LPS-induced acute lung injury is attenuated by phosphodiesterase inhibition: effects on proinflammatory mediators, metalloproteinases, NF-kappaB, and ICAM-1 expression.
BACKGROUND
Acute endotoxemia is characterized by an enhanced inflammatory response. Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to decrease TNF-alpha levels and to down-regulate neutrophil activation, likely because of increases in intracellular cyclic AMP. Its effects on lipopolysaccharide (LPS) induced lung injury, more specifically on tissue neutrophil infiltration and degranulation, adhesion molecule expression, and transcriptional factor activation, have not been fully investigated. We postulated that PTX treatment in acute endotoxemia downregulates the inflammatory response and may decrease lung injury.


METHODS
Male Sprague-Dawley rats were randomized into three groups: Sham (saline i.v.), LPS (5 mg/kg i.v.), and PTX + LPS (25 mg/kg and 5 mg/kg i.v., respectively; concomitant injection). After 4 hours, bronchoalveolar lavage fluid (BAL), plasma, and lungs were sampled. BAL IL-8 (ELISA), BAL MMP-2, plasma MMP-9, and BAL MMP-9 (Zymography) were measured. Lung histology (H&E), in addition to lung MPO, ICAM-1, and NF-kappaB expression evaluated by immunohistochemistry were analyzed. Lung NF-kappaB DNA binding was evaluated by electrophoretic mobility shift assay.


RESULTS
PTX treatment decreased BAL IL-8 levels, BAL MMP-2, and plasma MMP-9 activity. Lung neutrophil infiltration (MPO), ICAM-1 expression and NF-kappaB activation were decreased by PTX. In addition, PTX treatment caused a marked attenuation of LPS-induced lung injury.


CONCLUSIONS
Phosphodiesterase inhibition by PTX attenuates LPS-induced end-organ injury. In addition, proinflammatory cytokine production is also downregulated, likely because of the marked attenuation of NF-kappaB DNA binding and activation.
Coimbra
Raul
R
Division of Trauma and Surgical Critical Care, Department of Surgery, University of California San Diego School of Medicine, 200 W. Arbor Drive, San Diego, CA 92103-8896, USA. rcoimbra@ucsd.edu
Melbostad
Heidi
H
Loomis
William
W
Porcides
Rafael D
RD
Wolf
Paul
P
Tobar
Maria
M
Hoyt
David B
DB
D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D004927:Escherichia coli Infections / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*
D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; C440499:lipopolysaccharide, Escherichia coli O111 B4; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010431:Pentoxifylline