P-selectin is upregulated early in the course of hyperoxic lung injury in mice.

While treatment with supplemental oxygen is often essential in patients with lung disease, prolonged therapy may cause lung injury by itself. Although the mechanisms responsible for initiating hyperoxic lung damage almost certainly involve primary oxidative transformations, the possible contributions of inflammation to the tissue injury have been attracting increasing research activity. Increases in intercellular adhesion molecule-1 (ICAM-1) coincide with the inflammation, but in other models of inflammation transient adhesion mediated by members of the Selectin gene family was found to be essential before ICAM-1/beta 2 interactions could occur. We, therefore, wondered whether a similar sequence of initial transient adhesion followed by subsequent responses would be observed in hyperoxic lung inflammation. We, therefore, determined the effects of hyperoxia exposure on lung mRNA for P- and E-Selectin in mouse lungs. We found that there was no detectable mRNA for E-Selectin through 72 h of hyperoxia exposure by Northern blotting, but that mRNA for P-Selectin was detectable as early as 48 h after initiation of hyperoxia. To determine the location of P-Selectin upregulation we examined hyperoxia-exposed mouse lungs by in situ hybridization and found that the upregulation of P-Selectin at 48 h was localized to large muscularized vessels, at 72 h expression was detected in some medium size muscularized vessels, and at 96 h abundant expression was observed also on nonmuscularized small vessels. In conclusion, increases in mRNA for P-Selectin early in the course of hyperoxia exposure suggest that P-Selectin expression in hyperoxic lungs increases in parallel with upregulation of ICAM-1, leading to the accumulation of neutrophils in hyperoxic lungs, and that interventions targeting these two adhesion molecules may lead to a diminution in hyperoxic lung inflammation and lung injury.

Increases in lung tissue expression of intercellular adhesion molecule-1 are associated with hyperoxic lung injury and inflammation in mice.

Lung injury caused by breathing enriched oxygen continues to be a major problem in clinical medicine. Experimentally, hyperoxic lung injury is characterized by pulmonary edema and associated neutrophil accumulation. Although extensively investigated, the mechanisms for neutrophil accumulation and the role of this accumulation in hyperoxic lung injury remain controversial. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that when increased on endothelium by inflammatory cytokines leads to increased adhesion of neutrophils to the inflamed endothelium and transendothelial migration. The purpose of this study was to examine the role of inflammation in hyperoxia-induced lung injury by investigating ICAM-1 expression in the lungs of mice exposed to > 95% oxygen continuously. Lung tissue from mice exposed to > 95% oxygen was analyzed for ICAM-1 mRNA by slot blot analysis and for ICAM-1 protein expression. We also examined lungs from mice exposed to hyperoxia for up to 96 h by light microscopy to correlate pulmonary inflammation with ICAM-1 expression. We found that mRNA for ICAM-1 increased 56% over baseline after 48 h of exposure to hyperoxia, that ICAM-1 protein increased by more than 5-fold over baseline after 96 h of exposure to hyperoxia, and that lung inflammation and injury were not evident until 96 h of exposure. Our data demonstrate that exposure to hyperoxia causes an increase in ICAM-1 gene transcription and/or mRNA stability in mouse lungs, and that this increase is followed by an increase in ICAM-1 protein.(ABSTRACT TRUNCATED AT 250 WORDS)