Am. J. Respir. Crit. Care Med., Volume 162, Number 4, October 2000, 1539-1546

Albumin-mediated Regulation of Cellular Glutathione and Nuclear Factor Kappa B Activation

ANDRÉ M. CANTIN, BENOIT PAQUETTE, MARTIN RICHTER, and PIERRE LARIVÉE

Pulmonary Research Unit, Department of Medicine, and Department of Radiobiology, University of Sherbrooke, Sherbrooke, Quebec, Canada

Human serum albumin (HSA) is a cystine-rich serum protein taken up by many cells through receptor-mediated and fluid-phase endocytosis. We hypothesized that HSA may play a role in modulating cellular antioxidant redox signaling. Lung epithelial cells (A549), fibroblasts (HFL1), and blood lymphocytes had increased glutathione (GSH) levels after 8 h incubation with HSA. Similar GSH increases were observed with either plasma-derived or recombinant HSA. Serum depleted of HSA had no effect on cellular GSH. The GSH increase was also observed in normal murine lungs upon in vivo airway instillation of HSA. GSH enhancement was not related to the redox state of the free cysteine residue (Cys-34) on HSA, however, reduction of disulfide bonds in HSA inhibited the increase in cellular GSH. In addition, the albumin-mediated increase in GSH was inhibited by the vacuolar (H⁺)-ATPase inhibitors, bafilomycin A₁ and concanamycin, as well as by the membrane pH-disrupting ionophore monensin, but not by 20 mM NH₄Cl. The degree to which albumin increased GSH levels was sufficient to protect cells against H₂O₂-mediated cytotoxicity and to decrease TNF--mediated NF-B activation. We conclude that albumin specifically modulates cellular GSH levels, an effect sufficient to protect cells against oxidant injury and regulate NF-B activation.

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