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Published online before print April 13, 2007
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¶
From the Divisions of Nephrology and Hypertension* and Infectious Diseases, the Departments of Pathology and Immunology, and the Program in Translational Immunovirology and Biodefense,¶ Mayo Clinic College of Medicine, Rochester, Minnesota; and the Department of Molecular Genetics,|| Alton Ochsner Medical Foundation, New Orleans, Louisiana
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)-
B. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-B and less phosphorylation of its inhibitor, IB. 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-B 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.
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