Inhibition of poly (adenosine diphosphate-ribose) polymerase attenuates lung-kidney crosstalk induced by intratracheal lipopolysaccharide instillation in rats.
BACKGROUND
Acute respiratory distress syndrome (ARDS) is a severe form of lung injury that frequently occurs during pneumonia and sepsis. Lung inflammation in ARDS patients may have deleterious effects on remote organs such as the kidney. The nuclear enzyme poly(adenosine diphosphate-ribose) polymerase (PARP) enhances the nuclear factor (NF)-κB-dependent transcription of inflammatory cytokines. This study was conducted to elucidate two questions: first, whether the activation of PARP and NF-κB mediates the renal inflammation secondary to the lipopolysaccharide (LPS)-induced acute lung inflammation; second, whether a PARP inhibitor, 3-aminobenzamide (3-AB), attenuates lung and kidney inflammation by inhibiting NF-κB-dependent proinflammatory cytokines.


METHODS
Male Sprague-Dawley rats were anesthetized, ventilated, and divided into three groups; a control group (n = 8); an LPS group (n = 12) intratracheally instilled with LPS (16 mg/kg), and an LPS + 3-AB group (n = 12) given the same dose of LPS by the same method followed by an intravenous injection of 3-AB (20 mg/kg). Hemodynamics, arterial blood gas, and the plasma levels of lactate, creatinine and potassium were measured at 0,1,2,3, and 4 h after treatment. The lung wet/dry ratio was measured at 4 h. The mRNA expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the lung and kidney were measured by TaqMan real-time PCR. PARP and NF-κB in the lung and kidney were histologically examined by immunostaining and assigned expression scores.


RESULTS
LPS induced metabolic acidosis, hypotension, hypoxemia, increased the lung wet/dry ratio, increased the plasma levels of creatinine and potassium, and increased the cytokine mRNA expressions in the lung and kidney. All of these effects were associated with strong expression of PARP and NF-κB. Treatment with 3-AB prevented the LPS-induced metabolic acidosis and hypotension, reduced the plasma levels of lactate, creatinine and potassium, reduced the cytokine mRNA expressions, reduced the expression of PARP and NF-κB, improved pulmonary edema and oxygenation and preserved renal function.


CONCLUSIONS
The PARP inhibition attenuated lung-kidney crosstalk induced by intratracheal LPS instillation, partly via an inhibition of NF-κB dependent proinflammatory cytokines.
May Khin Hnin
MK
Si
Departments of Critical Care Medicine, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. c.mitaka.icu@tmd.ac.jp.
Chieko
C
Mitaka
Miniwan
M
Tulafu
Shinya
S
Abe
Masanobu
M
Kitagawa
Satoshi
S
Ikeda
Yoshinobu
Y
Eishi
Shunichi
S
Kurata
Makoto
M
Tomita
D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007773:Lactates / Q000097:blood; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009393:Nephritis / Q000503:physiopathology / Q000517:prevention & control*; D011014:Pneumonia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D011188:Potassium / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
D001549:Benzamides; D016207:Cytokines; D004791:Enzyme Inhibitors; D007773:Lactates; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D003404:Creatinine; D011065:Poly(ADP-ribose) Polymerases; D011188:Potassium