Abdel Salous

Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice

Lysophosphatidic acid (LPA) is a bioactive lipid mediator. Concentrations of the major LPA species in mouse plasma decreased uniformly following administration of a potent selective inhibitor of the LPA-generating lysophospholipase D autotaxin, identifying an active mechanism for removal of LPA from the circulation. LPA, akylglycerol phosphate (AGP), sphingosine 1-phosphate (S1P), and a variety of structural mimetics of these lipids, including phosphatase-resistant phosphonate analogs of LPA, were rapidly eliminated (t1/2 < 30 s) from the circulation of mice following intravenous administration of a single bolus dose without significant metabolism in situ in the blood. These lipids accumulated in the liver. Elimination of intravenously administered LPA was blunted by ligation of the hepatic circulation, and ∼90% of LPA administered through the portal vein was accumulated by the isolated perfused mouse liver at first pass. At early times following intravenous administration, more LPA was associated with a nonparenchymal liver cell fraction than with hepatocytes. Primary cultures of nonparenchymal liver cells rapidly assimilated exogenously provided LPA. Our results identify hepatic uptake as an important determinant of the bioavailability of LPA and bioactive lysophospholipid mimetics and suggest a mechanism to explain changes in circulating LPA levels that have been associated with liver dysfunction in humans.

Mice With Targeted Inactivation of Ppap2b in Endothelial and Hematopoietic Cells Display Enhanced Vascular Inflammation and Permeability

Objective—Lipid phosphate phosphatase 3 (LPP3), encoded by the PPAP2B gene, is an integral membrane enzyme that dephosphorylates, and thereby terminates, the G-protein–coupled receptor–mediated signaling actions of lysophosphatidic acid (LPA) and sphingosine-1-phosphate. LPP3 is essential for normal vascular development in mice, and a common PPAP2B polymorphism is associated with increased risk of coronary artery disease in humans. Herein, we investigate the function of endothelial LPP3 to understand its role in the development and human disease. Approach and Results—We developed mouse models with selective LPP3 deficiency in endothelial and hematopoietic cells. Tyrosine kinase Tek promoter–mediated inactivation of Ppap2b resulted in embryonic lethality because of vascular defects. LPP3 deficiency in adult mice, achieved using a tamoxifen-inducible Cre transgene under the control of the Tyrosine kinase Tek promoter, enhanced local and systemic inflammatory responses. Endothelial, but not hematopoietic, cell LPP3 deficiency led to significant increases in vascular permeability at baseline and enhanced sensitivity to inflammation-induced vascular leak. Endothelial barrier function was restored by pharmacological or genetic inhibition of either LPA production by the circulating lysophospholipase D autotaxin or of G-protein–coupled receptor–dependent LPA signaling. Conclusions—Our results identify a role for the autotaxin/LPA-signaling nexus as a mediator of endothelial permeability in inflammation and demonstrate that LPP3 limits these effects. These findings have implications for therapeutic targets to maintain vascular barrier function in inflammatory states.

Blood relatives: dynamic regulation of bioactive lysophosphatidic acid and sphingosine-1-phosphate metabolism in the circulation.

Lysophosphatidic acid and sphingosine 1-phosphate are bioactive lipid mediators with potent effects on cardiovascular development and vascular function. New studies define dynamic mechanisms that maintain physiologically relevant levels of both lipids in the blood. We review the mechanisms controlling the production, metabolism, and distribution of these lipids between vascular cells, circulating blood components, and the plasma.

Synergistic Effect of Anemia and Red Blood Cells Transfusion on Inflammation and Lung Injury

Anemia and resultant red blood cell transfusion may be associated with adverse long-term clinical outcomes. To investigate the mechanism(s) responsible, we profiled inflammatory biomarkers and circulating levels of the bioactive lysophospholipid mediator sphingosine-1-phosphate (S1P) in control and anemic mice with or without LPS-induced systemic inflammation. Acute anemia or lipopolysaccharide (LPS) challenge alone triggered an increase of circulating levels of the inflammatory markers IL-6 and keratinocyte-derived chemokine (CXCL1/KC). Moreover, administration of LPS to anemic mice reduced circulating S1P levels and augmented lung injury and pulmonary vascular permeability. Transfusion of aged, but not fresh, red blood cells (RBCs) worsened pulmonary vascular leak. S1P levels decline markedly during storage of mouse RBCs. Loading stored murine RBCs with S1P prior to transfusion partially attenuated anemia-associated acute pulmonary vascular leak. Taken together, our results indicate that anemia and systemic inflammation can alter the S1P buffering capacity of RBCs, suggesting possible strategies for alleviating transfusion-related lung injury in clinical practice.

Trends in mental health of an adolescent medicine clinic patient population.

The correlation between exposure to forms of violence and development of mental disorders in victims is well established. The purpose of this paper was to identify mental health problems in an adolescent medicine clinic population in Lexington, KY and to investigate potential correlation of mental disorders with psychosocial factors. Data were gathered from the charts of 169 adolescent clinic patients (age 10-22) seen in the clinic for mental health care and analyzed using Excel. Of the patient population, 68% were urban, whereas 32% were rural. In terms of gender, 40% of the patients were male and 60% were female, 80% were white, 13% black, and 7% had other racial background(s). The most prevalent mental disorders in this group were depression 32.12%, 13% with generalized anxiety disorder, 8.2% with an attention deficit disorder (including ADHD), and 5.76% with an adjustment disorder. The abovementioned demographic trends showed that depression continues to be the most common mental health problem in this population regardless of gender, ethnic origin, or economic status. This finding highlights the need for availability of mental health support to this patient population. Further work is needed to spotlight the most significant psychosocial factors and root causes of mental health conditions in this age group.

Substance abuse among adolescents: a cross-cultural review

This review aims to provide a global perspective on substance abuse among adolescents across different cultures and to review appropriate strategies in communicating with the adolescent population about substance abuse. Drug abuse continues to be a major public health issue in the United States, especially among adolescents. The attitude toward and involvement in drug abuse among adolescents is a complex problem shaped by multiple psychosocial parameters. Psychosocial variables such as ethnicity, and religion, and group dynamics, while deeply intertwined in shaping the cultural identity of adolescents, also deliver their impact to substance abuse in this patient population. In a society largely composed of a diverse immigrant population, cultural sensitivity of the healthcare provider to patient culture is critical to patient centered care and effective clinical outcomes. Summary: Cultural sensitivity of healthcare providers is critical to addressing the health needs of adolescent patients in the increasingly culturally heterogeneous patient population of the United States.