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

Abstract

Bronchopulmonary dysplasia is a leading cause of mortality and morbidity in preterm infants despite improved treatment modalities. Pentoxifylline, a phosphodiesterase inhibitor, inhibits multiple processes that lead 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 75 mg/kg pentoxifylline 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 with untreated hyperoxia-exposed controls. Monocyte chemoattractant protein-1 expression in lung homogenates was decreased, but the expressions of TNF-alpha, IL-6, matrix metalloproteinase-12, tissue factor, and plasminogen activator inhibitor-1 were 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.

Pentoxifylline and prevention of hyperoxia-induced lung ­injury in neonatal rats

“…Beneficial effects of PTX treatment on survival have been reported in sepsis and in HILI models (21,34). Our study demonstrated survival improvement from 54% to 88% with PTX.…”

“…The twice-a-day dosing used in this experiment might have not been optimal to exert all the potential benefits of PTX in the lungs of the newborn. However, this dosing was already found to be safe in preterm rats and beneficial in HILI as reported by ter Horst et al (21). Second, the animals most susceptible to oxygen-induced injury were not analyzed due to their death.…”

“…Hyperoxia was achieved in a sealed Plexiglas chamber as previously described (31). PTX (75 mg/kg equivalent to 3.75 ml/kg) based on the efficacy and safety data previously reported by ter Horst et al (21) or NS (same volume) was given via subcutaneous injection before O 2 exposure and then twice a day during continuous exposure to RA or O 2 for 4-9 d. Dams were rotated daily between RA and O 2 to avoid oxygen toxicity. Animals were killed on day 4 and 9 with intraperitoneal injections of Eutasol (0.15 ml/kg; Virbac AH, Fort Worth, TX) for subsequent studies.…”

“…Studies have also shown that PTX is able to attenuate lung injury related to mechanical ventilation and meconium (18,19). In neonatal HILI models, PTX treatment decreased IL-6 concentration in bronchoalveolar lavage (20), reduced alveolar fibrin deposition, and prolonged survival (21). However, whether PTX treatment affects AOE and VEGF expression in neonatal HILI is unknown.…”

Strategies to minimize lung injury in extremely low birth weight infants

“…Ter Horst et al mostraram que a pentoxifilina, uma metilxantina com efeito modulador, reduz o depósito de fibrina e aumenta a sobrevida de ratos recém-nascidos expostos à hiperóxia 78 . Trabalhos experimentais em nosso laboratório mostram que a pentoxifilina atenua o aumento dos mediadores inflamató-rios e, também, o edema pulmonar, após ventilação com volumes correntes elevados em ratos 79 .…”