Pentoxifylline Attenuates Lung Injury and Modulates Transcription Factor Activity in Hemorrhagic Shock

Abstract

Evidence exists that resuscitation with Ringer's lactate (RL) contributes to postshock inflammation and lung injury. We hypothesized that the anti-inflammatory agent pentoxifylline (PTX) attenuates postresuscitative lung injury through modulation of transcription factors after hemorrhagic shock. Male Sprague Dawley rats underwent a 1 h period of hypotension and resuscitation with RL (32 mL/kg) or RL + PTX (25 mg/kg). Lung sections were graded for histological injury and myeloperoxidase content. Cytokine-induced neutrophil chemoattractant concentration was determined by enzyme immunoassay. Matrix metalloproteinase-2 and -9 (MMP) activity was evaluated by zymography. Heme oxygenase-1, nuclear factor kappa B (NF-kappaB) p65 nuclear translocation, and cytoplasmic I-kappaB phosphorylation were assessed by Western blot. NF-kappaB and cAMP response element binding protein (CREB) DNA binding were determined by light shift chemiluminescent electrophoretic mobility shift assay. RL resuscitation led to statistically significant increases in all parameters of lung injury when compared with the negative control. The addition of PTX significantly decreased histology lung injury, myeloperoxidase content, cytokine-induced neutrophil chemoattractant by 48% (P < 0.05), heme oxygenase-1 expression by 50% (P < 0.05), MMP-2 activity by 70% (P < 0.05), MMP-9 activity by 44% (P < 0.05), cytoplasmic I-kappaB phosphorylation by 66% (P < 0.01), nuclear NF-kappaB p65 phosphorylation by 51% (P < 0.05), and NF-kappaB DNA binding by 42% (P < 0.05). In contrast, PTX increased CREB DNA binding by 69% when compared with RL alone (P < 0.04). The addition of PTX to conventional RL infusion after shock significantly reduced histological lung injury and pulmonary neutrophil activity when compared to treatment with RL alone. The administration of PTX was also associated with diminished NF-kappaB and enhanced CREB activation. Therefore, the administration of PTX may serve as a novel therapeutic adjunct after hemorrhagic shock.