Overwhelming accumulation of neutrophils is a significant component in septic lung damage, although the signaling mechanisms behind neutrophil infiltration in the lung remain elusive. In the present study, we hypothesized that geranylgeranylation might regulate the inflammatory response in abdominal
sepsis. Male C57BL/6 mice received the geranylgeranyl
transferase inhibitor,
GGTI-2133, before cecal
ligation and
puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were harvested for analysis of neutrophil infiltration, as well as
edema and
CXC chemokine formation. Blood was collected for analysis of Mac-1 on neutrophils and
CD40L on platelets. Gene expression of
CXC chemokines,
tumor necrosis factor-α (TNF-α), and
CCL2 chemokine was determined by quantitative RT-PCR in isolated alveolar macrophages. Administration of
GGTI-2133 markedly decreased CLP-induced infiltration of neutrophils,
edema, and tissue injury in the lung. CLP triggered clear-cut upregulation of Mac-1 on neutrophils. Inhibition of geranylgeranyl
transferase reduced CLP-evoked upregulation of Mac-1 on neutrophils in vivo but had no effect on
chemokine-induced expression of Mac-1 on isolated neutrophils in vitro. Notably,
GGTI-2133 abolished CLP-induced formation of
CXC chemokines, TNF-α, and CCL2 in alveolar macrophages in the lung. Geranylgeranyl
transferase inhibition had no effect on
sepsis-induced platelet shedding of
CD40L. In addition, inhibition of geranylgeranyl
transferase markedly decreased
CXC chemokine-triggered neutrophil chemotaxis in vitro. Taken together, our findings suggest that geranylgeranyl
transferase is an important regulator of
CXC chemokine production and neutrophil recruitment in the lung. We conclude that inhibition of geranylgeranyl
transferase might be a potent way to attenuate
acute lung injury in abdominal
sepsis.