Abstract
Background: Nerve injury induced protein 1 (Ninjurin 1 (Ninj1)) was first identified in Schwann cells and neurons contributing to cell adhesion and nerve regeneration. Recently, the role of Ninj1 has been linked to inflammatory processes in the central nervous system where functional repression reduced leukocyte infiltration and clinical disease activity during experimental autoimmune encephalomyelitis in mice [1]. But Ninj1 is also expressed outside the nervous system in various organs such as the liver and kidney as well as on leukocytes [2,3]. Therefore, we hypothesized that Ninj1 contributes to inflammation in general; that is, also outside the nervous system, with special interest in the pathogenesis of sepsis. Methods: Ninj1 was repressed by transfecting HMEC-1 cells, a human dermal microvascular endothelial cell line with siRNA targeting Ninj1 (siNinj1) or a negative control (siC). Subsequently, cells were stimulated with 100 ng/ml LPS (TLR4 agonist), 3 μg/ml LTA (TLR2 agonist) or 100 n/ml poly(I:C) (TLR3 agonist) for 3 hours. The inflammatory response was analyzed by real-time PCR. In addition, transmigration of neutrophils across a HMEC-1 monolayer was measured using transwell plates (pore size 3 μm). Results: Repression of Ninj1 by siRNA reduced Ninj1 mRNA expression in HMEC about 90% (Figure 1A). Reduced Ninj1 expression decreased neutrophil migration to 62.5% (Figure 1B) and TLR signaling. In detail, knockdown of Ninj1 significantly reduced TLR-2 and TLR-4 triggered expression of ICAM-1 and IL-6 (Figure 1C,D) while poly(I:C)-induced expression was only slightly reduced. To analyze a more specific TLR-3 target, we measured IP-10 mRNA expression, which was also significantly reduced in siNinj1-transfected cells (Figure 1E). Conclusion: Our in vitro data strongly indicated that Ninj1 is involved in regulation of TLR signaling and therewith contributes to inflammation. In vivo experiments will clarify its impact on systemic inflammation.
Highlights
Central venous catheterization (CVC) is a frequently performed procedure in ICUs for both monitoring and definitive central venous access
A functional FCGR2A polymorphism leading to amino acid change of histidine (H) to arginine (R) at position 131 appears to be a major candidate in adult invasive pneumococcal diseases (IPD)
Our study revealed no significant difference between the low-tidal volume ventilation and the traditional strategy ventilation groups in mean (± SD) ventilator-free days (12 ± 9 vs. 11 ± 8, P = non significant) respectively), the number of days without ventilator use during the first 28 days after randomization was greater in the low-tidal volume group
Summary
Central venous catheterization (CVC) is a frequently performed procedure in ICUs for both monitoring and definitive central venous access. Conclusion: GAPDH mRNA expression in patients with severe sepsis showed a marked increase compared with controls These data question the suitability of GAPDH as a housekeeper gene in gene expression profiling studies in sepsis. Cytokine gene expression profiling using the Quantigene plex assay is able to demonstrate distinct profiles in patients with severe sepsis This has the potential to be developed into a diagnostic/prognostic tool with larger studies. Results: In all studies we observed that elevated blood levels of ESM-1 correlated with the severity of sepsis and the poor outcome in patients with severe sepsis or in septic shock at ICU admission. In a context where respiratory failure is still the first cause of death in sepsis, our study analysis suggests that blood levels of ESM-1 may be a useful early biomarker of lung tissue injury and respiratory failure in ICU patients. Blood culture resulted positive in 40.6% of patients with sepsis
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