A novel fluid resuscitation strategy modulates pulmonary transcription factor activation in a murine model of hemorrhagic shock.

Introduction: Combining the hemodynamic and immune benefits of hypertonic saline with the anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline (HSPTX) as a hemorrhagic shock resuscitation strategy reduces lung injury when compared with the effects of Ringer's lactate (RL). We hypothesized that HSPTX exerts its anti-inflammatory effects by interfering with nuclear factor kappa B/cAMP response element-binding protein (NF-kappaB-CREB) competition for the coactivator CREB-binding protein (CBP) in lung tissue, thus affecting pro-inflammatory mediator production.

Methods: Male Sprague-Dawley rats underwent 60 minutes of hemorrhagic shock to reach a mean arterial blood pressure of 35 mmHg followed by resuscitation with either RL or HSPTX (7.

Pentoxifylline modulates p47phox activation and downregulates neutrophil oxidative burst through PKA-dependent and -independent mechanisms.

Background And Aim: Pentoxifylline (PTX) has been proven to be an inhibitor of fMLP-induced neutrophil (PMN) oxidative burst and is thought to function by increasing cAMP and Protein kinase A (PKA). We hypothesized that PTX diminishes production of the neutrophil respiratory burst by both PKA-dependent and independent mechanisms.

Material And Methods: Human neutrophils were isolated and stimulated with fMLP (1microM) alone or in combination with PTX (2mM).

Pentoxifylline attenuates leukoreduced stored blood-induced neutrophil activation through inhibition of mitogen-activated protein kinases.

Context: Transfusion of packed red blood cells is an independent risk factor for postoperative bacterial infections and multiple organ failure.

Materials And Methods: Whole blood was obtained from healthy volunteers to investigate the role of mitogen associated protein kinase (MAPK) pathways in PRBC-induced neutrophil respiratory burst, hypothesizing that the attenuating effects of pentoxifylline on this process are due to modulations in MAPK-associated signaling.

Results: Pre-incubation of neutrophils with supernatant prior to fMLP stimulation increased p38 MAPK and ERK phosphorylation over fMLP alone pentoxifylline significantly reduced p38MAPK and ERK phosphorylation in similarly stimulated neutrophils.

Phosphodiesterase inhibition attenuates alterations to the tight junction proteins occludin and ZO-1 in immunostimulated Caco-2 intestinal monolayers.

Aims: Under normal conditions, the intestinal mucosa acts as a local barrier to prevent the influx of luminal contents. The intestinal epithelial tight junction is comprised of several membrane associated proteins, including zonula occludens-1 (ZO-1) and occludin. Disruption of this barrier can lead to the production of pro-inflammatory mediators and ultimately multiple organ failure.

Burn-induced gut barrier injury is attenuated by phosphodiesterase inhibition: effects on tight junction structural proteins.

Loss of intestinal barrier function after burn injury allows movement of intraluminal contents across the mucosa, which can lead to the development of distant organ injury and multiple organ failure. Tight junction function is highly regulated by membrane-associated proteins including occludin and zonula occludens protein 1 (ZO-1), which can be modulated by systemic inflammation. We hypothesized that (1) burn injury leads to gut barrier injury, and (2) phosphodiesterase inhibition will attenuate these burn-induced changes.

Pentoxifylline attenuates pulmonary inflammation and neutrophil activation in experimental acute pancreatitis.

Objectives: Acute pancreatitis (AP) is associated with a systemic inflammatory response. Pentoxifylline (PTX) has been shown to attenuate neutrophil activation and end-organ injury in shock states such as hemorrhage and sepsis. We hypothesized that PTX would down-regulate AP-induced lung injury.

Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition.

Objective: The objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-alpha) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells.

Introduction: The production of TNF-alpha following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-alpha production in the presence of LPS remains unclear.

Hepatic transcription factor activation and proinflammatory mediator production is attenuated by hypertonic saline and pentoxifylline resuscitation after hemorrhagic shock.

Background: Fluid resuscitation can contribute to postshock inflammation and the development of end organ injury. We have previously observed an attenuation in pulmonary and ileal inflammation when hypertonic saline and pentoxifylline (HSPTX) were concomitantly administered after hemorrhage. We hypothesized that the attenuation in hepatic injury observed with HSPTX is associated with the reduction of transcription factor activation and proinflammatory mediator production when compared with Ringer's lactate (RL).

Pentoxifylline attenuates lung injury and modulates transcription factor activity in hemorrhagic shock.

Background: 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.

Methods: Male Sprague Dawley rats underwent a 1 h period of hypotension and resuscitation with RL (32 mL/kg) or RL + PTX (25 mg/kg).

The effects of a novel resuscitation strategy combining pentoxifylline and hypertonic saline on neutrophil MAPK signaling.

Background: The combination of hypertonic saline (HS) and pentoxifylline (PTX) has been shown to synergistically downregulate neutrophil oxidative burst in vitro. We investigated the effects of HS/PTX on human neutrophil mitogen-activated protein kinase (MAPK) signaling and the role of Protein kinase A (PKA) in this process.

Methods: Isolated neutrophils were treated with PTX (2 mmol/L), HS10 (10 mmol/L above isotonicity), and HS40 (40 mmol/L above isotonicity) alone or in combination for determination of intracellular cyclic adenosine monophosphate (cAMP) concentrations.

Hypertonic saline and pentoxifylline attenuates gut injury after hemorrhagic shock: the kinder, gentler resuscitation.

Background: We have previously demonstrated that postshock resuscitation with Hypertonic saline and Pentoxifylline (HSPTX) attenuates pulmonary and histologic gut injury when compared with Ringer's lactate (RL). In this study, we hypothesized that the decrease in gut injury observed with HSPTX is associated with the attenuation of inducible nitric oxide synthase (iNOS) activity and production of ileal proinflammatory mediators after hemorrhagic shock.

Methods: In a rat model of hemorrhagic shock, resuscitation was conducted with RL (32 mL/kg; n = 7) or HSPTX (4 mL/kg 7.

From acute pancreatitis to end-organ injury: mechanisms of acute lung injury.

Background: Multi-organ dysfunction, and in particular lung injury, is often responsible for the unfavorable outcome of patients with severe acute pancreatitis. Understanding of the mechanisms by which local inflammation in the pancreas leads to end-organ injury is crucial for the development of new therapeutic strategies.

Methods: A MEDLINE search was performed with the terms "acute pancreatitis," "lung injury," "inflammatory response," "SIRS," and "multi-organ dysfunction.

Patient factors and operating room resuscitation predict mortality in traumatic abdominal aortic injury: a 20-year analysis.

Background: Injuries to the abdominal aorta are rare and remain one of the most lethal causes of early death in trauma. The purposes of this study were to identify primary predictors of mortality and to examine the impact of a well-established operating room resuscitation protocol on survival in patients with traumatic aortic injury.

Methods: A 20-year retrospective review was performed of medical records and autopsy reports of trauma patients admitted with confirmed injury to the abdominal aorta.

Hypertonic saline and pentoxifylline reduces hemorrhagic shock resuscitation-induced pulmonary inflammation through attenuation of neutrophil degranulation and proinflammatory mediator synthesis.

Background: Ringer's lactate (RL), the current standard resuscitation fluid, potentiates neutrophil activation and is associated with pulmonary inflammation. Resuscitation with hypertonic saline and pentoxifylline (HSPTX) has been shown to attenuate hemorrhagic shock-induced injury when compared with RL. Because the neutrophil plays a major role in postshock inflammation, we hypothesized that HSPTX reduces pulmonary inflammation after resuscitation in comparison to RL.

Pentoxifylline attenuates stored blood-induced inflammation: A new perspective on an old problem.

Background: Blood transfusion is a risk factor for many inflammatory processes. Its supernatant fraction has been proven to activate neutrophils. We hypothesized that pentoxifylline (PTX) would attenuate stored blood-induced neutrophil activation and pro-inflammatory mediator production.

Neutrophil degranulation and the effects of phosphodiesterase inhibition.

Background: Neutrophils play a major role as the first line in host defense after exposure to bacterial products. However, an exaggerated inflammatory response characterized by overwhelming neutrophil activation can be injurious to the host. Pentoxifylline (PTX), a nonspecific phosphodiesterase inhibitor, has been shown to attenuate neutrophil oxidative burst and decrease proinflammatory mediator synthesis.

HSPTX protects against hemorrhagic shock resuscitation-induced tissue injury: an attractive alternative to Ringer's lactate.

Background: Conventional fluid resuscitation with Ringer's lactated (RL) activates neutrophils and causes end-organ damage. We have previously shown that HSPTX, a combination of small volume hypertonic saline (HS) and pentoxifylline (PTX), a phosphodiesterase-inhibitor, downregulates in vitro neutrophil activation and proinflammatory mediator synthesis. Herein, we hypothesized that HSPTX decreases end-organ injury when compared with RL in an animal model of hemorrhagic shock.