Skip to main content

Advertisement

SpringerLink
Log in

Chemokine upregulation in response to anal sphincter and pudendal nerve injury: potential signals for stem cell homing

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

Stromal derived factor-1 (SDF-1) and monocyte chemotactic protein-3 (MCP-3) are signals forcing the migration of bone marrow-derived stem cells to ischemic tissue. This study investigates SDF-1 and MCP-3 expression following direct injury to the anal sphincter and pudendal nerve and to determine if these same mechanisms have any role.

Methods

Chemokine expression was studied after anal sphincter injury in female rats after either a sphincterotomy (n = 15), pudendal nerve crush (PNC; n = 15), sham pudendal nerve crush (n = 15), or acted as unmanipulated controls (n = 5). Analysis was done at 1 h and 10 and 21 days after injury.

Results

After injury, SDF-1 expression increased 40.2 ± 6.42 (P = 0.01) at 1 h and 28.2 ± 2.37 (P = 0.01) at 10 days, respectively, compared to controls. Likewise, MCP-3 expression increased 40.8 ± 8.17 (P = 0.02) at the same intervals compared to controls. After PNC, SDF-1 expression increased 46.4 ± 6.01 (P = 0.02) and 50.6 ± 10.11 (P = 0.01), and MCP-3 expression increased 46.3 ± 7.76 (P = 0.03) and 190.8 ± 22.15 (P = 0.01), respectively, at the same time intervals compared to controls. However, when PNC was compared to sham injured, a significant increase was seen in SDF-1 and MCP-3 at 10 days. At 21 days, PNC compared to sham injured was significantly low in expression for both SDF-1 and MCP-3 (P < 0.05).

Conclusions

Direct anal sphincter injury results in higher levels of SDF-1 and MCP-3 expression soon after injury, whereas denervation via pudendal nerve crush results in greater SDF-1 and MCP-3 expression 10 days after injury. Chemokine overexpression suggests the potential for cell-based therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Thornton M, Lubowski D (2006) Obstetric-induced incontinence: a black hole of preventable morbidity. Aust N Z J Obstet Gynaecol 46:468–473

    Article  PubMed  Google Scholar 

  2. Wang A, Guess M, Connell K et al (2006) Fecal incontinence: a review of prevalence and obstetric risk factors. Int Urogynecol J Pelvic Floor Dysfunct 17:253–260

    Article  PubMed  CAS  Google Scholar 

  3. Fernando R, Sultan AH, Kettle C et al (2006) Methods of repair for obstetric anal sphincter injury. Cochrane Database of Syst Rev 3:CD002866

    CAS  Google Scholar 

  4. Malouf AJ, Chambers MG, Kamm MA (2001) Clinical and economic evaluation of surgical treatments for faecal incontinence. Br J Surg 88:1029–1036

    Article  PubMed  CAS  Google Scholar 

  5. White FA, Bhangoo SK, Miller RJ (2005) Chemokines: integrators of pain and inflammation. Nat Rev Drug Discov 4:834–844

    Article  PubMed  CAS  Google Scholar 

  6. Luster AD (1998) Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med 338:436–445

    Article  PubMed  CAS  Google Scholar 

  7. Schenk S, Mal N, Finan A et al (2007) Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells 25:245–251

    Article  PubMed  CAS  Google Scholar 

  8. Zhang M, Mal N, Kiedrowski M et al (2007) SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. Faseb J 21:3197–3207

    Article  PubMed  CAS  Google Scholar 

  9. Penn MS, Khalil MK (2008) Exploitation of stem cell homing for gene delivery. Expert Opin Biol Ther 8:17–30

    Article  PubMed  CAS  Google Scholar 

  10. Penn MS, Francis GS, Ellis SG et al (2002) Autologous cell transplantation for the treatment of damaged myocardium. Prog Cardiovasc Dis 45:21–32

    Article  PubMed  Google Scholar 

  11. Penn MS (2009) Importance of the SDF-1:CXCR4 axis in myocardial repair. Circ Res 104:1133–1135

    Article  PubMed  CAS  Google Scholar 

  12. Woo LL, Hijaz A, Kuang M et al (2007) Over expression of stem cell homing cytokines in urogenital organs following vaginal distention. J Urol 177:1568–1572

    Article  PubMed  CAS  Google Scholar 

  13. Zutshi M, Salcedo L, Hui P et al (2009) Rat anal sphincter physiology after pudendal nerve transection and sphincterotomy. Dis Colon Rectum 52:1321–1329

    Article  PubMed  Google Scholar 

  14. Damaser MS, Broxton-King C, Ferguson C et al (2003) Functional and neuroanatomical effects of vaginal distention and pudendal nerve crush in the female rat. J Urol 170:1027–1031

    Article  PubMed  Google Scholar 

  15. Yin JL, Shackel NA, Zekry A et al (2001) Real-time reverse transcriptase–polymerase chain reaction (RT-PCR) for measurement of cytokine and growth factor mRNA expression with fluorogenic probes or SYBR Green I. Immunol Cell Biol 79:213–221

    Article  PubMed  CAS  Google Scholar 

  16. Dudding TC, Vaizey CJ, Kamm MA (2008) Obstetric anal sphincter injury—incidence, risk factors, and management. Ann Surg 247:224–237

    Article  PubMed  Google Scholar 

  17. Handa VL, Zyczynski HM, Burgio KL et al (2007) The impact of fecal and urinary incontinence on quality of life 6 months after childbirth. Am J Obstet Gynecol 197:636.e1–636.e6

    Article  Google Scholar 

  18. Crowell MD, Schettler VA, Lacy BE et al (2007) Impact of anal incontinence on psychosocial function and health-related quality of life. Dig Dis Sci 52:1627–1631

    Article  PubMed  Google Scholar 

  19. Eogan M, O'Herlihy C (2006) Diagnosis and management of obstetric anal sphincter injury. Curr Opin Obstet Gynecol 18:141–146

    Article  PubMed  Google Scholar 

  20. Fitzgerald MP, Weber AM, Howden N et al (2007) Risk factors for anal sphincter tear during vaginal delivery. Obstet Gynecol 109:29–34

    Article  PubMed  Google Scholar 

  21. Lien KC, Morgan DM, Delancey JOL et al (2005) Pudendal nerve stretch during vaginal birth: a 3D computer simulation. Am J Obstet Gynecol 192:1669–1676

    Article  PubMed  Google Scholar 

  22. Safioleas M, Andromanakos N, Lygidakis N (2008) Anorectal incontinence: therapeutic strategy of a complex surgical problem. Hepatogastroenterology 55:1320–1326

    PubMed  CAS  Google Scholar 

  23. Schiedeck THK (2008) Diagnosis and therapy of stool incontinence. Chirurg 79:379–388

    Article  PubMed  CAS  Google Scholar 

  24. Halverson AL, Hull TL (2002) Long-term outcome of overlapping anal sphincter repair. Dis Colon Rectum 45:345–348

    Article  PubMed  Google Scholar 

  25. de Paula PR, Matos D, Franco M et al (2004) Why do anal wounds heal adequately? A study of the local immunoinflammatory defense mechanisms. Dis Colon Rectum 47:1861–1867

    Article  PubMed  Google Scholar 

  26. Rosenkilde MM, Schwartz TW (2004) The chemokine system—a major regulator of angiogenesis in health and disease. APMIS 112:481–495

    Article  PubMed  CAS  Google Scholar 

  27. Nath C, Gulati SC (1998) Role of cytokines in healing chronic skin wounds. Acta Haematol 99:175–179

    Article  PubMed  CAS  Google Scholar 

  28. Spadaro JA (1997) Mechanical and electrical interactions in bone remodeling. Bioelectromagnetics 18:193–202

    Article  PubMed  CAS  Google Scholar 

  29. Aloisi F, Columba-Cabezas S, Franciotta D et al (2008) Lymphoid chemokines in chronic neuroinflammation. J Neuroimmunol 198:106–112

    Article  PubMed  CAS  Google Scholar 

  30. Khatami M (2008) 'Yin and Yang' in inflammation: duality in innate immune cell function and tumorigenesis. Expert Opin Biol Ther 8:1461–1472

    Article  PubMed  CAS  Google Scholar 

  31. Liu C, Papewalis C, Domberg J et al (2008) Chemokines and autoimmune thyroid diseases. Horm Metab Res 40:361–368

    Article  PubMed  CAS  Google Scholar 

  32. Rovin BH (2008) The chemokine network in systemic lupus erythematous nephritis. Front Biosci 13:904–922

    Article  PubMed  CAS  Google Scholar 

  33. Shames BD, Zallen GS, McIntyre RC et al (2000) Chemokines as mediators of diseases related to surgical conditions. Shock 14:1–7

    Article  PubMed  CAS  Google Scholar 

  34. Miller RJ, Tran PB (2005) Chemokinetics. Neuron 47:621–623

    Article  PubMed  CAS  Google Scholar 

  35. Jiang HH, Pan HQ, Gustilo-Ashby MA et al (2009) Dual simulated childbirth injuries result in slowed recovery of pudendal nerve and urethral function. Neurourol Urodyn 28:229–235

    Article  PubMed  Google Scholar 

  36. Wai CY, Rahn DD, White AB et al (2008) Recovery of external anal sphincter contractile function after prolonged vaginal distention or sphincter transection in an animal model. Obstet Gynecol 111:1426–1434

    Article  PubMed  Google Scholar 

  37. Deister C, Schmidt CE (2006) Optimizing neurotrophic factor combinations for neurite outgrowth. J Neural Eng 3:172–179

    Article  PubMed  CAS  Google Scholar 

  38. English AW (2003) Cytokines, growth factors and sprouting at the neuromuscular junction. J Neurocytol 32:943–960

    Article  PubMed  CAS  Google Scholar 

  39. Chang CH, Rossi EA, Goldenberg DM (2007) The dock and lock method: a novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity. Clin Cancer Res 13:5586S–5591S

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Department of Colorectal Surgery, Research Protocol Committee of the Cleveland Clinic, Department of Biomedical Engineering, and the Stem Cell Biology and Regenerative Medicine. The authors would like to thank Brian Balog and Matthew Kiedrowski for their assistance and expertise.

Author information

Authors and Affiliations

  1. Department of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    Levilester Salcedo & Massarat Zutshi

  2. Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH, USA

    Hai-Hong Jiang & Margot Damaser

  3. Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA

    Nikolai Sopko & Marc Penn

Authors
  1. Levilester Salcedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikolai Sopko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hai-Hong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margot Damaser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marc Penn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Massarat Zutshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massarat Zutshi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Salcedo, L., Sopko, N., Jiang, HH. et al. Chemokine upregulation in response to anal sphincter and pudendal nerve injury: potential signals for stem cell homing. Int J Colorectal Dis 26, 1577–1581 (2011). https://doi.org/10.1007/s00384-011-1269-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-011-1269-6

Keywords

Search

Navigation