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J Appl Physiol (June 18, 2004). doi:10.1152/japplphysiol.00452.2004
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Submitted on May 5, 2004
Accepted on June 15, 2004

Pentoxifylline reduces fibrin deposition and prolongs survival in neonatal hyperoxic lung injury

Simone A J ter Horst1, Gerry T M Wagenaar1*, Eveline de Boer1, Margot A van Gastelen1, Joost C M Meijers2, Bart J Biemond3, Ben J H M Poorthuis1, and Frans J Walther4

1 Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
2 Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
3 Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
4 Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands; Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medican Center, Torrance, California, USA

* To whom correspondence should be addressed. E-mail: G.T.M.Wagenaar{at}lumc.nl.

Bronchopulmonary dysplasia is a leading cause of mortality and morbidity in preterm infants despite improved treatment modalities. Pentoxifylline, a phosphodiesterase inhibitor, inhibits multiple processes leading to neonatal hyperoxic lung injury, including inflammation, coagulation and edema. Using a preterm rat model, we investigated the effects of pentoxifylline on hyperoxia-induced lung injury and survival. Preterm rat pups were exposed to 100% oxygen and injected subcutaneously with 0.9% saline or pentoxifylline 75 mg/kg twice a day. On day 10, lung tissue was harvested for histology, fibrin deposition, and mRNA expression, and bronchoalveolar lavage fluid was collected for total protein concentration. Pentoxifylline treatment increased mean survival by 3 days (p=0.0018) and reduced fibrin deposition by 66% (p<0.001) in lung homogenates compared to untreated hyperoxia-exposed controls. Monocyte chemoattractant protein-1 expression in lung homogenates was decreased, but the expression of TNF-{alpha}, IL-6, matrix metalloproteinase-12, tissue factor, and plasminogen activator inhibitor-1 was similar in both groups. Total protein concentration in bronchoalveolar lavage fluid was decreased by 33% (p=0.029) in the pentoxifylline group. Pentoxifylline treatment attenuates alveolar fibrin deposition and prolongs survival in preterm rat pups with neonatal hyperoxic lung injury, probably by reducing capillary-alveolar protein leakage.




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