Pentoxifylline Reduces the Incidence and Severity of Necrotizing Enterocolitis in a Neonatal Rat Model

Abstract

Necrotizing enterocolitis (NEC) is a potentially fatal illness in premature neonates. Tumor necrosis factor alpha (TNF-␣) has been shown to play a central role in the inflammatory cascade leading to the development of NEC. Published evidence points to a significant role of pentoxifylline in inhibition of TNF-␣ and in reducing mucosal injury and improving healing in ischemiareperfusion experiments. Our aim was to investigate the effect of pentoxifylline on the incidence of NEC in a neonatal rat model. Newborn Sprague-Dawley rat pups originating from eight separate litters were delivered by cesarean section at 21.5 d and were formula fed from birth by orogastric gavage. The rat pups were randomized to receive either intraperitoneal pentoxifylline (15 mg/kg/dose) or placebo, given every 8 h beginning at 24 h of age, in a blinded fashion. Experimental NEC was induced by exposure to hypoxia for 60 s followed by cold stress at 4°C for 10 min. The animals were euthanized at development of NEC or at 96 h and intestinal tissue was processed and examined for histologic changes of NEC. The incidence of NEC was significantly lower in the pentoxifylline group [pentoxifylline 5/38 versus placebo 15/36; p ϭ 0.008, odds ratio (OR) ϭ 0.21 95% confidence interval (CI) 0.07-0.67]. Among the pups developing NEC, significantly fewer rat pups treated with pentoxifylline had severe (Ն3) intestinal injury scores [pentoxifylline 1/5 versus placebo 10/15; p ϭ 0.031, OR 0.06, 95% CI 0.01-0.79]. We conclude that intraperitoneal administration of pentoxifylline significantly reduced the incidence and severity of NEC in our experimental animal model. (Pediatr Res 60: 185-189, 2006)

Necrotizing enterocolitis: A multifactorial disease with no cure

“…These include anti-TNF-α [82] , PAF receptor antag onists [203] , heparin-binding EGF-like g rowth factor [204] , anti-inflammator y cytokines (IL-10) [205] , pentoxifylline [206] , intestinal trefoil factor 3 [207] , and glucagon-like peptide 2. Recent research has identified that complex glycosphingolipids in the form of gangliosides act as bioactive factors down-regulating many acute proinflammatory signals in the intestinal mucosa.…”

Pentoxifylline associated to hypertonic saline solution attenuates inflammatory process and apoptosis after intestinal ischemia/reperfusion in rats

“…With different mechanisms of action, the aim is to eliminate or to reduce the production of ROS, interleukins, tumor necrosis factor alpha (TNF-α), platelet activating factor and adhesion molecules 14,15 .…”

“…TNF-α has been demonstrated 15 . In experimental NEC model in rats, authors found that pentoxifylline was able to significantly attenuate the degree of injury to the intestinal mucosa.…”

“…It was observed a synergistic effect between HS and PTX, which probably resulted from the improvement in splanchnic circulation and restoration of intestinal microcirculation, with further reduction in erythrocytes and entotelial cells edema, increased mucosal oxygenation and reduced production of cytokines, particularly TNF-α, and ROS. Hemorrheological factors could be involved in the preservation of the intestinal wall, increasing expression of Bcl-2 by determining the blockade on the the outbreak of apoptosis as a mecanism of more intense aggression by the mesenteric I/R, such as, restored erythrocytes deformation capacity, reduction on blood viscosity and thus blood shear force 15,18,34 .…”

New Frontiers of Necrotizing Enterocolitis: From Pathophysiology to Treatment

“…Pentoxifylline is one of these agents studied but a very weak evidence found for usage as combination therapy to antbiotics in neonatal sepsis in a Cochrane review with a relative risk of NEC of 0.62 [101] [102]. In another study which intra-peritoneal pentoxifylline used in neonatal rat model, it was found that NEC incidence and severity reduced [103]. • Amniotic fluid; In experimental animal models, in vitro proliferation and migration of gut epithelial cells was provided by both porcine and human amniotic fluid [109].…”