Anti-HMGB1 polyclonal antibody

Background. Metrics for evaluating low-quality kidneys have failed to predict outcomes or reduce the kidney refusal and discard rates. Kidneys from extended-criteria donors (ECDs) and kidneys with >= 85% kidney donor profile indexes (KDPIs) might have different sensitivities to the proinflammatory milieu generated by brain death. We aimed to identify gene expression profile differences in innate immunity pathways between low-quality and ideal kidneys. Methods. Preimplantation kidney biopsies from ECD (n = 41) and standard-criteria donor (n = 39) were evaluated for real-time quantitative polymerase chain reaction gene expression using the TaqMan Gene Expression Array Plates system for genes Toll-like receptor-4 (TLR4), high-mobility group box 1, nuclear factor kappa beta, myeloid differentiation primary response 88, interferon (IFN)-gamma, interleukin (IL)1-beta, tumor necrosis factor alpha, caspase-1 (CASP1), intercellular adhesion molecule 1, IL-10, heme oxygenase 1 hypoxia-inducible factor 1 (HIF-1), monocyte chemotactic protein 1, transforming growth factor beta 1, TIR-domain containing adapter inducing interferon-beta (TRIF), TRIF-related adaptor molecule, interferon regulatory factor 3 (IRF-3), receptor-interacting protein 1, IFN beta-1, and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex. Gene expression was also evaluated in kidneys with KDPI >= 85. Results. ECD biopsies showed significantly higher expression of IL-10, TLR4, high-mobility group box 1, IFN-gamma, TRIF-related adapter molecule, IRF-3, HIF-1, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex, CASP1, and IL-1 beta (P < 0.05) compared with standard-criteria donor biopsies. IRF-3, HIF-1, and CASP1 were exclusively upregulated in ECD kidneys. Compared with kidneys with KDPIs <85%, kidneys with KDPIs >= 85% had very similar gene transcripts as those observed in ECD kidneys, except that tumor necrosis factor alpha and monocyte chemotactic protein 1 expression was only elevated in kidneys with KDPIs >= 85%. Significant positive correlations were found between the different genes upregulated and the increase in KDPIs. Conclusions. Our results showed that TLR4 and inflammasome pathways are enhanced in low-quality kidneys and suggest that blocking of some targets might improve transplant outcomes and reduce discard rates.

Purpose: Neuroinflammation and disruption of blood brain barrier (BBB) are important players in epileptogenesis, ictogenesis and pharmacoresistance. In this context, we investigated blood levels of HMGB1 and other inflammatory and BBB markers after generalized and focal to bilateral tonic-clonic seizures in serum, summarized under the term generalized convulsive seizures (GCS). Methods: We included consenting adults who were admitted to the epilepsy monitoring unit. Blood samples were drawn at baseline and immediately after a GCS as well as after 2, 6 and 24 h. We measured leukocytes, c-reactive protein (CRP), the danger-associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and S100, receptor of advanced glycation end products (RAGE) alongside the BBB markers intercellular adhesion molecule-1 (ICAM1) and matrix metalloproteinase 9 (MMP9). Noradrenaline and lactate measurements were available from a previous study. P-levels < 0.05 were regarded as significant. Results: Twenty-eight patients with 28 GCS were included. Leukocytosis occurred immediately after GCS and normalized within two hours (p < 0.001). S100 and HMGB1 both increased by similar to 80 % (p < 0.001). MMP9 peaked after six hours with levels at 48.6 % above baseline. RAGE decreased by 17.6 % with a nadir at 24 h. CRP increased by 118 % with a peak at 24 h. ICAM1 remained stable (p = 0.068). Postictal HMGB1 correlated with postictal leukocytosis (r = 0.42; p = 0.025) and with MMP9 levels six hours later (r = 0.374; p = 0.05). Postictal lactate levels correlated with MMP9 at 6 h (r = 0.48; p = 0.01) and CRP at 24 h (r = 0.39; p = 0.04). Postictal noradrenaline correlated with lactate (r = 0.57; p = 0.02) and leukocytes (r = 0.39; p = 0.047). Discussion: The serum level of the DAMPs HMGB1 and S100 increase immediately after GCS. The hypothetical mechanism includes central nervous processes, such as glutamate toxicity and ROS release from seizing neurons but also muscular tissues. BBB breakdown is marked by the release of MMP9. Further research is needed to understand the complex interactions between electrical and metabolic stress, neuroinflammation and BBB mechanics in seizures and epilepsy. Conclusion: Our study reveals signs of inflammation, neuronal damage and transitory disruption of BBB following single GCS, underscoring the widespread and possibily detrimental effects of recurrent seizures on brain properties. The long term impact on the disease course, however, is unclear.