Short-course Rapamycin Treatment Preserves Airway Epithelium and Protects Against Bronchiolitis Obliterans

Overview

Journal Ann Thorac Surg

Publisher Elsevier

Specialties General Surgery
Pulmonary Medicine

Date 2013 Jun 29

PMID 23806229

Citations 2

Authors

Jacob R Gillen

Yunge Zhao

David A Harris

Damien J LaPar

Irving L Kron

Christine L Lau

Affiliations

Soon will be listed here.

Abstract

Background: Damage to airway epithelium is closely related to the development of bronchiolitis obliterans (BO) in pulmonary transplantation. Rapamycin protects against BO development in a murine model, but its use in patients undergoing lung transplantation is limited by its side effects. We hypothesized that short-course rapamycin dosing could be used to prevent airway epithelium loss and protect against BO development in a murine model.

Methods: A total alloantigenic mismatch, murine, heterotopic tracheal transplant model of BO was used. Animals were treated with either rapamycin or dimethyl sulfoxide (controls) according to one of three treatment regimens: (1) days 1 through 14 after transplantation, (2) days 3 through 7 after transplantation, or (3) days 14 through 28 after transplantation. Epithelial loss was assessed by use of hematoxylin and eosin stains 14 and 28 days after transplantation. Tracheal luminal obliteration was assessed at 28 days.

Results: Early rapamycin treatment was protective against epithelial loss 14 days after transplantation in comparison with control animals (p < 0.001). Rapamycin treatment from days 1 to 14 was more effective at epithelial preservation (p = 0.002) and reducing luminal obliteration (p < 0.001) at 28 days than was rapamycin treatment from days 3 to 7. Late rapamycin treatment (days 14 to 28) allowed for recovery of the previously denuded epithelium at 28 days (92.5% epithelial loss to 35.6%) and a reduction in BO (p < 0.001).

Conclusions: Short-course rapamycin treatment protects against airway epithelium loss and subsequent development of BO in a murine model. Because of its immunosuppressive and antifibrotic effects, rapamycin may prove to be the ideal medication to prevent chronic rejection and BO in patients undergoing lung transplantation.

Citing Articles

Rapamycin prevents bronchiolitis obliterans through increasing infiltration of regulatory B cells in a murine tracheal transplantation model.

Zhao Y, Gillen J, Meher A, Burns J, Kron I, Lau C J Thorac Cardiovasc Surg. 2015; 151(2):487-96.e3.

PMID: 26481278 PMC: 4728002. DOI: 10.1016/j.jtcvs.2015.08.116.

Inducible costimulatory molecule deficiency induced imbalance of Treg and Th17/Th2 delays rejection reaction in mice undergoing allogeneic tracheal transplantation.

Xu J, Wu Y, Wang G, Qin Y, Zhu L, Tang G Am J Transl Res. 2015; 6(6):777-85.

PMID: 25628788 PMC: 4297345.

References

Phillips R, Burdick M, Hong K, Lutz M, Murray L, Xue Y . Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest. 2004; 114(3):438-46. PMC: 484979. DOI: 10.1172/JCI20997. View

Hele D, Yacoub M, Belvisi M . The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis. Respir Res. 2001; 2(3):169-83. PMC: 2002070. DOI: 10.1186/rr55. View

Wang Y, Hayward S, Cao M, Thayer K, Cunha G . Cell differentiation lineage in the prostate. Differentiation. 2002; 68(4-5):270-9. DOI: 10.1046/j.1432-0436.2001.680414.x. View

Lau C, Zhao Y, Kron I, Stoler M, Laubach V, Ailawadi G . The role of adenosine A2A receptor signaling in bronchiolitis obliterans. Ann Thorac Surg. 2009; 88(4):1071-8. PMC: 2782901. DOI: 10.1016/j.athoracsur.2009.06.032. View

Christie J, Edwards L, Kucheryavaya A, Benden C, Dobbels F, Kirk R . The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Lung and Heart-Lung Transplant Report--2011. J Heart Lung Transplant. 2011; 30(10):1104-22. DOI: 10.1016/j.healun.2011.08.004. View

ADAMS B, Brazelton T, Berry G, Morris R . The role of respiratory epithelium in a rat model of obliterative airway disease. Transplantation. 2000; 69(4):661-4. DOI: 10.1097/00007890-200002270-00031. View

Metz C . Fibrocytes: a unique cell population implicated in wound healing. Cell Mol Life Sci. 2003; 60(7):1342-50. PMC: 11138753. DOI: 10.1007/s00018-003-2328-0. View

Mehrad B, Burdick M, Strieter R . Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int J Biochem Cell Biol. 2009; 41(8-9):1708-18. PMC: 2681415. DOI: 10.1016/j.biocel.2009.02.020. View

Boehler A, Chamberlain D, Kesten S, Slutsky A, Liu M, Keshavjee S . Lymphocytic airway infiltration as a precursor to fibrous obliteration in a rat model of bronchiolitis obliterans. Transplantation. 1997; 64(2):311-7. DOI: 10.1097/00007890-199707270-00023. View

10.

Saunders R, Siddiqui S, Kaur D, Doe C, Sutcliffe A, Hollins F . Fibrocyte localization to the airway smooth muscle is a feature of asthma. J Allergy Clin Immunol. 2008; 123(2):376-384. PMC: 3992369. DOI: 10.1016/j.jaci.2008.10.048. View

11.

Genden E, Boros P, Liu J, Bromberg J, Mayer L . Orthotopic tracheal transplantation in the murine model. Transplantation. 2002; 73(9):1420-5. DOI: 10.1097/00007890-200205150-00010. View

12.

Ahya V, McShane P, Baz M, Valentine V, Arcasoy S, Love R . Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation. J Heart Lung Transplant. 2010; 30(2):175-81. DOI: 10.1016/j.healun.2010.08.010. View

13.

Harris D, Zhao Y, LaPar D, Emaminia A, Steidle J, Stoler M . Inhibiting CXCL12 blocks fibrocyte migration and differentiation and attenuates bronchiolitis obliterans in a murine heterotopic tracheal transplant model. J Thorac Cardiovasc Surg. 2012; 145(3):854-61. PMC: 3573249. DOI: 10.1016/j.jtcvs.2012.03.079. View

14.

Zhao Y, Steidle J, Upchurch G, Kron I, Lau C . Prevention of the second stage of epithelial loss is a potential novel treatment for bronchiolitis obliterans. J Thorac Cardiovasc Surg. 2012; 145(4):940-947.e1. PMC: 3602313. DOI: 10.1016/j.jtcvs.2012.07.098. View

15.

Pham P, Pham P, Danovitch G, Ross D, Gritsch H, Kendrick E . Sirolimus-associated pulmonary toxicity. Transplantation. 2004; 77(8):1215-20. DOI: 10.1097/01.tp.0000118413.92211.b6. View

16.

King-Biggs M, Dunitz J, Park S, Kay Savik S, Hertz M . Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation. 2003; 75(9):1437-43. DOI: 10.1097/01.TP.0000064083.02120.2C. View

17.

Frost A . Bronchiolitis obliterans: the Achilles heel of lung transplantation. Verh K Acad Geneeskd Belg. 2003; 64(5):303-19; discussion 319-22. View

18.

Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U . Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011; 377(9768):837-47. DOI: 10.1016/S0140-6736(10)62318-5. View

19.

Mehrad B, Burdick M, Zisman D, Keane M, Belperio J, Strieter R . Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun. 2006; 353(1):104-8. DOI: 10.1016/j.bbrc.2006.11.149. View

20.

Strieter R, Keeley E, Burdick M, Mehrad B . The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Trans Am Clin Climatol Assoc. 2009; 120:49-59. PMC: 2744511. View