Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation

S. N. Mitruka, S. M. Pham, A. Zeevi, S. Li, J. Cai, G. J. Burckart, S. A. Yousem, R. J. Keenan, B. P. Griffith, N. K. Altorki, C. M. Wei, W. A. Cook, Robert Dowling

Research output: Contribution to journalArticle

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Abstract

Background: The incidence of acute rejection and the morbidity of systemic cyclosporine (INN: ciclosporin) after lung transplantation is significant. Experimental evidence suggests that the allograft locally modulates the immune mechanisms of acute rejection. The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the inflammatory cytokines involved in acute rejection. Methods: Unilateral orthotopic left lung transplantation was performed in 64 rats (ACI to Lewis), which were divided into eight groups (each group, n = 8): group A, no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per day, respectively; groups E to H, systemic cyclosporine 2, 5, 10, and 15 mg/kg per day, respectively. After the animals were killed on postoperative day 2, 4, or 6, the transplanted lung, native lung, spleen, and blood were collected. Histologic studies, high- pressure liquid chromatography for trough cyclosporine concentrations, and reverse-transcriptase polymerase chain reaction for cytokine gene expression were performed. Results: Untreated animals showed grade 4 rejection by postoperative day 6. Aerosol cyclosporine prevented acute rejection in a dose-dependent fashion, with group D animals (3 mg/kg per day) showing minimal grade 1 changes. Among animals receiving systemic cyclosporine, only group H (15 mg/kg per day) controlled (grade 1) rejection. However, aerosol cyclosporine, at an 80% lower dose, achieved significantly lower concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/mg, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in the blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection. Reverse-transcriptase polymerase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of interleukin-6, interleukin-10, and interferon-γ, in group D versus group H recipient allografts. Conclusion: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allograft rejection. Effective graft levels and low systemic drug delivery required significantly lower doses than systemic therapy alone. The gene expression of proinflammatory cytokines involved in allograft rejection was suppressed by aerosol cyclosporine therapy.

Original languageEnglish (US)
Pages (from-to)28-37
Number of pages10
JournalJournal of Thoracic and Cardiovascular Surgery
Volume115
Issue number1
DOIs
StatePublished - Jan 1 1998

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Lung Transplantation
Aerosols
Cyclosporine
Allografts
Cytokines
Reverse Transcriptase Polymerase Chain Reaction
Transplants
Lung
Inbred ACI Rats
Gene Expression
Nitric Oxide Synthase Type II
Pharmaceutical Preparations
Interleukin-10
Interferons
Inhalation
Interleukin-6
Spleen
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Mitruka, S. N. ; Pham, S. M. ; Zeevi, A. ; Li, S. ; Cai, J. ; Burckart, G. J. ; Yousem, S. A. ; Keenan, R. J. ; Griffith, B. P. ; Altorki, N. K. ; Wei, C. M. ; Cook, W. A. ; Dowling, Robert. / Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation. In: Journal of Thoracic and Cardiovascular Surgery. 1998 ; Vol. 115, No. 1. pp. 28-37.
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abstract = "Background: The incidence of acute rejection and the morbidity of systemic cyclosporine (INN: ciclosporin) after lung transplantation is significant. Experimental evidence suggests that the allograft locally modulates the immune mechanisms of acute rejection. The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the inflammatory cytokines involved in acute rejection. Methods: Unilateral orthotopic left lung transplantation was performed in 64 rats (ACI to Lewis), which were divided into eight groups (each group, n = 8): group A, no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per day, respectively; groups E to H, systemic cyclosporine 2, 5, 10, and 15 mg/kg per day, respectively. After the animals were killed on postoperative day 2, 4, or 6, the transplanted lung, native lung, spleen, and blood were collected. Histologic studies, high- pressure liquid chromatography for trough cyclosporine concentrations, and reverse-transcriptase polymerase chain reaction for cytokine gene expression were performed. Results: Untreated animals showed grade 4 rejection by postoperative day 6. Aerosol cyclosporine prevented acute rejection in a dose-dependent fashion, with group D animals (3 mg/kg per day) showing minimal grade 1 changes. Among animals receiving systemic cyclosporine, only group H (15 mg/kg per day) controlled (grade 1) rejection. However, aerosol cyclosporine, at an 80{\%} lower dose, achieved significantly lower concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/mg, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in the blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection. Reverse-transcriptase polymerase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of interleukin-6, interleukin-10, and interferon-γ, in group D versus group H recipient allografts. Conclusion: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allograft rejection. Effective graft levels and low systemic drug delivery required significantly lower doses than systemic therapy alone. The gene expression of proinflammatory cytokines involved in allograft rejection was suppressed by aerosol cyclosporine therapy.",
author = "Mitruka, {S. N.} and Pham, {S. M.} and A. Zeevi and S. Li and J. Cai and Burckart, {G. J.} and Yousem, {S. A.} and Keenan, {R. J.} and Griffith, {B. P.} and Altorki, {N. K.} and Wei, {C. M.} and Cook, {W. A.} and Robert Dowling",
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Mitruka, SN, Pham, SM, Zeevi, A, Li, S, Cai, J, Burckart, GJ, Yousem, SA, Keenan, RJ, Griffith, BP, Altorki, NK, Wei, CM, Cook, WA & Dowling, R 1998, 'Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation', Journal of Thoracic and Cardiovascular Surgery, vol. 115, no. 1, pp. 28-37. https://doi.org/10.1016/S0022-5223(98)70439-8

Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation. / Mitruka, S. N.; Pham, S. M.; Zeevi, A.; Li, S.; Cai, J.; Burckart, G. J.; Yousem, S. A.; Keenan, R. J.; Griffith, B. P.; Altorki, N. K.; Wei, C. M.; Cook, W. A.; Dowling, Robert.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 115, No. 1, 01.01.1998, p. 28-37.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation

AU - Mitruka, S. N.

AU - Pham, S. M.

AU - Zeevi, A.

AU - Li, S.

AU - Cai, J.

AU - Burckart, G. J.

AU - Yousem, S. A.

AU - Keenan, R. J.

AU - Griffith, B. P.

AU - Altorki, N. K.

AU - Wei, C. M.

AU - Cook, W. A.

AU - Dowling, Robert

PY - 1998/1/1

Y1 - 1998/1/1

N2 - Background: The incidence of acute rejection and the morbidity of systemic cyclosporine (INN: ciclosporin) after lung transplantation is significant. Experimental evidence suggests that the allograft locally modulates the immune mechanisms of acute rejection. The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the inflammatory cytokines involved in acute rejection. Methods: Unilateral orthotopic left lung transplantation was performed in 64 rats (ACI to Lewis), which were divided into eight groups (each group, n = 8): group A, no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per day, respectively; groups E to H, systemic cyclosporine 2, 5, 10, and 15 mg/kg per day, respectively. After the animals were killed on postoperative day 2, 4, or 6, the transplanted lung, native lung, spleen, and blood were collected. Histologic studies, high- pressure liquid chromatography for trough cyclosporine concentrations, and reverse-transcriptase polymerase chain reaction for cytokine gene expression were performed. Results: Untreated animals showed grade 4 rejection by postoperative day 6. Aerosol cyclosporine prevented acute rejection in a dose-dependent fashion, with group D animals (3 mg/kg per day) showing minimal grade 1 changes. Among animals receiving systemic cyclosporine, only group H (15 mg/kg per day) controlled (grade 1) rejection. However, aerosol cyclosporine, at an 80% lower dose, achieved significantly lower concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/mg, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in the blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection. Reverse-transcriptase polymerase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of interleukin-6, interleukin-10, and interferon-γ, in group D versus group H recipient allografts. Conclusion: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allograft rejection. Effective graft levels and low systemic drug delivery required significantly lower doses than systemic therapy alone. The gene expression of proinflammatory cytokines involved in allograft rejection was suppressed by aerosol cyclosporine therapy.

AB - Background: The incidence of acute rejection and the morbidity of systemic cyclosporine (INN: ciclosporin) after lung transplantation is significant. Experimental evidence suggests that the allograft locally modulates the immune mechanisms of acute rejection. The purpose of this study was to determine whether aerosolized cyclosporine would prevent acute cellular rejection, achieve effective graft concentrations with low systemic drug delivery, and locally affect production of the inflammatory cytokines involved in acute rejection. Methods: Unilateral orthotopic left lung transplantation was performed in 64 rats (ACI to Lewis), which were divided into eight groups (each group, n = 8): group A, no treatment; groups B to D, aerosol cyclosporine 1 to 3 mg/kg per day, respectively; groups E to H, systemic cyclosporine 2, 5, 10, and 15 mg/kg per day, respectively. After the animals were killed on postoperative day 2, 4, or 6, the transplanted lung, native lung, spleen, and blood were collected. Histologic studies, high- pressure liquid chromatography for trough cyclosporine concentrations, and reverse-transcriptase polymerase chain reaction for cytokine gene expression were performed. Results: Untreated animals showed grade 4 rejection by postoperative day 6. Aerosol cyclosporine prevented acute rejection in a dose-dependent fashion, with group D animals (3 mg/kg per day) showing minimal grade 1 changes. Among animals receiving systemic cyclosporine, only group H (15 mg/kg per day) controlled (grade 1) rejection. However, aerosol cyclosporine, at an 80% lower dose, achieved significantly lower concentrations of cyclosporine in the graft (12,349 vs 28,714 ng/mg, p = 0.002004) and blood (725 vs 3306 ng/ml, p = 0.000378). Group F (systemic 5 mg/kg per day) had higher cyclosporine concentrations in the blood than group D (p = 0.004572) and similar tissue concentrations (p = 0.115180), yet had grade 2 rejection. Reverse-transcriptase polymerase chain reaction demonstrated equivalent suppression of inducible nitric oxide synthase but a 20- to 25-fold higher expression of interleukin-6, interleukin-10, and interferon-γ, in group D versus group H recipient allografts. Conclusion: Local delivery of cyclosporine by aerosol inhalation dose-dependently prevented acute pulmonary allograft rejection. Effective graft levels and low systemic drug delivery required significantly lower doses than systemic therapy alone. The gene expression of proinflammatory cytokines involved in allograft rejection was suppressed by aerosol cyclosporine therapy.

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