Systemic Soluble Receptor for Advanced Glycation Endproducts Is a Biomarker of Emphysema and Associated with AGER Genetic Variants in Patients with Chronic Obstructive Pulmonary Disease

Rationale: Emphysema in COPD can be characterized by high resolution chest CT (HRCT); however, the repeated use of HRCT is limited due to concerns regarding radiation exposure and cost. Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation end products (sRAGE), a candidate systemic biomarker identified in this study, with SNPs in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods and Measurements: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 COPD patients enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1847 COPD patients, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Main results: sRAGE was identified as a biomarker of DLCO and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased GOLD stage and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (p<0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (p=0.0014) and ECLIPSE (7.07x10-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (p=0.01) and DLCO (p=0.01) in the TESRA study. Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Abstract word count: 249 words

CD38 Facilitates Recovery from Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It causes progressive tissue atrophy and consequent neurological dysfunctions. TBI is accompanied by neuroinflammation, a process mediated largely by microglia. CD38 is an ectoenzyme that promotes transmembrane signaling via the synthesis of potent calcium mobilizing agents or via its receptor activity. CD38 is expressed in the brain in various cell types including microglia. In previous studies, we showed that CD38 regulates microglial activation and response to chemokines. In view of the important role of neuroinflammation in TBI and the effects of CD38 on microglial responses, the present study examines the role of CD38 in the recovery of mice from closed head injury (CHI), a model of focal TBI. For this purpose, CD38-deficient and wild-type (WT) mice were subjected to a similar severity of CHI and the effect of the injury on neurobehavioral and cognitive functions was assessed by the Neurological Severity Score (NSS) and the Object Recognition Test, at various time points post-injury. The results show that recovery after CHI (as indicated by the NSS) was significantly lower in CD38-deficient mice than in WT mice and that the object recognition performance after injury was significantly impaired in injured CD38-deficient mice than in WT mice. In addition, we also observed that the amount of activated microglia/macrophages at the injury site was significantly lower in CD38-deficient mice compared with WT mice. Taken together, our findings indicate that CD38 plays a beneficial role in the recovery of mice from CHI and that this effect is mediated, at least in part, via the effect of CD38 on microglia responses