Increase In Pulmonary Permeability Research Articles

Integrative Omics of Aspiration in Lung Transplantation

<h3>Purpose</h3> Prior studies have defined lung biomarkers associated with graft injury in lung transplant. We have developed a lung metabolomic profile of bile acid aspiration. We correlated the metabolites of aspiration to other omic measures of lung injury. <h3>Methods and Materials</h3> We performed metabolomic profiling on 29 recipients who had episodic bile detected in lung lavages. Each patient contributed a lung lavage specimen that was positive and negative for bile acid resulting in 58 total samples. Lavages were tested using C18 liquid chromatography coupled to mass spectroscopy. We used three approaches: Principle component analysis, Principle component regression, and Hierarchical clustering analysis. 252 Bile acid associated features were found at the intersection of these approaches. Cluster analysis developed 6 clusters positively or negatively associated with aspiration. Clusters were evaluated against biomarkers CXCL9, CXCL10, MCP1, FoxP3 and GranzymeB. <h3>Results</h3> Bile acid aspiration was associated with a distinct metabolomic profile resolved using 3 bioinformatics approaches with a bias of increased small species in the bile positive samples, suggesting an increase in pulmonary permeability with aspiration. Presence of bile only weakly correlated with the other omic markers of injury (r .17-.26, p .09-.2). Individual bile acid associated clusters showed significant positive and negative correlation with known other markers of injury. [figure 1] <h3>Conclusions</h3> In this discovery phase study there is a strong association between metabolomic features of bile acid aspiration and known biomarkers of injury from other omic platforms. This strengthens the claim that aspiration of gastric contents is dangerous and also provides an avenue for risk stratification in a prospective cohort of patients.

Orthopedic Trauma-Induced Pulmonary Injury in the Obese Zucker Rat

Obese subjects with orthopedic trauma exhibit increased inflammation and an increased risk of pulmonary edema. Prostaglandin E(2) (PGE(2) ) production is elevated during inflammation and associated with increased vascular permeability. We hypothesize that pulmonary edema in obesity following orthopedic trauma is due to elevated PGE(2) and resultant increases in pulmonary permeability. Orthopedic trauma was induced in both hindlimbs in lean (LZ) and obese Zucker rats (OZ). On the following day, plasma interleukin-6 (IL-6) and PGE(2) levels, pulmonary edema, and pulmonary gas exchange capability were compared between groups: LZ, OZ, LZ with trauma (LZT), and OZ with trauma (OZT). Vascular permeability in isolated lungs was measured in LZ and OZ before and after application of PGE(2) . As compared with the other groups, the OZT exhibited elevated plasma IL-6 and PGE(2) levels, increased lung wet/dry weight ratio and bronchoalveolar protein concentration, and an impaired pulmonary gas exchange. Indomethacin treatment normalized plasma PGE(2) levels and pulmonary edema. Basal pulmonary permeability in isolated lungs was higher in OZ than LZ, with a further increase in permeability following treatment with PGE(2) . These results suggest that pulmonary edema in OZ following orthopedic trauma is due to an elevated PGE(2) and resultant increases in pulmonary permeability.

Growth Hormone Releasing Peptide-2, a Ghrelin Agonist, Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are the most common complications of sepsis, and the mortality of sepsis-induced ALI remains high in critically ill patients. Growth hormone releasing peptide-2 (GHRP-2), a ghrelin agonist, has been shown to exert beneficial effects on various inflammatory diseases. We therefore explored whether GHRP-2 possesses anti-inflammatory properties in the pathogenesis of lipopolysaccharide (LPS)-induced ALI. Male Sprague-Dawley rats were intratracheally instilled with LPS (2 mg/kg) to induce ALI. ALI was confirmed with lung tissue injury (histopathological examination), enhanced lung edema (wet-to-dry weight ratio), and neutrophil infiltration (myeloperoxidase activity) at 6 h after LPS exposure. The analyses of bronchoalveolar lavage fluid showed the significant increases in pulmonary permeability (total cells and protein) and the levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). In contrast, these lung injury indexes were attenuated in rats that received a subcutaneous injection of GHRP-2 (100 microg/kg) 0.5 h prior to LPS administration. To further explore the potential anti-inflammatory mechanism of GHRP-2 in LPS-induced ALI, we assessed of nuclear factor-kappaB (NF-kappaB) activity in lung tissues at 6 h after LPS challenge. We thus found that pretreatment with GHRP-2 markedly suppressed the activation of NF-kappaB in lung tissues. These results indicate that GHRP-2 attenuated LPS-induced ALI. Early protection appears to be mediated partly through the inhibition of NF-kappaB pathway activation. The present study indicates that GHRP-2 acts as a potential therapeutic reagent for treating ALI.

Secondary effects of femoral instrumentation on pulmonary physiology in a standardised sheep model:: What is the effect of lung contusion and reaming?

Intramedullary nailing is the treatment of choice for patients with femoral shaft fractures. However, there is an ongoing debate in multiple trauma patients with associated lung contusion when primary or secondary definitive stabilisation of the long bone fracture should be performed, as nailing is thought to play an important role in the pathogenesis of adult respiratory distress syndrome (ARDS). In a standardised sheep model, this study aimed to quantify the development of acute pulmonary endothelial changes, to assess the activation of polymorphonuclear leucocytes (PMNL) and to observe the effects on the coagulation system associated with the reamed nailing procedure. Furthermore, the effect of coexisting lung contusion in an experimental model was evaluated. The animals were randomly assigned to one of four different groups (6 animals/group). In control groups, only a sham operation (thoracotomy) was performed, whereas in study groups, lung contusion was induced prior to femoral stabilisation either by external fixation or reamed femoral nailing. Using bronchoalveolar lavage (BAL) pulmonary permeability changes were quantified and PMNL activation was assessed by chemiluminescence. Additionally PMNL diapedesis and interstitial lung oedema were determined by histological analysis. All animals were sacrificed 4 h after the start of the femoral instrumentation. Without an associated lung injury, instrumentation of the femoral canal with the reamed nailing technique induced a transient increase in pulmonary permeability. In the face of an induced lung contusion, reamed femoral nailing resulted in significant increases in PMNL activation, pulmonary permeability and interstitial lung oedema, compared with external fixation. Without pulmonary contusion, reaming of the femoral canal was associated with a transient increase in pulmonary permeability. This was exacerbated in the presence of lung contusion along with increased PMNL activation. External fixation did not provoke similar changes. The findings of this study support the view that reaming of the femoral canal should be avoided in polytrauma patients with severe chest trauma as it could act as an additional stimulus for adverse outcome. Temporary external fixation appears to be a safe method for fracture stabilisation until inflammatory and coagulatory disturbances after trauma have been normalized.

A 21-aminosteroid, U-74006F, attenuates endotoxin-induced lung injury in awake sheep.

The purpose of the present study was to examine the efficacy of U-74006F, a 21-aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6-keto-prostaglandin (PG) F1 alpha in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 microgram/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U-74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U-74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U-74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6-keto-PGF1 alpha levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U-74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.

Coagulatory response after femoral instrumentation after severe trauma in sheep.

Pulmonary complications after intramedullary femoral nailing have been attributed to bone marrow fat embolization and a variety of cascade effects. We investigated whether the coagulatory response after intramedullary femoral nailing in merino sheep is altered after severe trauma. Adult merino sheep were submitted to hemorrhagic shock (2 hours, 50 mm Hg) and unilateral lung contusion. After recovery (day 3 of the study), reamed femoral intramedullary nailing (RFN), unreamed femoral intramedullary nailing (UFN), or plate osteosynthesis of the femur (P) was performed. Pulmonary artery pressure, central venous levels of factor V, protein C, antithrombin III, and fibrinogen, were determined. At 1 and 3 days before and after femur instrumentation, pulmonary capillary permeability was assessed on the basis of the comparative albumin content in bronchoalveolar lavage fluid. Group RFN, n=8; group UFN, n=7; group P, n=6. A significant (p < 0.05) postoperative increase in the relative albumin content in terms of the BAL/plasma albumin ratio was measured in group RFN (day 3 preoperatively: 0.38+/-0.05 day 3 postoperatively: 0.53+/-0.06, p < 0.05 (RFN vs. P), which contrasted with group UFN (day 3 preoperatively: 0.44+/-0.09, day 3 postoperatively: 0.46+/-0.09, no significant difference). This evidence of increased pulmonary permeability occurred in association with evidence of increased activation of coagulation factors (data presented as percentage of day 3 preoperative baseline values). The data for fibrinogen (15 min postoperatively) is as follows: group RFN, 74+/-9% (p < 0.05 vs. P); group UFN, 83+/-8% (not significant); group P, 98+/-6%. The data for antithrombin III (15 min. postoperatively) is as follows: group RFN, 72+/-6% (p < 0.05 vs. P); group UFN, 79+/-8% (not significant); group P, 92+/-8% (not significant). After severe trauma, an increase of pulmonary permeability after reamed femoral nailing was associated with increased consumption of coagulation factors. After unreamed nailing, a similar trend was apparent, but this was not found to be statistically significant. These data provide support for the theory that after severe trauma, unreamed femoral nailing reduces but does not abolish pulmonary sequelae when compared with reamed femoral nailing.

Inactivation of xanthine oxidase activity by tungstate attenuates the increase in pulmonary permeability associated with liver ischemia

Inactivation of xanthine oxidase activity by tungstate attenuates the increase in pulmonary permeability associated with liver ischemia

Sensitivity to endotoxin in rabbits is increased after hemorrhagic shock

The immunoinflammatory response following trauma and hemorrhage may predispose to the development of sepsis and multiple-organ failure syndrome. Cardiac output (CO), arterial pressure, arterial PO2, and pulmonary permeability index were measured. We examined the sensitivity of rabbits to infusions of lipopolysaccharide (LPS) after hemorrhagic shock. Shock was produced by reducing CO to 40% of baseline for 90 min, followed by resuscitation with shed blood and then with lactated Ringer solution to maintain CO near baseline. Animals were assigned to three groups: 1) hemorrhagic shock only, 2) LPS only, and 3) hemorrhagic shock + LPS. Groups 1 and 3 were subjected to hemorrhagic shock on day 1. Escherichia coli LPS was infused (1.0 microgram/kg i.v.) into groups 2 and 3 on day 2. Fluid resuscitation with lactated Ringer solution was continued in an effort to maintain CO at baseline. Five hours after LPS infusion, 125I-albumin was injected intravenously, and rabbits were killed 1 h later for measurement of pulmonary permeability index. LPS infusion after shock (group 3) caused significant decreases in CO, arterial pressure, and PO2 and an increase in pulmonary permeability. These changes were not seen in the groups 1 and 2. We conclude that hemorrhagic shock and resuscitation result in a proinflammatory state, leading to increased sensitivity to subsequent exposure to LPS.