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Published ahead of print on October 30, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2009-0208OC
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Submitted on June 14, 2009
Accepted on October 29, 2009

Mechanisms behind Local Immunosuppression Using Inhaled Tacrolimus in Preclinical Models of Lung Transplantation

Tobias Deuse1, Francis Blankenberg2, Munif Haddad3, Hermann Reichenspurner4, Neil Phillips5, Robert C Robbins1, and Sonja Schrepfer1*

1 Cardiothoracic Surgery, Stanford University, Stanford, California, United States, 2 Radiology, Stanford University, Stanford, California, United States, 3 Clinical Chemistry, University Heart Center Hamburg, Hamburg, Germany, 4 Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany, 5 Pediatrics, Division of Human Gene Therapy, Stanford University, Stanford, California, United States

* To whom correspondence should be addressed. E-mail: schrepfer{at}stanford.edu.

Background: Inhaled immunosuppression with tacrolimus (TAC) is a novel strategy after lung transplantation. Here we investigate the feasibility of tacrolimus delivery via aerosol, assess its immunosuppressive efficacy, reveal possible mechanisms of action, and evaluate its airway toxicity. Material and Methods: Rats received 4mg/kg TAC via oral (PO) or inhaled administration (AER). Pharmacokinetic properties were compared and in vivo airway toxicity was assessed. Full-thickness human airway epithelium (AE) was grown in vitro at air-liquid interface. Equal TAC doses (10-1000ng) were either added to the bottom chamber (MED) or aerosolized for gas phase exposure (AER). AE TAC absorption, cell toxicity, and the interaction of TAC with NF{kappa}B activation were studied. Results: SPECT imaging demonstrated a linear tracer accumulation within the lungs during TAC inhalation. TAC AER generated higher lung tissue levels, but 11-times lower blood levels. Airway histology and gene expression did not reveal drug toxicity after 3 weeks of treatment. In vitro AE exposed to TAC 10-1000ng PO or AER maintained its pseudostratified morphology, did not show cell toxicity, and maintained its epithelial integrity with tight junction formation. TAC AER-treated AE absorbed the drug from their apical surface and generated lower-chamber TAC concentrations sufficient to suppress activated lymphocytes. TAC AER, better than TAC MED, prevented AE IFN-{gamma}, IL-10, IL-13, MCP-1, RANTES, and TNF-{alpha} up-regulation. TAC was found to inhibit airway epithelial cell NF{kappa}B activation. Conclusions: TAC can easily and effectively be delivered into the lungs without causing airway toxicity and decreases inflammatory AE cytokine production via inhibition of NF{kappa}B activation.


Key words: inhaled immunosuppression • lung transplantation • tacrolimus • NFkb






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