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Am J Pathol. 2007 Jun;170(6):1820-30.

Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1-/- mice.

Author information

1
Division of Nephrology and Hypertension, Department of Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.

Abstract

Lipopolysaccharide (LPS) induces the stress-responsive gene heme oxygenase-1 (HO-1). The present study examined the significance of HO-1 in response to LPS. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked a greater reduction in glomerular filtration rate and renal blood flow, increased renal cytokine expression, and increased activation of nuclear factor (NF)-kappaB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-kappaB and less phosphorylation of its inhibitor, IkappaB. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked markedly greater elevations in serum levels of Th1 cytokines, Th2 cytokines, chemokines, and cytokines that stimulate bone marrow progenitors. The liver, a major source of serum cytokines, showed an increased activation of NF-kappaB in LPS-treated HO-1(-/-) mice. In addition, LPS provoked widespread apoptosis of immune cells in the spleen and thymus in HO-1(-/-) mice but not in HO-1(+/+) mice. We conclude that HO-1 deficiency exhibits a heightened and dysregulated inflammatory response to LPS accompanied by greater impairment in renal hemodynamic response and widespread apoptosis of immune cells. Because polymorphisms in the HO-1 gene with diminished HO activity predispose to human disease, we speculate that our findings may be relevant to the clinical outcome in patients with sepsis syndromes.

PMID:
17525251
PMCID:
PMC1899452
DOI:
10.2353/ajpath.2007.061093
[Indexed for MEDLINE]
Free PMC Article

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