Peroxisome proliferator-activated receptor (
PPAR)-γ is a
ligand-activated
transcription factor and regulates
inflammation. Posttranslational modifications regulate the function of PPARγ, potentially affecting
inflammation. PPARγ contains a
mitogen-activated protein kinase (MAPK) site, and phosphorylation by
extracellular signal-regulated kinase (ERK)-1/2 leads to inhibition of PPARγ. This study investigated the kinetics of PPARγ expression and activation in parenchymal and immune cells in
sepsis using the
MAPK/ERK kinase (MEK)-1 inhibitor, an upstream
kinase of ERK1/2. Adult male Sprague Dawley rats were subjected to polymicrobial
sepsis by cecal
ligation and
puncture. Rats received
intraperitoneal injection of vehicle or the MEK1 inhibitor
PD98059 (5 mg/kg) 30 min before cecal
ligation and
puncture. Rats were euthanized at 0, 1, 3, 6 and 18 h after cecal
ligation and
puncture. Control animals used were animals at time 0 h. Lung, plasma and peripheral blood mononuclear cells (PBMCs) were collected for biochemical assays. In vehicle-treated rats, polymicrobial
sepsis resulted in significant
lung injury. In the lung and PBMCs, nuclear levels of PPARγ were decreased and associated with an increase in phosphorylated PPARγ and phosphorylated ERK1/2 levels. Treatment with the MEK1 inhibitor increased the antiinflammatory plasma
adipokine adiponectin, restored PPARγ expression in PBMCs and lung, and decreased
lung injury. The inflammatory effects of
sepsis cause changes in PPARγ expression and activation, in part, because of phosphorylation of PPARγ by ERK1/2. This phosphorylation can be reversed by ERK1/2 inhibition, thereby improving
lung injury.