Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

INTRODUCTION: The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis. METHODS: Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions. RESULTS: Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness. CONCLUSIONS: In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function

The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia

BACKGROUND: Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion. METHODS: We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD). RESULTS: There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects. CONCLUSIONS: Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion

The impact of place and legacy framing on climate action: a lifespan approach

Despite several decades of research on more effectively communicating climate change to the general public, there is only limited knowledge about how older adults engage with an issue that will shape and define future generations. We focus on two key factors that may motivate younger and older adults to engage in climate change action, legacy concern and place attachment, and assess whether older adults differ in any appreciable way from the general population in this domain. We randomly exposed participants of different ages to either a Legacy, Place, or control writing induction task before they completed various self-report measures. Both induction conditions were associated with significantly greater pro-environmental behavioral intentions and donations for all age groups when compared to the control condition. Legacy motivation and biophilia were used as manipulation checks and found to partially mediate these effects. Findings suggest that legacy and place message framing may be useful in prompting adults of all ages to take action to help combat climate change

Novel Role of the Human Alveolar Epithelium in Regulating Intra-Alveolar Coagulation

Intra-alveolar fibrin deposition is a common response to localized and diffuse lung infection and acute lung injury (ALI). We hypothesized that the alveolar epithelium modulates intra-alveolar fibrin deposition through activation of protein C. Our obejctives were to determine whether components of the protein C activation pathway are present in the alveolar compartment in ALI and whether alveolar epithelium is a potential source. In patients with ALI, pulmonary edema fluid levels of endothelial protein C receptor (EPCR) were higher than plasma, suggesting a source in the lung. To determine whether alveolar epithelial cells are a potential source, protein C activation by A549, small airway epithelial, and primary human alveolar epithelial type II cells was measured. All three cell types express thrombomodulin (TM) and EPCR, and activate protein C on the cell surface. Activation of protein C was inhibited by cytomix (TNF-α, IL-1β, and IFN-γ). Release of EPCR and TM into the conditioned medium was inhibited by the metalloproteinase inhibitors tumor necrosis factor protease inhibitor (TAPI) and GM6001, indicating that the shedding of EPCR and TM from the alveolar epithelium is mediated by a metalloproteinase. These findings provide new evidence that the alveolar epithelium can modulate the protein C pathway and thus could be an important determinant of alveolar fibrin deposition. Local fibrin deposition may be a fundamental mechanism for the lung to localize and confine injury, thus limiting the risk of dissemination of injury or infection to the systemic circulation

Biomarkers of disordered coagulation and fibrinolysis in acute lung injury and acute respiratory distress syndrome

Comparison of plasma levels of biomarkers of disordered coagulation and fibrinolysis in 50 patients with acute lung injury and acute respiratory distress syndrome ventilated with low-tidal-volume ventilation. Plasma levels of protein C were significantly lower in nonsurvivors compared with survivors. Plasma levels of thrombomodulin were significantly higher in nonsurvivors compared with survivors. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) were significantly higher in nonsurvivors compared with survivors. Data shown as boxplots: horizontal line, median; box, 25th to 75th percentiles; error bars, 10th to 90th percentiles. *= 0.0003, **= 0.005 and = 0.01 compared with survivors, Mann–Whitney U test.<p><b>Copyright information:</b></p><p>Taken from "Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury"</p><p>http://ccforum.com/content/12/2/R41</p><p>Critical Care 2008;12(2):R41-R41.</p><p>Published online 21 Mar 2008</p><p>PMCID:PMC2447583.</p><p></p

Vascular endothelial cadherin shedding is more severe in sepsis patients with severe acute kidney injury

Abstract Background Vascular endothelial cadherin (VE-cadherin) is a membrane protein that is the major component of adherens junctions between endothelial cells. It is crucial for regulating vascular integrity, endothelial permeability, and angiogenesis. During inflammatory processes, VE-cadherin is shed into circulation (sVE-cadherin). Plasma sVE-cadherin is elevated in sepsis, malignancy, autoimmune diseases, and coronary atherosclerosis. However, the relationship between specific organ failures, especially severe acute kidney injury (AKI) defined by requirement for renal replacement therapy (AKI-RRT), and plasma sVE-cadherin levels in severe sepsis has not been well studied. Methods The present study is a prospective study of critically ill adults with sepsis and acute respiratory failure (age ≥ 18 years) enrolled in the Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma sVE-cadherin was measured at study enrollment. Primary analysis focused on the association between sVE-cadherin levels and the development of AKI, AKI-RRT, other organ dysfunction as defined by Brussels organ failure scores, pulmonary versus non-pulmonary sepsis, acute respiratory distress syndrome (ARDS), and in-hospital mortality. Results Of 228 severe sepsis patients included, 80 (35%) developed AKI-RRT. Plasma sVE-cadherin levels at enrollment were significantly higher in patients with AKI-RRT compared with patients without AKI-RRT (p = 0.003). Plasma sVE-cadherin levels by quartile were significantly higher in severe sepsis patients with acute kidney injury stage 3 (p = 0.044) as defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Patients with greater than 2 organ failures had higher plasma sVE-cadherin levels than patients with 2 or fewer organ failures (p < 0.001). In a multivariable analysis, plasma sVE-cadherin was independently associated with AKI-RRT (odds ratio 6.44 per log increase in plasma sVE-cadherin, 95% CI 1.126–36.847, p = 0.036). Plasma sVE-cadherin levels were significantly higher in patients with non-pulmonary sepsis compared to pulmonary sepsis (p < 0.001). Conclusion Shedding of sVE-cadherin is associated with severe acute kidney injury and with more severe organ dysfunction in patients with sepsis, suggesting that breakdown of endothelial adherens junctions may contribute to the pathogenesis of organ dysfunction in sepsis. Further studies of sVE-cadherin as a biomarker of disease severity in clinical sepsis are needed to better elucidate the role of VE-cadherin shedding in sepsis-induced severe organ dysfunction