Huacheng Zhou

Carbon monoxide inhalation decreased lung injury via anti-inflammatory and anti-apoptotic effects in brain death rats.

Brain death (BD) induces acute lung injury and makes donor lungs unfit for transplantation. Carbon monoxide (CO) inhalation at 50–500 ppm exerts anti-inflammatory and anti-apoptosis effects in several lung injury models. We examined whether CO inhalation would show favorable effects on lung injury in BD rats. BD rats inhaled 250 ppm CO for two hours. Inhalation decreased the severity of lung injury, as checked by histological examination. CO treatment reversed aggravation in PaO2/FiO2, base excess and pH of BD rats. CO inhalation downregulated the pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6), and inhibited activity of myeloperoxidase in lung tissue. Inhalation significantly decreased cell apoptosis of lungs, and inhibited mRNA expression of intercellular adhesion molecule-1 and caspase-3 in the lungs. Further, the inhalation activated phosphorylation of p38 expression and inhibited phosphorylation of extracellular signal-regulated kinase expression in the lungs. In conclusion, CO exerts potent protective effects on lungs from BD rats, exhibiting anti-inflammatory and anti-apoptosis functions by modulating the mitogen-activated protein kinase signal transduction.

Protection against lung graft injury from brain-dead donors with carbon monoxide, biliverdin, or both

BACKGROUND The process of brain death can induce acute lung injury in donors and aggravate ischemia-reperfusion injury in grafts. Carbon monoxide (CO) and biliverdin (BV) have been shown to attenuate ischemia-reperfusion injury. We therefore examined if the administration of both CO and BV provide enhanced cytoprotection against lung graft injury from brain-dead (BD) rat donors. METHODS Brain death was induced in all donors, after which they were observed for 1.5 hours and then underwent lung transplantation. The recipients were ventilated with 40% oxygen (control group), ventilated with 250 ppm CO in 40% oxygen (CO group), treated with BV (35 mg/kg) intraperitoneally (BV group), or treated with CO and BV conjointly (COBV group) before transplantation (n = 8 each group). The recipients were sacrificed 2 hours after lung transplantation by exsanguination. Serum levels of interleukin (IL)-8 and tumor necrosis factor (TNF)-α were measured by enzyme-linked immunosorbent assay. RESULTS CO and/or BV treatment attenuated partial pressure of arterial oxygen (Pao(2))/fraction of inspired oxygen (Fio(2)) aggravation in the recipients after reperfusion, reduced the wet weight/dry weight ratio, decreased the lung injury score, inhibited the activity of myeloperoxidase in grafts, and decreased serum levels of IL-8 and TNF-α compared with the control group (p < 0.05). The COBV group had significantly decreased malonaldehyde levels and increased superoxide dismutase levels in lung grafts compared with the CO group (p < 0.05). The static pressure-volume curve of the lungs was ameliorated in the CO group, BV group, and COBV group compared with the control group (p < 0.05). CONCLUSIONS CO and BV exert protective effects through anti-inflammatory and anti-oxidant mechanisms, and dual treatment provided enhanced cytoprotection against lung graft injury from BD rat donors.

Hydrogen inhalation decreases lung graft injury in brain-dead donor rats

BACKGROUND The process of brain death induces acute lung injury in donors and aggravates ischemia-reperfusion injury (IRI) in grafts. Hydrogen, a new anti-oxidant, attenuates IRI in several organ transplant models. We examined whether 2% inhaled hydrogen would show favorable effects on lung grafts from brain-dead donor rats. METHODS Brain-dead donor rats inhaled mixed gases with either 50% oxygen and 50% nitrogen or mixed gases with 2% hydrogen, 50% oxygen and 48% nitrogen for 2 hours. The recipients inhaled the same gas as the donors and were euthanized 2 hours after lung transplantation. RESULTS Hydrogen improved PaO(2)/FIO(2) and PVO(2)/FIO(2) from the arterial and pulmonary venous blood in recipients and decreased the lung injury score in grafts from brain-dead donors. Hydrogen decreased the amount of IL-8 and TNF-α in serum, inhibited the activity of malondialdehyde and myeloperoxidase, and increased the activity of superoxide dismutase in the lung grafts from brain-dead donors. Furthermore, hydrogen decreased the apoptotic index of the cells and inhibited the protein expression of intercellular adhesion molecule-1 and caspase-3 in lung grafts from brain-dead donors. CONCLUSIONS Hydrogen can exert protective effects on lung grafts from brain-dead donors through anti-inflammatory, anti-oxidant and anti-apoptotic mechanisms.

Exogenous Biliverdin Improves the Function of Lung Grafts From Brain Dead Donors in Rats

BACKGROUND Biliverdin, a product of heme oxygenase-1 (HO-1), ameliorates the posttransplant functions of heart, kidney, and liver. In this study, we investigated the effects of biliverdin on lung grafts from brain dead (BD) rat donors. METHODS Male Wistar rats were randomly divided into 3 groups. The sham group (n = 7), did not undergo BD. Both donor and recipient rats in the BD biliverdin group (n = 8) were injected with biliverdin (35 mg/kg in 1 mL) intraperitoneally after confirmed BD and transplantation. In the BD group (n = 8), both donor and recipient rats received the same volume of saline (35 mg/kg in 1 mL) as the BD biliverdin group. All donor rats were observed for 1.5 hours before undergoing lung transplantation. Two hours after transplantation, we obtained blood and lung graft samples. RESULTS Biliverdin reversed the aggravation of Pa(O(2)) in recipients, reduced the grafts wet/dry ratio, decreased the severity of lung injury measured by histologic examination, reduced serum tumor necrosis factor-alpha and interleukin-8 levels and inhibited myeloperoxidase activity (MPO) in the grafts. Furthermore, it significantly decreased malonaldehyde levels and increased superoxide dismutase levels. Biliverdin reduced cell apoptosis, activated protein expression of biliverdin reductase, and inhibited expression of HO-1 and nuclear factor (NF)-kappaB in lung grafts. CONCLUSION Biliverdin exerts protective effects on lung grafts from BD donors through anti-inflammatory, antioxidant, and anti-apoptotic mechanisms.

Ultrasound-guided Versus Fluoroscopy-controlled Lumbar Transforaminal Epidural Injections: A Prospective Randomized Clinical Trial.

Objectives:Recently, most lumbar spine injections have been administered under ultrasound (US) guidance; however, there is no standard method for US-guided lumbar transforaminal epidural injection (TFEI). In this study, we evaluated the accuracy, effect on pain relief, and safety of US-guided lumbar TFEI. Methods:A total of 80 patients with low back pain and radicular pain were enrolled. The patients were randomly assigned to either the fluoroscopy (FL) group or the US group. The FL-guided approaches were performed under standardized procedures using the C-arm, whereas the US-guided injections were performed with an US device with a linear probe, and were verified by FL. The needle tip reached the lateral side of the lamina in the axis view and the middle of the adjacent facet joints in the parasagittal view. Afterward, the needle was advanced slightly deeper until the loss-of-resistance test was positive. Results:The success ratio of the US-guided interventions was 85%. The operation time in the US group (518±103 s) was shorter than the FL group (929±228 s) (P<0.05). In addition, the radiation dosage in the US group (2640±906 &mgr;Gy m2) was lower than in the FL group (8992±2132 &mgr;Gy m2). There was no significant difference in pain relief between the US and FL groups. No serious complication was observed in any of the patients in either group. Discussion:Lumbar TFEI under US guidance was feasible, safe, and required less radiation to achieve the same benefit as the FL-guided interventions.

Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats

Hydrogen has antioxidant and anti-inflammatory effects on lung ischemia–reperfusion injury when it is inhaled by donor or/and recipient. This study examined the effects of lung inflation with 3% hydrogen during the cold ischemia phase on lung graft function in rats. The donor lung was inflated with 3% hydrogen, 40% oxygen, and 57% nitrogen at 5 mL/kg, and the gas was replaced every 20 min during the cold ischemia phase for 2 h. In the control group, the donor lung was inflated with 40% oxygen and 60% nitrogen at 5 mL/kg. The recipient was euthanized 2 h after orthotropic lung transplantation. The hydrogen concentration in the donor lung during the cold ischemia phase was 1.99–3%. The oxygenation indices in the arterial blood and pulmonary vein blood were improved in the hydrogen group. The inflammation response indices, including lung W/D ratio, the myeloperoxidase activity in the grafts, and the levels of IL-8 and TNF-α in serum, were significantly lower in the hydrogen group (5.2 ± 0.8, 0.76 ± 0.32 U/g, 340 ± 84 pg/mL, and 405 ± 115 pg/mL, respectively) than those in the control group (6.5 ± 0.7, 1.1 ± 0.5 U/g, 443 ± 94 pg/mL, and 657 ± 96 pg/mL, respectively (P < 0.05), and the oxidative stress indices, including the superoxide dismutase activity and the level of malonaldehyde in lung grafts were improved after hydrogen application. Furthermore, the lung injury score determined by histopathology, the cell apoptotic index, and the caspase-3 protein expression in lung grafts were decreased after hydrogen treatment, and the static pressure–volume curve of lung graft was improved by hydrogen inflation. In conclusion, lung inflation with 3% hydrogen during the cold ischemia phase alleviated lung graft injury and improved graft function.

Hypercapnic acidosis confers antioxidant and anti-apoptosis effects against ventilator-induced lung injury.

Hypercapnic acidosis may attenuate ventilator-induced lung oxidative stress injury and alveolar cell apoptosis, but the underlying mechanisms are poorly understood. We examined the effects of hypercapnic acidosis on the role of apoptosis signal-regulating kinase 1 (ASK1), which activates the c-Jun N-terminal kinase (JNK) and p38 cascade in both apoptosis and oxidative reactions, in high-pressure ventilation stimulated rat lungs. Rats were ventilated with a peak inspiratory pressure (PIP) of 30 cmH2O for 4 h and randomly given FiCO2 to achieve normocapnia (PaCO2 at 35–45 mm Hg) or hypercapnia (PaCO2 at 80–100 mm Hg); normally ventilated rats with PIP of 15 cmH2O were used as controls. Lung injury was quantified by gas exchange, microvascular leaks, histology, levels of inflammatory cytokines, and pulmonary oxidative reactions. Apoptosis through the ASK1-JNK/p38 mitogen-activated protein kinase (MAPK) cascade in type II alveolar epithelial cells (AECIIs) were evaluated by examination of caspase-3 activation. The results showed that injurious ventilation caused significant lung injury, including deteriorative oxygenation, changes of histology, and the release of inflammatory cytokines. In addition, the high-pressure mechanical stretch also induced apoptosis and caspase-3 activation in the AECIIs. Hypercapnia attenuated these responses, suppressing the ASK1 signal pathways with its downstream kinase phosphorylation of p38 MAPK and JNK, and caspase-3 activation. Thus, hypercapnia can attenuate cell apoptosis and oxidative stress damage in rat lungs during injurious ventilation, at least in part, due to the suppression of the ASK1-JNK/p38 MAPK pathways.

Desflurane affords greater protection than halothane in the function of mitochondria against forebrain ischemia reperfusion injury in rats.

BACKGROUND: Halothane and desflurane have been shown to attenuate neuronal injury; however, the effects of these anesthetics on mitochondria are unclear. We investigated whether halothane and desflurane affect the function of mitochondria after cerebral ischemia in rats. METHODS: Forty male Wistar rats were randomly divided into four groups (n = 10 each): sham group; 1.5 minimal alveolar concentration (MAC) halothane group; 1.0 MAC desflurane; and 1.5 MAC desflurane group. Forebrain ischemia was induced after 40-min inhalation of 1.5 MAC halothane, 1.0 MAC or 1.5 MAC desflurane by clamping the bilateral common carotid arteries and decreasing arterial blood pressure. After isolation of the brain mitochondria, mitochondrial membrane permeability was assayed spectrophotometrically with 40–200 &mgr;M Ca2+, and mitochondrial membrane potentials were measured by a fluorospectrophotometer with the addition of rhodamine 123. The activities of mitochondrial respiratory chain complexes were also assayed spectrophotometrically. RESULTS: The results showed obvious mitochondrial swelling, loss of membrane potential with the addition of Ca2+, and inhibition of the activities of complexes I + III and IV after forebrain ischemia reperfusion injury. Compared with the 1.5 MAC halothane group, 1.0 and 1.5 MAC desflurane reduced mitochondrial swelling by 23.9% (P < 0.001) and 23.2% (P < 0.001), whereas membrane potential dissipation was suppressed by 22.4% (P = 0.013) and 20.4% (P = 0.027). The activities of complexes I + III and IV were better preserved in 1.0 MAC and 1.5 MAC desflurane groups than in the 1.5 MAC halothane group by 34.6% (P = 0.027), 38.7% (P = 0.011), 53.9% (P = 0.009), and 55.8% (P = 0.007), respectively. CONCLUSIONS: Desflurane shows better preservation of mitochondrial function at 4 h after cerebral ischemia reperfusion injury, indicated by inhibition of mitochondrial swelling, increase of membrane potential, and improvement of functions of mitochondria respiratory complexes I + III and IV when compared with halothane.

Inflation with carbon monoxide in rat donor lung during cold ischemia phase ameliorates graft injury.

Carbon monoxide (CO) attenuates lung ischemia reperfusion injury (IRI) via inhalation, and as an additive dissolved in flush/preservation solution. This study observed the effects of lung inflation with CO on lung graft function in the setting of cold ischemia. Donor lungs were inflated with 40% oxygen + 60% nitrogen (control group) or with 500 ppm CO + 40% oxygen + nitrogen (CO group) during the cold ischemia phase and were kept at 4℃ for 180 min. Recipients were sacrificed by exsanguinations at 180 min after reperfusion. Rats in the sham group had no transplantation and were performed as the recipients. Compared with the sham group, the oxygenation determined by blood gas analysis and the pressure–volume curves of the lung grafts decreased significantly, while the wet weight/dry weight (W/D) ratio, inflammatory reaction, oxidative stress, and cell apoptosis increased markedly (P < 0.05). However, compared to the control group, CO treatment improved the oxygenation (381 ± 58 vs. 308 ± 78 mm Hg) and the pressure–volume curves (15.8 ± 2.4 vs. 11.6 ± 1.7 mL/kg) (P < 0.05). The W/D ratio (4.6 ± 0.6) and the serum levels of interleukin-8 (279 ± 46 pg/mL) and tumor necrosis factor-α (377 ± 59 pg/mL) in the CO group decreased significantly compared to the control group (5.8 ± 0.8, 456 ± 63 pg/mL, and 520 ± 91 pg/mL) (P < 0.05). In addition, CO inflation also significantly decreased malondialdehyde activity and apoptotic cells in grafts, and increased the superoxide dismutase content. Briefly, CO inflation in donor lungs in the setting of cold ischemia attenuated lung IRI and improved the graft function compared with oxygen.

Lung inflation with hydrogen sulfide during the warm ischemia phase ameliorates injury in rat donor lungs via metabolic inhibition after cardiac death.

Background. Hydrogen sulfide attenuates lung ischemia‐reperfusion injury when inhaled or administered intraperitoneally. This study investigated the effects of lung inflation with H2S during the warm ischemia phase on lung grafts from rat donors after cardiac death. Methods. One hour after cardiac death, donor lungs were inflated in situ for 2 h with either O2 or H2S (O2 or H2S group) during the warm ischemia phase or were deflated as a control procedure (n = 8). After 3 h of cold preservation, lung transplantation was performed. During the warm ischemia phase, the metabolism and mitochondrial structures of donor lungs were analyzed. Arterial blood gas analysis was performed on the recipients. Protein expression in the graft of nuclear factor E2‐related factor (Nrf)2 and nuclear factor kappa B (NF‐&kgr;B) was analyzed by Western blotting, and static compliance, inflammation, oxidative stress, and cell apoptosis were assessed after 3 h of reperfusion. Results. When the O2 and H2S groups were compared with the control group, the mitochondrial structures were improved, and lactic acid levels, inflammation, oxidative stress, and cell apoptosis were significantly decreased; and glucose levels, as well as graft oxygenation and static compliance were increased. Simultaneously, the above indices showed further improvements, and the Nrf2 protein expression was significantly greater, and NF‐&kgr;B protein expression was less in the H2S group than the O2 group. Conclusion. Lung inflation with H2S during the warm ischemia phase inhibited metabolism in donor lungs via mitochondrial protection, attenuated graft ischemic‐reperfusion injury, and improved graft function through NF‐&kgr;B‐dependent anti‐inflammatory and Nrf2‐dependent antioxidative and antiapoptotic effects.