PMID- 16395275
OWN - NLM
STAT- MEDLINE
DCOM- 20060810
LR  - 20131121
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 69
IP  - 7
DP  - 2006 Apr
TI  - Acute nephrotoxic and obstructive injury primes the kidney to endotoxin-driven 
      cytokine/chemokine production.
PG  - 1181-8
AB  - Gram-negative sepsis is a frequent complication in patients with acute renal 
      failure. This study tested whether acute tubular injury, for example, induced by 
      cisplatin (CP) or urinary tract obstruction, enhances renal cytokine responses to 
      endotoxin (lipopolysaccharide (LPS)), potentially contributing to tissue damage. 
      CD-1 mice were subjected to CP or vehicle injection. After 24 or 72 h, LPS or its 
      vehicle was given. At 2 h post LPS or vehicle administration, plasma/renal 
      cortical tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein-1 
      (MCP-1), and interleukin-10, and their corresponding renal cortical mRNAs were 
      assessed (representing pro-anti-inflammatory cytokines, and a chemokine, 
      respectively). Comparable studies were conducted in mice 24 h post unilateral 
      ureteral obstruction (UUO). Cultured human proximal tubular (HK-2) cell TNF-alpha 
      responses to CP+/-LPS were also assessed. CP alone caused either minimal or no 
      increases in cytokine levels. However, CP dramatically augmented cytokine 
      responses to LPS (up to 5-10 x vs LPS alone). The cytokine increases were 
      paralleled by changes in their mRNAs. UUO also sensitized to LPS. CP alone did 
      not alter HK-2 cell TNF-alpha/mRNA. However, CP 'primed' the cells to LPS 
      (approximately 50-100% greater TNF-alpha/mRNA increases vs LPS alone). CP+LPS 
      also caused synergistic cell death (lactate dehydrogenase release). We conclude 
      that (1) diverse forms of tubular injury can sensitize the kidney to LPS, 
      increasing cytokine production; (2) proximal tubules are involved; (3) LPS 
      'priming' has broad-based consequences, impacting diverse pro- and 
      anti-inflammatory pathways; and (4) increased transcriptional events may be at 
      least partially involved.
FAU - Zager, R A
AU  - Zager RA
AD  - Department of Medicine, University of Washington, Seattle, Washington, USA. 
      dzager@fhcrc.org
FAU - Johnson, A C M
AU  - Johnson AC
FAU - Hanson, S Y
AU  - Hanson SY
FAU - Lund, S
AU  - Lund S
LA  - eng
GR  - R01 DK68520-01/DK/NIDDK NIH HHS/United States
GR  - R37 DK38432/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Endotoxins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 130068-27-8 (Interleukin-10)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Acute Kidney Injury/chemically induced/pathology
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/pharmacology
MH  - Chemokines/*genetics
MH  - Cisplatin/*toxicity
MH  - Cytokines/*genetics
MH  - Endotoxins/*toxicity
MH  - Humans
MH  - Interleukin-10/pharmacology
MH  - Kidney/drug effects/*injuries/*pathology
MH  - Kidney Tubules, Proximal/drug effects
MH  - L-Lactate Dehydrogenase
MH  - Male
MH  - Mice
MH  - RNA, Messenger/genetics
MH  - Tumor Necrosis Factor-alpha/genetics/pharmacology
EDAT- 2006/01/06 09:00
MHDA- 2006/08/11 09:00
CRDT- 2006/01/06 09:00
PHST- 2006/01/06 09:00 [pubmed]
PHST- 2006/08/11 09:00 [medline]
PHST- 2006/01/06 09:00 [entrez]
AID - S0085-2538(15)51624-4 [pii]
AID - 10.1038/sj.ki.5000022 [doi]
PST - ppublish
SO  - Kidney Int. 2006 Apr;69(7):1181-8. doi: 10.1038/sj.ki.5000022.