, et al. (1999) Intestinal cytokine response after gut ischemia: role of gut barrier failure. Ann. Surg. 229:478–86.CrossRefGoogle Scholar
  14. 14.
    Faries PL, Simon RJ, Martella AT, Lee MJ, Machiedo GW. (1998) Intestinal permeability correlates with severity of injury in trauma patients. J. Trauma. 44:1031–6.CrossRefGoogle Scholar
  15. 15.
    Swank GM, Deitch EA. (1996) Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J. Surg. 20:411–7.CrossRefGoogle Scholar
  16. 16.
    Jin W, et al. (2008) Increased intestinal inflammatory response and gut barrier dysfunction in Nrf2-deficient mice after traumatic brain injury. Cytokine. 44:135–40.CrossRefGoogle Scholar
  17. 17.
    Sarr MG, Bulkley GB, Zuidema GD. (1983) 1337 Pre-operative recognition of intestinal strangulation obstruction: prospective evaluation of diagnostic capability. Am. J. Surg. 145:176–82.CrossRefGoogle Scholar
  18. 18.
    Leffall LD, Syphax B. (1970) Clinical aids in strangulation intestinal obstruction. Am. J. Surg. 120:756–9.CrossRefGoogle Scholar
  19. 19.
    Murray MJ, Gonze MD, Nowak LR, Cobb CF. (1994) Serum D(−)-lactate levels as an aid to diagnosing acute intestinal ischemia. Am. J. Surg. 167:575–8.CrossRefGoogle Scholar
  20. 20.
    Poeze M. (1999) D-lactate as an early marker of intestinal ischaemia after ruptured abdominal aortic aneurysm repair: reply. Br. J. Surg. 86:712.CrossRefGoogle Scholar
  21. 21.
    Assadian A, et al. (2006) Plasma D-lactate as a potential early marker for colonic ischaemia after open aortic reconstruction. Eur. J. Vasc. Endovasc. Surg. 31:470–4.CrossRefGoogle Scholar
  22. 22.
    Delaney CP, O’Neill S, Manning F, Fitzpatrick JM, Gorey TF. (1999) Plasma concentrations of glutathione S-transferase isoenzyme are raised in patients with intestinal ischaemia. Br. J. Surg. 86:1349–53.CrossRefGoogle Scholar
  23. 23.
    Gearhart SL, et al. (2003) Prospective assessment of the predictive value of alpha-glutathione S-transferase for intestinal ischemia. Am. Surg. 69:324–9.PubMedGoogle Scholar
  24. 24.
    Cronk DR, et al. (2006) Intestinal fatty acid binding protein (I-FABP) for the detection of strangulated mechanical small intestinal obstruction. Curr. Surg. 63:322–5.CrossRefGoogle Scholar
  25. 25.
    Mittak M, Karlik T. (2008) Diagnostics of intestinal ischemia: influence of surgery on plasma levels of I-FABP as the marker of enterocyte injury. Rozhl. Chir. 87:16–20.PubMedGoogle Scholar
  26. 26.
    Acosta S, Nilsson TK, Bjorck M. (2004) D-dimer testing in patients with suspected acute thromboembolic occlusion of the superior mesenteric artery. Br. J. Surg. 91:991–4.CrossRefGoogle Scholar
  27. 27.
    Icoz G, et al. (2006) Is D-dimer a predictor of strangulated intestinal hernia? World J. Surg. 30:2165–9.CrossRefGoogle Scholar
  28. 28.
    Polk JD, et al. (2008) Clinical utility of the cobalt-albumin binding assay in the diagnosis of intestinal ischemia. J. Trauma. 64:42–5.CrossRefGoogle Scholar
  29. 29.
    Bounous G, Echave V, Vobecky SJ, Navert H, Wollin A. (1984) Acute necrosis of the intestinal mucosa with high serum levels of diamine oxidase. Dig. Dis. Sci. 29:872–4.CrossRefGoogle Scholar
  30. 30.
    Herrera Hernández MF, et al. (1989) Immunoreactive urinary thromboxane B2 in experimental mesenteric thrombosis in dogs. Rev. Invest. Clin. 41:123–7.PubMedGoogle Scholar
  31. 31.
    Tyers M, Mann M. (2003) From genomics to proteomics. Nature. 422:193–7.CrossRefGoogle Scholar
  32. 32.
    O’Farrell PH. (1975) High resolution two-dimensional electrophoresis of proteins. J. Biol. Chem. 250:4007–21.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Unlu M, Morgan ME, Minden JS. (1997) Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis. 18:2071–7.CrossRefGoogle Scholar
  34. 34.
    Tonge R, et al. (2001) Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology. Proteomics. 1:377–96.CrossRefGoogle Scholar
  35. 35.
    Van den Bergh G, Arckens L. (2004) Fluorescent two-dimensional difference gel electrophoresis unveils the potential of gel-based proteomics. Curr. Opin. Biotechnol. 15:38–43.CrossRefGoogle Scholar
  36. 36.
    Yan JX, et al. (2002) Fluorescence two-dimensional difference gel electrophoresis and mass spectrometry based proteomic analysis of Escherichia coli. Proteomics. 2:1682–98.CrossRefGoogle Scholar
  37. 37.
    Zhou G, et al. (2002) 2D differential in-gel electrophoresis for the identification of esophageal scans cell cancer-specific protein markers. Mol. Cell. Proteomics. 1:117–24.CrossRefGoogle Scholar
  38. 38.
    Ma Y, et al. (2009) Searching for serum tumor markers for colorectal cancer using a 2-D DIGE approach. Electrophoresis. 30:2591–9.CrossRefGoogle Scholar
  39. 39.
    Rodriguez-Pineiro AM, Blanco-Prieto S, Sanchez-Otero N, Rodríguez-Berrocal FJ, de la Cadena MP. (2010) On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion. J. Proteomics. 73:1511–22.CrossRefGoogle Scholar
  40. 40.
    Zubaidah RM, et al. (2008) 2-D DIGE profiling of hepatocellular carcinoma tissues identified isoforms of far upstream binding protein (FUBP) as novel candidates in liver carcinogenesis. Proteomics. 8:5086–96.CrossRefGoogle Scholar
  41. 41.
    Zipplies JK, et al. (2010) Kininogen in autoimmune uveitis: decrease in peripheral blood stream versus increase in target tissue. Invest. Ophthalmol. Vis. Sci. 51:375–82.CrossRefGoogle Scholar
  42. 42.
    Tumani H, et al. (2009) Candidate biomarkers of chronic inflammatory demyelinating polyneuropathy (CIDP): proteome analysis of cerebrospinal fluid. J. Neuroimmunol. 214:109–12.CrossRefGoogle Scholar
  43. 43.
    English JA, Dicker P, Focking M, Dunn MJ, Cotter DR. (2009) 2-D DIGE analysis implicates cytoskeletal abnormalities in psychiatric disease. Proteomics. 9:3368–82.CrossRefGoogle Scholar
  44. 44.
    Grzeskowiak JK, et al. (2009) 2-D DIGE to expedite downstream process development for human monoclonal antibody purification. Protein Expr. Purif. 66:58–65.CrossRefGoogle Scholar
  45. 45.
    Seneviratne CJ, Wang Y, Jin L, Abiko Y, Samaranayake LP. (2010) Proteomics of drug resistance in Candida glabrata biofilms. Proteomics. 10:1444–54.CrossRefGoogle Scholar
  46. 46.
    Faca VM, et al. (2008) A mouse to human search for plasma proteome changes associated with pancreatic tumor development. PLoS Med. 5:e123.CrossRefGoogle Scholar
  47. 47.
    Ma YL, et al. (2009) Heterogeneous nuclear ribonucleoprotein A1 is identified as a potential biomarker for colorectal cancer based on differential proteomics technology. J. Proteome Res. 8:4525–35.CrossRefGoogle Scholar
  48. 48.
    Ma Y, et al. (2009) Proteomics identification of desmin as a potential oncofetal diagnostic and prognostic biomarker in colorectal cancer. Mol. Cell Proteomics. 8:1878–90.CrossRefGoogle Scholar
  49. 49.
    Liu W, et al. (2010) Identification of HSP27 as a potential tumor marker for colorectal cancer by the two-dimensional polyacrylamide gel electrophoresis. Mol. Biol. Rep. 37:3207–16.CrossRefGoogle Scholar
  50. 50.
    Peng J, et al. (2009) A rat-to-human search for proteomic alterations reveals transgelin as a biomarker relevant to colorectal carcinogenesis and liver metastasis. Electrophoresis. 30:2976–87.CrossRefGoogle Scholar
  51. 51.
    Thomas CE, Sexton W, Benson K, Sutphen R, Koomen J. (2010) Urine collection and processing for protein biomarker discovery and quantification. Cancer Epidemiol. Biomarkers Prev. 19:953–9.CrossRefGoogle Scholar
  52. 52.
    Gamagedara S, Gibbons S, Ma Y. (2011) Investigation of urinary pteridine levels as potential biomarkers for noninvasive diagnosis of cancer. Clin. Chim. Acta. 412:120–8.CrossRefGoogle Scholar
  53. 53.
    Alban A, et al. (2003) A novel experimental design for comparative two-dimensional gel analysis: two-dimensional difference gel electrophoresis incorporating a pooled internal standard. Proteomics. 3:36–44.CrossRefGoogle Scholar
  54. 54.
    Berg DJ, et al. (1996) Enterocolitis and colonic cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J. Clin. Invest. 98:1010–20.CrossRefGoogle Scholar
  55. 55.
    Martin B. (2007) Prevention of gastrointestinal complications in the critically ill patient. ASACN Adv. Crit. Care. 18:158–66.Google Scholar
  56. 56.
    Wang N, et al. (2010) Evidence for tight junction protein disruption in intestinal mucosa of malignant obstructive jaundice patients. Scand. J. Gastroenterol. 45:191–9.CrossRefGoogle Scholar
  57. 57.
    Roxas JL, et al. (2010) Enterohemorrhagic E. coli alters murine intestinal epithelial tight junction protein expression and barrier function in a Shiga toxin independent manner. Lab. Invest. 90:1152–68.CrossRefGoogle Scholar
  58. 58.
    McCall IC, et al. (2009) Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization. Toxicol. Appl. Pharmacol. 241:61–70.CrossRefGoogle Scholar
  59. 59.
    Qin H, Zhang Z, Hang X, Jiang Y. (2009) L. plantarum prevents enteroinvasive Escherichia coli-induced tight junction proteins changes in intestinal epithelial cells. BMC Microbiol. 9:63.CrossRefGoogle Scholar
  60. 60.
    Perkins NJ, Schisterman EF. (2006) The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am. J. Epidemiol. 163:670–5.CrossRefGoogle Scholar
  61. 61.
    Schisterman EF, Faraggi D, Reiser B. (2004) Adjusting the generalized ROC curve for covariates. Stat. Med. 23:3319–31.CrossRefGoogle Scholar
  62. 62.
    Evennett NJ, Petrov MS, Mittal A, Windsor JA. (2009) Systematic review and pooled estimates for the diagnostic accuracy of serological markers for intestinal ischemia. World J. Surg. 33:1374–83.CrossRefGoogle Scholar
  63. 63.
    Handley SA, Dube PH, Miller VL. (2006) Histamine signaling through the H-2 receptor in the Peyer’s patch is important for controlling Yersinia enterocolitica infection. Proc. Natl. Acad. Sci. U S A. 103:9268–73.CrossRefGoogle Scholar
  64. 64.
    Kahlson G, Rosengren E. (1968) New approaches to the physiology of histamine. Physiol. Rev. 48:155–96.CrossRefGoogle Scholar
  65. 65.
    Fujimoto K, et al. (1992) Histamine and histidine decarboxylase are correlated with mucosal repair in rat small intestine after ischemia-reperfusion. J. Clin. Invest. 89:126–33.CrossRefGoogle Scholar
  66. 66.
    Mei Q, Sundler F. (1999) Local downregulation of enterochromaffin-like cell histamine formation in ulcer healing: a study in rats. Digestion. 60:227–37.CrossRefGoogle Scholar
  67. 67.
    Wu ZD, Wu ZH. (2004) Surgery. Beijing, China; People’s Medical Publishing House.Google Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Jian-Jun Yang
    • 1
  • Yan-Lei Ma
    • 1
  • Peng Zhang
    • 1
  • Hong-Qi Chen
    • 1
  • Zhi-Hua Liu
    • 1
  • Huan-Long Qin
    • 1
  1. 1.Department of SurgeryThe Sixth People’s Hospital Affiliated to Shanghai Jiao Tong UniversityShanghaiP.R. China

Personalised recommendations