Bactericidal activity of alveolar macrophages is suppressed by V-ATPase inhibition.
Bafilomycin A(1), 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 A(1) on resident alveolar macrophages (mphi). Treatment of alveolar mphi with bafilomycin A(1) (10 microM, 1 h) caused a significant decrement in cytosolic pH. This was accompanied by marked alteration of mphi 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 A(1) significantly reduced the production of reactive oxygen species (ROS). On the other hand, cell spreading was enhanced significantly by bafilomycin A(1). Comparable changes in ROS generation and mphi spreading were produced by altering cytosolic pH through changes in extracellular pH (pH(o)) in the absence of bafilomycin A(1). These findings suggest that the agent's effects on ROS production and mphi spreading were related to the accompanying changes in cytosolic pH. The enzyme inhibitor also altered mphi 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 pH(o). The results demonstrate that V-ATPase activity is an important determinant of mphi functioning and structure. Therapeutic use of V-ATPase inhibitors might be expected to compromise the bactericidal activity of alveolar mphi.
Bidani
A
A
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-0876, USA.
Reisner
B S
BS
Haque
A K
AK
Wen
J
J
Helmer
R E
RE
Tuazon
D M
DM
Heming
T A
TA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D018942:Macrolides; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D008855:Microscopy, Electron, Scanning; D010587:Phagocytosis / Q000187:drug effects*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology; D025262:Vacuolar Proton-Translocating ATPases
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D018942:Macrolides; D017382:Reactive Oxygen Species; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases