Ozone induction of cytokine‐induced neutrophil chemoattractant (CINC) and nuclear factor‐κb in rat lung: inhibition by corticosteroids

Abstract

We determined in rat lung whether ozone exposure was associated with the expression of the chemokine, cytokineinduced neutrophil chemoattractant (CINC), and of the transcription factor, NF-~cB. CINC mRNA expression peaked at 2 h after cessation of ozone exposure, and returned to basal levels by 24 h. DNA-binding activity of NF-KB showed a marked increase after ozone, maximal at 2 h. Dexamethasone inhibited CINC mRNA and NF-KB expression, together with neutrophilic inflammation. Our data supports the concept that ozone leads to NF-~cB activation which increases CINC mRNA expression. These series of events could lead to neutrophilic inflammation.Key words: Ozone; Chemokine; CINC mRNA; Lung inflammation; NF-xB Norway rat lung. Recent cloning and sequencing of the CINC gene has shown a binding site for the transcription regulating factor, nuclear factor-xB in its promoter region [12]. To determine whether any increase in CINC transcription was associated with the activation of NF-xB-binding to the CINC promoter, we examined NF-~cB-binding activity to nuclear extracts purified from rat lung after exposure to ozone. To examine further the association of NF-xB-binding and CINC expression, we studied the effect of corticosteroid treatment on these parameters. Because activated glucocorticoid receptors are known to prevent NF-lcB-binding [13], we also studied whether corticosteroids could inhibit both NF-xB-binding and CINC expression, in addition to neutrophilic inflammation, following ozone exposure.

Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats

“…The decrease caused by Dexa 5 -Man 10 -HSA was attributable to less activated KC and less infiltrating granulocytes as found by immunohistochemical analysis (data not shown). Dexamethasone is known to inhibit both ROS synthesis and the synthesis of chemotactic factors by KC, [40][41][42] thus confirming effective delivery of dexamethasone into the KC. Equimolar amounts of free dexamethasone did not reduce the amount of ROSproducing cells, showing the increased efficacy of targeted dexamethasone, despite the cell-activating effects of the carrier Man 10 -HSA.…”

Differential Effects of Ebselen on Neutrophil Recruitment, Chemokine, and Inflammatory Mediator Expression in a Rat Model of Lipopolysaccharide-Induced Pulmonary Inflammation

“…Within the CXC chemokine subfamily, the presence of a glutamate-leucine-arginine (ELR) motif before the first conserved cysteine residue confers selectivity in recruiting neutrophils (30), and the ELR-containing CXC chemokines, CINC, and MIP-2 are potent inducers of neutrophil activation and their directional migration (17,18,(31)(32)(33). We have therefore investigated whether the effect of ebselen on neutrophil recruitment might be achieved through inhibition of the macrophage CXC chemokines CINC-1 and MIP-2.…”

The murine neutrophil-chemoattractant chemokines LIX, KC, and MIP-2 have distinct induction kinetics, tissue distributions, and tissue-specific sensitivities to glucocorticoid regulation in endotoxemia

“…Stimulus-specific differences in glucocorticoid sensitivity may also account for the more potent effect of dexamethasone on lung KC and MIP-2 expression observed in ozone-exposed rats [55,56]. Because the mechanisms of glucocorticoid attenuation of gene induction are complex, the existence of inducer-and cell type-specific effects is not unexpected [16,57].…”