Mechanisms behind Local Immunosuppression Using Inhaled Tacrolimus in Preclinical Models of Lung Transplantation
2010
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. Rats received 4 mg/kg TAC via oral or inhaled (AER) administration. Pharmacokinetic properties were compared, and in vivo airway toxicity was assessed. Full-thickness human airway epithelium (AE) was grown in vitro at an air–liquid interface. Equal TAC doses (10–1,000 ng) were either added to the bottom chamber (MED) or aerosolized for gas-phase exposure (AER). Airway epithelium TAC absorption, cell toxicity, and interactions of TAC with NFκB activation were studied. Single-photon emission computed tomography demonstrated a linear tracer accumulation within the lungs during TAC inhalation. The AER TAC generated higher lung-tissue concentrations, but blood concentrations that were 11 times lower. Airway histology and gene expression...
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