The Effect of Immunosuppression on Airway Integrity.

Background: Insults to the airway epithelium play a key role in constrictive bronchiolitis following lung transplantation (LTx), the typical hallmark of chronic rejection. Our hypothesis is that immunosuppressives might affect airway integrity. Methods: A biculture of lung bronchial epithelial cells (16HBE) and lung microvascular endothelial cells (HLMVEC) was exposed to immunosuppressives (serum through levels) for 24h or 4 days. Cytotoxicity, trans-epithelial electrical resistance (TEER) and permeability was measured after exposure to monotherapies and combination therapies. Apoptosis, oxidative stress, inflammation (IL-8), real time PCR for epithelial-to-mesenchymal-transition (EMT) and tight junction proteins were assessed in exposed cells. Results: MMF and combination therapies including MMF, at serum trough levels and higher, are toxic for the 16HBE cells after 4 days exposure. Moreover, already after 24h, TEER of cells exposed to MMF decreases and permeability increases. MMF did not induce apoptosis, oxidative stress, loss of tight junctions or production of IL-8 after 24h, but possibly induces EMT in epithelial cells. MMF was detectable at both sides of the biculture and was also present in broncho-alveolar-lavage (BAL) of LTx patients. Other immunosuppressives were not toxic, neither changed TEER or permability. Conclusions: Our findings suggest that MMF is present in the airways of lung transplant patients and might affect the structural integrity of the airway, which needs further investigation and validation in the clinical setting. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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