Search

Background. Excessive autophagy is a major mechanism of myocardial ischemia reperfusion injury (I/RI) in diabetes with enhanced oxidative stress. Antioxidant N-acetylcysteine (NAC) reduces myocardial I/RI. It is unknown if inhibition of autophagy may represent a mechanism whereby NAC confers cardioprotection in diabetes. Methods and Results. Diabetes was induced in Sprague-Dawley rats with streptozotocin and they were treated without or with NAC (1.5 g/kg/day) for four weeks before being subjected to 30-minute coronary occlusion and 2-hour reperfusion. The results showed that cardiac levels of 15-F2t-Isoprostane were increased and that autophagy was evidenced as increases in ratio of LC3 II/I and protein P62 and AMPK and mTOR expressions were significantly increased in diabetic compared to nondiabetic rats, concomitant with increased postischemic myocardial infarct size and CK-MB release but decreased Akt and eNOS activation. Diabetes was also associated with increased postischemic apoptotic cell death manifested as increases in TUNEL positive cells, cleaved-caspase-3, and ratio of Bax/Bcl-2 protein expression. NAC significantly attenuated I/RI-induced increases in oxidative stress and cardiac apoptosis, prevented postischemic autophagy formation in diabetes, and reduced postischemic myocardial infarction (all p<0.05). Conclusions. NAC confers cardioprotection against diabetic heart I/RI primarily through inhibiting excessive autophagy which might be a major mechanism why diabetic hearts are less tolerant to I/RI.

Diabetic neuropathic pain (DNP) is a common and serious complication of diabetic patients. The pathogenesis of DNP is largely unclear. The proinflammation proteins, CXCR4, and TNF-α play critical roles in the development of pain, while their relative roles in the development of DNP and especially its progression is unknown. We proposed that establishment of diabetic pain models in rodents and evaluating the stability of behavioral tests are necessary approaches to better understand the mechanism of DNP. In this study, Von Frey and Hargreaves Apparatus was used to analyze the behavioral changes of mechanical allodynia and heat hyperalgesia in streptozotocin-induced diabetic rats at different phases of diabetes. Moreover, CXCR4 and TNF-α of spinal cord dorsal and dorsal root ganglia (DRG) were detected by western blotting and immunostaining over time. The values of paw withdrawal threshold (PWT) and paw withdrawal latencies (PWL) were reduced as early as 1 week in diabetic rats and persistently maintained at lower levels during the progression of diabetes as compared to control rats that were concomitant with significant increases of both CXCR4 and TNF-α protein expressions in the DRG at 2 weeks and 5 weeks (the end of the experiments) of diabetes. By contrast, CXCR4 and TNF-α in the spinal cord dorsal horn did not significantly increase at 2 weeks of diabetes while both were significantly upregulated at 5 weeks of diabetes. The results indicate that central sensitization of spinal cord dorsal may result from persistent peripheral sensitization and suggest a potential reference for further treatment of DNP.

Acute lung injury (ALI) is a severe complication of orthotopic liver transplantation (OLT) with unclear underline mechanism. Toll-like receptor 4 (TLR4) has been identified as a key receptor mediating inflammation. We hypothesized that TLR4-mediated pulmonary inflammation may contribute to development of ALI during OLT. Patients with or without ALI were observed for serum cytokines and expression of TLR4 on peripheral blood polymorphonuclear leukocytes (PMNs). Next, rats which underwent orthotopic autologous liver transplantation (OALT) were divided into sham and model groups. Pulmonary function and the level of TLR4 expression and cytokines were analyzed. Furthermore, the role of TLR4 in OALT-mediated ALI was assessed in rats treated with TLR4-siRNA before OALT. The PMNs TLR4 expression and the serum TNF-αand IL-βlevel were higher in patients with ALI than those with non-ALI. Interestingly, lung TLR4 expression was significantly increased after 8 hours of OALT with increased levels of TNF-αand IL-β, which lead to lung pathological damage and an increase of lung myeloperoxidase content. Moreover, knockdown of TLR4 reduced lung cytokines release and reversed the above pathologic changes after OALT and finally improved rats’ survival rate. In conclusion, TLR4 overexpression, potentially by stimulating proinflammatory cytokine overproduction, contributes to the development of ALI after OLT.

Inhalation anesthetic isoflurane inhibits hypoxia pulmonary vasoconstriction (HPV), while dexmedetomidine (Dex) could reduce the dose of isoflurane inhalation and potentiate HPV, but the mechanism is unclear. Inhibition of reactive oxygen species (ROS) production can favor HPV during one-lung ventilation (OLV). Similarly, nitric oxide (NO), an important endothelium-derived vasodilator in lung circulation, can decrease the regional pulmonary vascular resistance of ventilated lung and reduce intrapulmonary shunting. We hypothesized that Dex may augment HPV and improve oxygenation during OLV through inhibiting oxidative stress and increasing NO release. Patients undergoing OLV during elective thoracic surgery were randomly allocated to either isoflurane + saline (NISO,n=24) or isoflurane + dexmedetomidine (DISO,n=25) group. Anesthesia was maintained with intravenous remifentanil and inhalational isoflurane (1.0–2.0%), with concomitant infusion of dexmedetomidine 0.7 μgkg−1h−1in DISO and saline 0.25 mL kg−1h−1in NISO group. Hemodynamic variables or depth of anesthesia did not significantly differ between groups. Administration of Dex significantly reduced Qs/Qt and increased PaO2after OLV, accompanied with reduced lipid peroxidation product malondialdehyde and higher levels of SOD activity as well as serum NO (allP<0.05DISO versus NISO). In conclusion, reducing oxidative stress and increasing NO release during OLV may represent a mechanism whereby Dex potentiates HPV.

Inflammatory response is usually associated with various traumatic insults. In addition, traumatic injury produces excessive proinflammatory mediators and subsequent activating or recruiting immune cells into the target organs and results in systemic inflammatory response. However, the complex pathways and mechanisms of inflammatory responses on traumatic injury have not been clearly elucidated. The aim of this special issue is to describe the role of inflammation in traumatic injury, providing an up-to-date viewpoint for therapeutic approaches. Patients after tangential excision surgery usually suffered from tremendous pain, which leads to anxiety, emergency, agitation, and inflammatory reaction. W. Geng et al. showed that preoperative administration of flurbiprofen axetil decreased postoperative tramadol consumption and the visual analog scale after surgery. In addition, flurbiprofen axetil attenuated emergency agitation score and Ramsay score after extubation and reduced the systemic levels of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 after the operation. The adverse events induced by intubation and extubation may cause intracranial hemorrhage and increase of intracranial pressure, especially in posterior fossa surgery patients. C. Tang et al. suggested that I-gel combined with tracheal intubation could reduce the stress response of posterior fossa surgery patients. Plasma β-endorphin, cortisol, interleukin-6, tumor necrosis factor-α, malondialdehyde concentrations, and blood glucose were decreased in I-gel facilitated endotracheal tube intubation group. Utilization of I-gel combined with endotracheal tube in posterior fossa surgery may lower inflammatory and oxidative response. Y. Chen et al. reported that sepsis-induced acute intestinal injury was attenuated by dexmedetomidine treatment. The protective effects of dexmedetomidine on sepsis-induced injury may be associated with the inhibition of inflammation via modulating toll-like receptor 4 pathway. Inhalation anesthetics isoflurane may inhibit hypoxia pulmonary vasoconstriction. In addition, dexmedetomidine can reduce the dose of isoflurane inhalation and potentiate hypoxia pulmonary vasoconstriction. R. Xia et al. reported that dexmedetomidine could augment hypoxia pulmonary vasoconstriction and improve oxygenation during one-lung ventilation through inhibiting oxidative stress and increasing nitric oxide release. Histone deacetylases modulate cytokine synthesis and release. Trichostatin A, a histone deacetylase inhibitor, is documented to be anti-inflammatory and neuroprotective. C.-H. Hsing et al. indicated that trichostatin A reduced lipopolysaccharide-induced neuroinflammation and cognitive dysfunction. J.-A. Lin et al. first identified the effects of bone components on toll-like receptor 4 surface expression. Toll-like receptor 4 surface expression in human monocytes was used as the main target to assess immune dysfunction following bone component exposure. They found that bone component exposure downregulated toll-like receptor 4 surface expression. Perinatal insults and subsequent neuroinflammation is the major mechanism of neonatal brain injury. C.-Y. Chen et al. reported that hypoxic preconditioning conferred strong neuroprotection, likely through suppression of glial activation and subsequent inflammatory responses after hypoxia-ischemia insults in neonatal rats. The elderly hip fracture is one of the most common injuries and represents a high incidence of complications and mortality. L. Gan et al. examined the influence of immediate surgery on systemic inflammatory response and lung injury induced by elderly hip fracture. They found that the elderly hip fracture could result in systemic inflammatory response and lung injury. In addition, the proximal femoral intramedullary pinning surgery following hip fracture aggravated the above pathological states by increasing the mitochondrial DNA release. Cardiopulmonary bypass induces neutrophil activation and release of matrix metalloproteinases-9, contributing to postoperative pulmonary infiltration and dysfunction. T.-C. Lin et al. reported that elective cardiac surgery with cardiopulmonary bypass induced short-term elevation of plasma metalloproteinases-9 concentrations within 24 hours. However, increase of neutrophils and reduced oxygenation are not correlated with cardiopulmonary bypass time and postoperative pulmonary dysfunction. Y. Tian et al. suggested that combination of 3-day captopril treatment and isoflurane preconditioning additively attenuated myocardial ischemia reperfusion by reducing oxidative stress and inflammation. Acute kidney injury is a frequent and severe complication during sepsis. Though fluid resuscitation is the main therapy, heart failure is usually lethal for those patients receiving large volumes of fluids. Y. Wang et al. reported that single small-volume resuscitation with hydroxyethyl starch and hypertonic saline hydroxyethyl starch could attenuate endotoxemia-induced kidney injury. Resveratrol, a natural polyphenolic compound of grape and red wine, owns potential anti-inflammatory effects, which results in the reduction of cytokines overproduction, the inhibition of neutrophil activity, and the alteration of adhesion molecules expression. Resveratrol has been shown to reduce organ damage following traumatic and shock-like states. Such protective phenomenon is reported to be implicated in a variety of intracellular signaling pathways including the activation of estrogen receptor, the regulation of the sirtuin 1/nuclear factor-kappa B and mitogen-activated protein kinases/hemeoxygenase-1 pathway, and the mediation of proinflammatory cytokines, reactive oxygen species formation and reaction. F.-C. Liu et al. reviewed the organ-protective and anti-inflammatory effects of resveratrol in trauma-hemorrhagic injury. S. Hamaguchi et al. reported elevated circulating free DNA levels during early-phase sepsis might represent a candidate biomarker for the severity of sepsis. In addition, regulatory T cells suppress excessive immune responses and are potential therapeutic targets in autoimmune disease and organ transplantation rejection. C. Jun et al. found that recruitment of regulatory T cells into the kidney was related to the recovery of renal function after ischemia–reperfusion injury. Together, the reviews, research articles, and clinical studies that are featured in this special issue enhance our knowledge base of inflammation in traumatic injury. Huang-Ping Yu Fu-Chao Liu Chung-Hsi Hsing Zhengyuan Xia Mashkoor A. Choudhry Irshad H. Chaudry

Background.Pretreatment with the angiotensin-converting inhibitor captopril or volatile anesthetic isoflurane has, respectively, been shown to attenuate myocardial ischemia reperfusion (MI/R) injury in rodents and in patients. It is unknown whether or not captopril pretreatment and isoflurane preconditioning (Iso) may additively or synergistically attenuate MI/R injury.Methods and Results.Patients selected for heart valve replacement surgery were randomly assigned to five groups: untreated control (Control), captopril pretreatment for 3 days (Cap3d), or single dose captopril (Cap1hr, 1 hour) before surgery with or without Iso (Cap3d+Iso and Cap1hr+Iso). Rabbit MI/R model was induced by occluding coronary artery for 30 min followed by 2-hour reperfusion. Rabbits were randomized to receive sham operation (Sham), MI/R (I/R), captopril (Cap, 24 hours before MI/R), Iso, or the combination of captopril and Iso (Iso+Cap). In patients, Cap3d+Iso but not Cap1hr+Iso additively reduced postischemic myocardial injury and attenuated postischemic myocardial inflammation. In rabbits, Cap or Iso significantly reduced postischemic myocardial infarction. Iso+Cap additively reduced cellular injury that was associated with improved postischemic myocardial functional recovery and reduced myocardial apoptosis and attenuated oxidative stress.Conclusion.A joint use of 3-day captopril treatment and isoflurane preconditioning additively attenuated MI/R by reducing oxidative stress and inflammation.