Shock/sepsis/trauma/critical carePentoxifylline Attenuates Lung Injury and Modulates Transcription Factor Activity in Hemorrhagic Shock
Introduction
Hemorrhagic shock is a major cause of death during the initial phases of trauma. For those who survive, the duration and depth of ischemia and subsequent reperfusion have been linked to the development of acute lung injury (ALI) and multisystem organ failure [1]. ALI and its most severe form, acute respiratory distress syndrome (ARDS), are characterized by disruption of the pulmonary endothelial barrier, which leads to interstitial edema, reduced lung compliance, and persistent hypoxia [2]. There is much evidence to suggest that the host’s own neutrophil population plays a central role in the development of ALI and ARDS. More specifically, migration in response to chemokines such as interleukin-8 (IL-8), degranulation of proteolytic enzymes, and generation of the respiratory burst have all been recognized as critical neutrophil functions leading to resuscitation-induced lung injury [3, 4].
The rapid production of local chemokines and cytokines, including IL-8, after ischemia and reperfusion is preceded by and dependent on an increase in the corresponding mRNA transcripts and is a direct consequence of the initiation of proinflammatory gene transcription [5, 6]. The 5′ region of these particular genes have been shown to contain promoter regions that can bind transcriptional factors such as nuclear factor-kappa B (NF-κB) and cyclic-3′,5′-adenosine monophosphate (cAMP) response element binding protein (CREB), which are capable of modulating proinflammatory gene transcription in a positive or negative manner [7]. Therefore, strategies aimed at the modulation of neutrophil or transcriptional factor activation may reduce the incidence and severity of lung injury after shock.
The present standard of care for the treatment of hemorrhagic shock involves the intravenous infusion of large amounts crystalloids. However, there is recent evidence suggesting that the choice of postshock resuscitation strategy can also modulate the inflammatory response. Therefore, in terms of inflammation, the type of fluid used to restore perfusion may be just as important as restoring perfusion itself. Racemic Ringer’s lactate (RL), the current clinical resuscitative fluid, has been shown to contribute to lung injury by augmenting neutrophil oxidative burst, adhesion molecule expression, endothelial dysfunction, and cellular apoptosis in animal models of ischemia-reperfusion [8, 9, 10, 11].
Pentoxifylline (1-[5-oxohexyl]-3,7-dimethylxanthine; PTX), a methylxanthine derivative and nonspecific phosphodiesterase inhibitor, has been clinically used in the treatment of intermittent claudication in patients with peripheral and cerebrovascular atherosclerotic disease [12]. Through its hemorheologic properties, PTX enhances the deformability of red blood cells and as a result improves microvascular blood flow. Recently, studies examining the effects of PTX have been focused on its role as an immune modulator. In prospective, randomized, double-blind, placebo-controlled trials, the administration of PTX reduced mortality in neonatal sepsis and acute alcoholic hepatitis [13, 14]. PTX has been also shown to attenuate a variety proinflammatory neutrophil functions which are important in the development and propagation of host organ injury such as degranulation, adherence, and generation of the respiratory burst in animal models of ischemia-reperfusion and endotoxemia [15, 16, 17, 18, 19]. Since PTX alone is not capable of volume expansion, its role as an adjunct to standard RL resuscitation is an attractive resuscitation alternative. In this series, we hypothesized that the combination of RL and PTX attenuates posthemorrhagic shock resuscitation-induced lung injury through the modulation of neutrophil function and pulmonary transcription factor activation when compared to classic RL resuscitation in vivo.
Section snippets
Materials and Methods
The experiment was approved by the University of California Animal Subjects Committee and was in accordance with guidelines established by the National Institutes of Health.
Histological Lung Injury
Lung specimens from those animals treated with standard RL resuscitation developed significant histological changes including cellular infiltration, edema, and alveolar-capillary membrane thickening (Fig. 1). In contrast, the addition of PTX to RL infusion after shock attenuated the severity of this injury to a level observed in the sham animals. The severity scores for interstitial inflammation, neutrophil infiltration, and congestion were all markedly higher in the RL group (11.4 ± 2) than
Discussion
Despite marked improvements in hospital care over the past four decades, the mortality rate for ALI and ARDS in trauma patients remains near 40% [27]. To date, no pharmacologic therapy has demonstrated a survival benefit in multicenter trials. Recently, conventional fluid resuscitation with RL has been shown to contribute to neutrophil activation and end organ injury [8, 9, 10, 11]. Consequently, there has been increased interest in alternative strategies or pharmacologic adjuncts that can be
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2020, European Journal of PharmacologyCitation Excerpt :The results of this study indicate that pentoxifylline suppressed TNF-α production in a dose-dependent manner in alveolar macrophages in sarcoidosis, which is mainly driven by proinflammatory and anti-inflammatory mediators. Data from another study in rat model demonstrated that pentoxifylline suppressed cytokine-induced neutrophil chemoattractant, NF-κB, Matrix metalloproteinase-2, and -9 (MMP) and myeloperoxidase content (Deree et al., 2007). It was reported that, MMPs are well-known inflammatory mediators that contribute to the aggravation of ALI and ARDS by accelerating the secretion of neutrophils into the lung (Corbel et al., 2000; Torii et al., 1997).
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