Pentoxifylline reduces acute lung injury in chronic endotoxemia.
BACKGROUND
Pentoxifylline (PTX) attenuates end-organ injury in models of sepsis and hemorrhage. PTX is thought to act by inhibiting phosphodiesterase, thus increasing cAMP and decreasing tumor necrosis factor-alpha (TNF-alpha) synthesis. The effects of PTX on neutrophil and endothelial cell adhesion molecules and, ultimately, organ injury in a chronic endotoxemia model have not been studied. We hypothesized that continuous infusion of PTX reduces acute lung injury (ALI) caused by chronic lipopolysaccharide (LPS) exposure.


METHODS
Male Sprague-Dawley rats were given continuous infusion of LPS, PTX + LPS combined, or saline (sham) by implantable pumps. Neutrophil CD11b expression, lung histopathology, lung intercellular adhesion molecule-1 (ICAM-1) expression assessed by immune staining, serum TNF-alpha, serum interleukin-6 (IL-6), and bronchoalveolar lavage (BAL) IL-8 were evaluated at different time points. Lung injury was graded in a blinded fashion from 0 (normal) to 4 (severe) for interstitial inflammation, neutrophil infiltration, congestion, and edema. Total lung injury score (TLIS) was calculated by adding listed categories. White cell count in the peripheral blood and in the BAL was also performed.


RESULTS
Animals treated with PTX + LPS showed a significant reduction in lung injury score, a marked decrease in ICAM-1 expression, and a significant decrease in IL-8 levels in the BAL and serum IL-6 levels when compared with LPS-treated animals.


CONCLUSIONS
Continuous infusion of PTX reduces ALI caused by chronic endotoxemia. The effect seems to be a result of decreased expression of endothelial and epithelial ICAM-1 and modulation of proinflammatory cytokine synthesis.
Division of Trauma, Department of Surgery, University of California San Diego School of Medicine, San Diego, California, USA.
Christopher
C
Michetti
Raul
R
Coimbra
David B
DB
Hoyt
William
W
Loomis
Wolfgang
W
Junger
Paul
P
Wolf
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D039481:CD11b Antigen / Q000032:analysis; D002908:Chronic Disease; D004487:Edema; D019446:Endotoxemia / Q000150:complications*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000032:analysis; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010431:Pentoxifylline / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D039481:CD11b Antigen; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D010431:Pentoxifylline