TY - JOUR
T1 - Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1-/- mice
AU - Tracz, Michal J.
AU - Juncos, Julio P.
AU - Grande, Joseph P.
AU - Croatt, Anthony J.
AU - Ackerman, Allan W.
AU - Rajagopalan, Govindarajan
AU - Knutson, Keith L.
AU - Badley, Andrew D.
AU - Griffin, Matthew D.
AU - Alam, Jawed
AU - Nath, Karl A.
PY - 2007/6
Y1 - 2007/6
N2 - 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)-κB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-κB and less phosphorylation of its inhibitor, IκB. 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-κB 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.
AB - 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)-κB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-κB and less phosphorylation of its inhibitor, IκB. 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-κB 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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U2 - 10.2353/ajpath.2007.061093
DO - 10.2353/ajpath.2007.061093
M3 - Article
C2 - 17525251
AN - SCOPUS:34447332538
SN - 0002-9440
VL - 170
SP - 1820
EP - 1830
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -