Pentoxifylline and tumour necrosis factor-induced lung injury

Zabel, P.; Schade, F. U.

doi:10.1183/09031936.94.07081389

Cited by 10 publications

(4 citation statements)

References 14 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, TNF-␣ is able to induce increased pulmonary permeability and reduced surfactant production and is thereby supposed to be involved in the pathogenesis of the various lung injuries, including meconium-induced pulmonary damage (36 -40). As also evident from our data, these lung injury processes are effectively prevented by PTX (41,42) and thus may contribute to the improved ventilatory function in the meconium-contaminated areas of the treated neonatal lungs. Although PTX additionally may have significant hemodynamic properties, the reduction of permeability damage is unlikely attributed to alterations in pulmonary microvascular pressure (22).…”

Section: /Ml); Bal Fluid Tnf-␣ (Pg/ml) and Total Protein (Mg/ml) Concsupporting

confidence: 55%

Pentoxifylline Reduces Regional Inflammatory and Ventilatory Disturbances in Meconium-Exposed Piglet Lungs

et al. 2004

View full text Add to dashboard Cite

Neonatal meconium aspiration frequently produces severe respiratory distress, which is associated with patchy pulmonary neutrophil influx and inflammatory injury. To examine the effects of pentoxifylline (PTX), a potent anti-inflammatory agent, on regional pulmonary inflammation and ventilation after meconium aspiration, we studied 17 anesthetized and ventilated neonatal piglets (age Ͻ2 d) for 12 h. After unilateral intrapulmonary instillation of meconium, PTX treatment was started in nine animals, and eight untreated animals served as controls. Bronchoalveolar lavage (BAL) fluid and lung tissue were studied for inflammatory variables at the end of the study, and changes in regional ventilation were serially analyzed with a dynamic pulmonary x-ray imaging method. Meconium insufflation increased BAL fluid total cell, neutrophil, and macrophage counts and tumor necrosis factor-␣ (TNF-␣) and protein concentrations as well as lung tissue myeloperoxidase activity in the instilled lungs, compared with the noninstilled side. PTX treatment prevented the increase of BAL fluid alveolar macrophage count and TNF-␣ and protein concentrations in the meconium-instilled lungs but had no significant effect on the pulmonary neutrophil accumulation. Ventilation of the meconium-insulted lung was initially disturbed similarly in both study groups, but PTX administration prevented the sustained local ventilatory perturbation at 4, 6, and 12 h after meconium instillation. The results thus indicate that PTX treatment may attenuate meconium-induced regional ventilation derangements, mainly through its effects on local alveolar macrophages and TNF-␣ production as well as alveolocapillary permeability rather than via significant prevention of accumulation of active neutrophils in the insulted lungs. Perinatal aspiration of meconium frequently produces respiratory failure with hypoxemia, hypercapnia, and acidosis in the newborn infant and may be complicated by air leaks, pulmonary hypertension, hypoxic organ damage, and long-term pulmonary sequelae (1,2). The pathophysiology of the meconium aspiration syndrome (MAS) is complex and includes initial mechanical obstruction of the airways, ventilation/perfusion mismatch, surfactant inactivation, and progressively developing inflammatory lung injury (1-6). Aspirated meconium may directly damage the alveolar-capillary membrane and may also augment pulmonary injury through activation of alveolar macrophages, inflammatory cytokine production, and accumulation of polymorphonuclear neutrophils (PMNs) (1,2,6,7). Whereas the uneven distribution of inhaled meconium leads to localized areas of injury with variable aeration of the affected lungs, the contribution and mechanisms of the patchy inflammatory processes to the pulmonary dysfunction induced by meconium aspiration is still unclear. Consequently, the therapeutic value of anti-inflammatory agents in the management of MAS remains controversial (6,8 -12).Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, has hemorheol...

show abstract

Section: /Ml); Bal Fluid Tnf-␣ (Pg/ml) and Total Protein (Mg/ml) Concsupporting

confidence: 55%

Pentoxifylline Reduces Regional Inflammatory and Ventilatory Disturbances in Meconium-Exposed Piglet Lungs

et al. 2004

View full text Add to dashboard Cite

show abstract

“…In particular, TNF-␣ along with PAF has been implicated to play a central role in the inflammatory cascade leading to NEC (7,11). TNF-␣ triggers the production of several inflammatory cytokines including PAF, is one of the most potent inducers of oxygen radicals in neutrophils and plays an important role in the regulation of intestinal epithelial cell apoptosis (34,35). The beneficial effects of pentoxifylline in our study could be related to the inhibition of TNF-␣, indirect inhibition of PAF, reduction in free radicals, and activation of leukocytes.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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)

show abstract

“…Moreover, most of the deleterious effects of sepsis can be mimicked by the administration of TNF and, to a lesser extent, IL-1 (23)(24)(25)(26). However, although attempts to neutralize TNF and other inflammatory cytokines have been shown to be beneficial in animal models of sepsis syndrome, inhibition of TNF in patients with sepsis has not been successful (27)(28)(29). In fact, TNF blockade has been shown to increase lethality in some patients with sepsis, particularly those with Gram-positive infection (30).…”

Section: Intrapulmonary Tnf Gene Therapy Reverses Sepsis-inducedmentioning

confidence: 99%

Intrapulmonary TNF Gene Therapy Reverses Sepsis-Induced Suppression of Lung Antibacterial Host Defense

Chen

Reddy

Newstead

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

Sepsis syndrome is frequently complicated by the development of nosocomial infections, particularly Gram-negative pneumonia. Although TNF-α (TNF) has been shown to mediate many of the pathophysiologic events in sepsis, this cytokine is a critical component of innate immune response within the lung. Therefore, we hypothesized that the transient transgenic expression of TNF within the lung during the postseptic period could augment host immunity against nosocomial pathogens. To test this, mice underwent 26-gauge cecal ligation and puncture (CLP) as a model of abdominal sepsis, followed 24 h later by intratracheal (i.t.) administration of Pseudomonas aeruginosa. In animals undergoing sham surgery followed by bacterial challenge, Pseudomonas were nearly completely cleared from the lungs by 24 h. In contrast, mice undergoing CLP were unable to clear P. aeruginosa and rapidly developed bacteremia. Alveolar macrophages (AM) recovered from mice 24 h after CLP produced significantly less TNF ex vivo, as compared with AM from sham animals. Furthermore, the adenoviral mediated transgenic expression of TNF within the lung increased survival in CLP animals challenged with Pseudomonas from 25% in animals receiving control vector to 91% in animals administered recombinant murine TNF adenoviral vector. Improved survival in recombinant murine TNF adenoviral vector-treated mice was associated with enhanced lung bacterial clearance and proinflammatory cytokine expression, as well as enhanced AM phagocytic activity and cytokine expression when cultured ex vivo. These observations suggest that intrapulmonary immunostimulation with TNF can reverse sepsis-induced impairment in antibacterial host defense.

show abstract

Pentoxifylline and tumour necrosis factor-induced lung injury

Cited by 10 publications

References 14 publications

Pentoxifylline Reduces Regional Inflammatory and Ventilatory Disturbances in Meconium-Exposed Piglet Lungs

Pentoxifylline Reduces Regional Inflammatory and Ventilatory Disturbances in Meconium-Exposed Piglet Lungs

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

Intrapulmonary TNF Gene Therapy Reverses Sepsis-Induced Suppression of Lung Antibacterial Host Defense

Contact Info

Product

Resources

About