Survival Pathway Signal Transduction is Reduced in Alveolar Macrophages during Pneumocystis Pneumonia

Abstract

PNEUMOCYSTIS pneumonia (PcP) causes increased alveolar macrophage apoptosis in humans, rats, and mice (Lasbury et al. 2006). The apoptosis of these cells proceeds via caspase-9 activation, as inhibition of caspase-9 activation increases alveolar macrophage numbers and prolongs survival of rats and mice with PcP (Lasbury et al. 2006). While a pro-apoptotic signal may be present in the lung during Pneumocystis infection, reduced alveolar macrophage resistance to apoptosis may also result in the reduction of alveolar macrophage numbers. Akt-1 is a kinase that acts to promote survival of cells. Akt-1, after it is activated by phosphorylation, is anti-apoptotic. Akt-1 can phosphorylate caspase-9 to prevent its activation (Cardone et al. 1998), inhibit forkhead transcription factor activity (Brunet et al. 1999), phosphorylate glycogen synthase kinase (GSK-3b) to inhibit its pro-apoptotic activities (Pap and Cooper 1998), and inhibit mitochondrial damage by promoting the release of the anti-apoptotic molecules Bcl-xl and Bcl-2 from Bad (del Peso et al. 1997). To begin to determine the role of Akt-1 in the apoptosis of alveolar macrophages during PcP, we assessed the expression and activation of Akt-1.