, Volume 178, Issue 2, pp 91-104
Date: 12 Feb 2014

Bactericidal Activity of Alveolar Macrophages is Suppressed by V-ATPase Inhibition

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Abstract

Bafilomycin A1, a selective inhibitor of V-type H+-translocating ATPase (V-ATPase), may be a useful adjunct in cancer chemotherapy (Altan et al. [1998] J Exp Med 187:1583–1598). Therapeutic uses of the enzyme inhibitor need to consider the agent's potential effects on normal (nontumor) cells. This study determined the effects of bafilomycin A1 on resident alveolar macrophages (mφ). Treatment of alveolar mφ with bafilomycin A1 (10 μM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mφ bactericidal capabilities. The enzyme inhibitor caused a marginal reduction in the phagocytosis of opsonized Staphylococcus aureus and significantly suppressed intracellular killing of the phagocytosed bacteria. In keeping with the effects on intracellular killing, bafilomycin A1 significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly by bafilomycin A1. Comparable changes in ROS generation and mφ spreading were produced by altering cytosolic pH through changes in extracellular pH (pHo) in the absence of bafilomycin A1. These findings suggest that the agent's effects on ROS production and mφ spreading were related to the accompanying changes in cytosolic pH. The enzyme inhibitor also altered mφ morphology, leading to the shortening of microvilli and focal loss of surface ruffles. These morphologic effects differed from those produced by altering cytosolic pH by changes in pHo. The results demonstrate that V-ATPase activity is an important determinant of mφ functioning and structure. Therapeutic use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mφ.

Accepted for publication: 20 January 2000