Search

Background: Cerebral ischemia is characterized by its rapid onset and high rates of recurrence, morbidity, and mortality, with blood-brain barrier (BBB) permeability playing a vital role in brain injury. Therefore, it is important to understand the molecular mechanism which regulates the BBB during cerebral ischemia. Materials and methods: An in vitro model of oxygen-glucose deprivation (OGD) and an in vivo model of cerebral ischemia/reperfusion (I/R) were constructed. PD-1 overexpression vectors and vectors containing si-RNA were transfected and injected into in vitro and in vivo models. Western blotting, real-time quantitative PCR (qPCR), immunofluorescence (IF) analysis, and immunohistochemical staining were employed to evaluate the expression levels of programmed cell death-1 (PD-1), microglia M1 and M2 biomarkers, and tight junction proteins. Flow cytometry and ELISA were used to measure the levels of pro-inflammatory cytokines. The BBB permeability of brain tissues was evaluated by Evans blue dye (EBD) extravasation and transendothelial electrical resistance (TEER). Brain water content was measured to assess the extent of inflammatory exudation. The infarct volume and neurological severity score (NSS) were used to assess the severity of brain injury. Brain cell apoptosis was assessed by the TUNEL assay and hematoxylin-eosin (H&E) staining. Results: PD-1 helped to convert the microglia M1 phenotype to the M2 phenotype and to reduce BBB permeability both in vitro and in vivo. Overexpression of PD-1 promoted a shift of the M1 phenotype to the M2 phenotype and reduced BBB permeability via the ERK and p38 MAPK signaling pathways. PD-1 reduced inflammatory exudation, BBB permeability, cell apoptosis, and brain injury in vivo. Conclusion: Our present study verified that PD-1 exerts an anti-inflammatory effect by converting the microglia M1 phenotype to the M2 phenotype, reducing BBB permeability, and thereby relieves brain injury caused by cerebral ischemia. PD-1 is potential therapeutic target for brain injury caused by cerebral ischemia.

Objective: To investigate whether esmolol could improve clinical outcome and tissue oxygen metabolism by controlling heart rate (HR) in patients with septic shock., Methods: A single-center double-blinded randomized controlled trial was conducted. The patients suffering from septic shock received 6-hour early goal directed herapy (EGDT) with pulmonary artery wedge pressure ≥ 12 mmHg (1 mmHg = 0.133 kPa) or central venous pressure CVP) ≥ 12 mmHg requiring norepinephrine to maintain mean arterial pressure (MAP) ≥ 65 mmHg and HR ≥ 95 bpm admitted to intensive care unit (ICU) of Guangdong General Hospital from September 2013 to September 2014 were enrolled. They were randomly divided into esmolol group and control group by computer-based random number generator. All patients received conventional basic treatment, while those in the esmolol group received in addition persistent esmolol infusion by micro pump with dosage of 0.05 mg · kg(-1) · min(-1) with the dosage adjusted to maintain HR lower than 100 bpm within 24 hours. The patients in control group did not receive drug intervention for HR. The primary end-points consisted of length of stay in ICU and 28-day mortality. The secondary end-points included hemodynamic parameters [HR, MAP, CVP, cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI)] and tissue oxygen metabolism parameters [central venous oxygen saturation (ScvO2), lactate level (Lac)] before and 24, 48, 72 hours after the treatment., Results: A total of 48 patients with septic shock were enrolled with 24 patients in esmolol group and 24 in control group. (1) The primary end-points: compared with control group, the length of stay in the ICU in the esmolol group was significantly shortened (days: 13.75 ± 8.68 vs. 21.70 ± 6.06, t = 3.680, P = 0.001), and 28-day mortality was significantly lowered [25.0% (6/24) vs. 62.5% (15/24 ), χ2 = 6.857, P = 0.009]. (2) The secondary end-points: there were no significant difference in the hemodynamic and tissue metabolism parameters before treatment between two groups. No significant difference was found between before and after treatment of all above parameters in control group. HR and Lac in the esmolol group were obviously declined, SVI, SVRI, SCvO2 were gradually increased, but no significant difference in MAP, CVP, and CI was found. Compared with the control group, HR in the esomolol group was significantly lowered (bpm: 84.4 ± 3.5 vs. 111.2 ± 7.2, P < 0.01), SVRI and ScvO2 were significantly increased from 24 hours [SVRI (kPa · s · L(-1) ·m(-2)): 137.9 ± 1.6 vs. 126.9 ± 1.3, ScvO2: 0.652 ± 0.017 vs. 0.620 ± 0.017, both P < 0.01]; SVI was significantly increased (mL/m2: 39.9 ± 2.2 vs. 36.8 ± 1.7, P < 0.01) and Lac level significantly declined from 48 hours (mmol/L: 2.8 ± 0.3 vs. 3.4 ± 0.3, P < 0.01)., Conclusion: The results demonstrate that HR controlled by a titrated esmolol infusion given to septic shock patients was associated with an improvement in tissue metabolism, reduction in the length of ICU stay and lowering of 28-day mortality.