A mouse model of acute lung injury implicates phospholipase Cε in neutrophilic inflammation through CXC chemokine production

We have shown that phospholipase Ce (PLCe), an effector of Ras and Rap small GTPases, is expressed in bronchial epithelial cells, and plays an important role in T helper 2 cell-mediated airway inflammation with eosinophilic infiltration. The purpose of this study is to examine whether PLCe is involved also in the pathogenesis of neutrophil-mediated airway inflammation. ALI was experimentally induced by intratracheal administration of LPS in PLCe +/+ mice and PLCe ΔX/ΔX mice whose PLCe was catalytically inactive. Effects of PLCe genotype on the development of ALI were analyzed at 24 h after the LPS inhalation. Effects of PLCe deficiency on cytokine production were analyzed by RT-PCR both in vivo and in vitro . In contrast with PLCe +/+ mice, the lung wet/dry weight ratio was decreased in PLCe ΔX/ΔX mice. The accumulation of inflammatory cells in the lungs were histologically reduced in PLCe ΔX/ΔX mice. In addition, an increase in neutrophil number in BALF was suppressed in PLCe ΔX/ΔX mice. These data indicated that the development of LPS-induced ALI was attenuated in PLCe ΔX/ΔX mice. Comparison of the cytokine mRNA levels of the total lungs by qRT-PCR of LPS-stimulated mice indicated that PLCe deficiency attenuated the LPS-induced expression of the CXC family chemokines. Such PLCe genotype-dependent cytokine induction was recapitulated in primary-cultured alveolar epithelial cells stimulated with LPS. These results suggest that PLCe-mediated induction of the CXC family chemokines by the structural cells plays an important role in neutrophil mediated airway inflammation and that PLCe could be a molecular target for the treatment of patients with ARDS.