Rotation scarf + Akin osteotomy for severe hallux valgus with a new evaluation index: distance between the first and second metatarsals.

BACKGROUND: Although rotation scarf + Akin osteotomy has been described for correcting hallux valgus deformity, the treatment efficacy of rotation scarf + Akin osteotomy for severe hallux valgus should be further studied. The purpose of our study was to evaluate the outcomes of rotation scarf + Akin osteotomy on severe hallux valgus. METHODS: We conducted a retrospective study of patients with hallux valgus who underwent surgery using rotation scarf + Akin osteotomy in our hospital between June 2014 and January 2020. The parameters evaluated include (1) the hallux valgus angle (HVA), (2) intermetatarsal angle (IMA), (3) distal metatarsal articular angle (DMAA), (4) tibial sesamoid position (TSP), (5) the length of first metatarsal bone and (6) ratio between the vertical distance from the lateral of the first metatarsal head to the medial of the second metatarsal head and the vertical distance of lateral of the second metatarsal head to the medial of the third metatarsal head (MT-I to II/II to III distance). A visual analog scale (VAS) was used to evaluate the degree of pain before and at the last follow-up after the operation. The American Orthopaedic Foot & Ankle Society (AOFAS) Forefoot Score wasassessed before and at the last follow-up after the operation. Patient satisfaction assessment was also conducted at the time. RESULTS: All radiological parameters including, HVA, IMA, DMAA and TSP,, significantly improved (p < 0.001). The length of the first metatarsal was shortened 3.1 mm on average. The MT-I to II/II to III distance was also reduced to 1.8 after surgery and 3.3 before surgery. The VAS score and AOFAS score was also statistically significant before operation and at the last follow-up after the operation (p < 0.001). Forty-one (82%) feet in patients were very satisfied or satisfied. CONCLUSION: Rotation scarf + Akin osteotomy is demonstrated to be safe, effective, and feasible for correcting severe hallux valgus. It can obtain good long-term correction with a low incidence of recurrence and metatarsalgia. Postoperative satisfaction and functional recovery of patients are significantly improved. The MT-I to II/II to III distance, a new evaluation indicator, can be better evaluate the correction of hallux valgus.

Role of Parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury.

BACKGROUND: We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsis-induced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice. METHODS: Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout. KEY RESULTS: PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin-/- mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkin-dependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy. CONCLUSIONS: These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

Comparison of Ultrasound-guided Transverse Carpal Ligament Release via Different Approaches in Carpal Tunnel Syndrome: A Prospective, Randomized, Controlled Trial.

BACKGROUND: Ultrasound-guided transverse carpal ligament (TCL) needle release has been demonstrated to be an effective treatment for carpal tunnel syndrome (CTS). However, no existing evidence has investigated the comparative efficacy of different release approaches. OBJECTIVE: To compare the efficacy of ultrasound-guided TCL needle release via different approaches for patients with mild to moderate CTS over a 12-month follow-up. STUDY DESIGN: A prospective, randomized, controlled trial. SETTING: Outpatient clinic at a university hospital. METHODS: Sixty-four patients with mild to moderate CTS (> 3 months' duration) were randomly assigned to either the long-axis group (one session of ultrasound-guided corticosteroid injection plus long-axis TCL needle release) or the short-axis group (one session of ultrasound-guided corticosteroid injection plus short-axis TCL needle release) in a one-to-one ratio. The primary outcomes were the symptom severity scale (SSS) and functional severity scale (FSS) scores of the Boston Carpal Tunnel Questionnaire (BCTQ). The secondary outcomes were electrophysiological studies, including distal motor latency (DML) and sensory nerve conduction velocity (SNCV), cross-sectional area (CSA) of the median nerve (MN), and patient-reported successful clinical response. Assessments were performed before treatment and at one, 3, 6, and 12 months after treatment. RESULTS: A total of 60 patients (30 per group) completed the trial. Compared to the baseline, both groups exhibited improvement in SSS, FSS, SNCV, DML, and CSA at all follow-up time points, with statistical differences for SSS, FSS, and SNCV at 3, 6, and 12 months (P < 0.05), DML at 6 and 12 months (P < 0.05), and CSA at each follow-up time point (P < 0.05). Compared to the short-axis group, the long-axis group exhibited more improvement in SSS and FSS at all follow-up time points, with statistical differences at 3, 6, and 12 months (P < 0.05), and in SNCV and DML at 6 and 12 months (P < 0.05). Although the long-axis patients exhibited more improvement in their wrists' CSAs, the intergroup differences were nonsignificant at all follow-up time points (P > 0.05). Four patients in the short-axis group experienced recurrent symptoms and underwent surgery at 12 months, whereas no recurrence was observed in the long-axis group. LIMITATIONS: A relevant future trial with a longer follow-up period than this one used is still necessary. CONCLUSIONS: Ultrasound-guided TCL needle release via the long-axis approach appears to be more effective than the short-axis approach for treating mild to moderate CTS.

[Design and application of alaryngeal mask and monitoring device facilitating withdrawal of endotracheal tube].

Percutaneous dilatational tracheostomy (PDT) is a surgical method for quickly establishing an artificial airway, which has been favored by clinicians because of its simple operation, small trauma and bedside operation. However, for patients with tracheal intubation in intensive care unit (ICU), the tip and balloon of the existing endotracheal tube will not only hinder percutaneous puncture, but also hinder insertion of guidewire and tracheotomy tube, and consequently affect the process of PDT. On the contrary, blind withdrawal of the existing endotracheal tube may cause the tracheal tube tipleave the glottis, leading to an emergency airway situation that endangers the patient's life. Therefore, the medical staff from intensive care medicine department of the First People's Hospital of Chenzhou designed a laryngeal mask and its monitoring device, which is convenient for withdrawal of endotracheal tube, and obtained the national utility model patent of China (patent number: ZL 2020 2 2795887.1). The device is composed of a laryngeal mask and a monitoring device. The laryngeal mask mainly includes a laryngeal mask body, a vent tube, a guidance tube and other components. The laryngeal mask body is mainly used to seal the throat and provide the air supply channel for the patient together with the ventilation tube. The main function of the guidance tube is to accommodate the tracheal tube and facilitate the withdrawal of the inserted tracheal tube. During percutaneous dilatation tracheotomy, this device can monitor the withdrawal of tracheal catheter in real time, and immediately ensure the airway patency of patients without re-intubation when the cuff of tracheal catheter exits the glottis. The utility model has the advantages of real-time monitoring, simple operation, safety and convenience, and is worthy of transformation and promotion.

Inhibition of CISD1 alleviates mitochondrial dysfunction and ferroptosis in mice with acute lung injury.

The NET family member, CDGSH iron-sulfur domain-containing protein 1 (CISD1), is located in theoutermembrane of mitochondria, where it regulates energy and iron metabolism. CISD1 has vital functions in certain human diseases; however, its function in acute lung injury (ALI) is unknown. ALI pathogenesis critically involves mitochondrial dysfunction and ferroptosis, which might be regulated by CISD1. Therefore, we investigated CISD1's function in mitochondrial dysfunction and ferroptosis regulation in lipopolysaccharide (LPS)-induced ALI. We found that CISD1 was upregulated in LPS-induced ALI,and silencing Cisd1 prevented cell apoptosis and increased cell viability. When CISD1was inhibited by mitoNEET ligand-1 (NL-1) there was a significant mitigation of pathological injury and lung edema, and reduced numbers of total cells, polymorphonuclear leukocytes, and a decreased protein content in the bronchoalveolar lavage fluid (BALF). Moreover, inhibition of CISD1 markedly decreased the interleukin (IL)6, IL-1ß, and tumor necrosis factor alpha (TNF-α) levels in the lungs and BALF of ALI-model mice. Silencing of Cisd1 prevented LPS-induced mitochondrial membrane potential depolarization, cellular ATP reduction, and reactive oxygen species (ROS) accumulation, suggesting mitochondrial protection. ALI activated ferroptosis, as evidenced by the increased lipid-ROS, intracellular Fe2+ level, reduced Gpx4 (glutathione peroxidase 4) expression, and the glutathione/glutathione disulfide ratio. Interestingly, inhibition of CISD1 reduced LPS-induced ferroptosis in vivo and in vitro. In conclusion, inhibition of CISD1 alleviated mitochondrial dysfunction and ferroptosis in LPS-induced ALI, identifying CISD1 as possible target for therapy of LPS-induced ALI.

Inhibition of SIRT6 aggravates p53-mediated ferroptosis in acute lung injury in mice.

Although studies have shown that protein 53 (p53)-mediated ferroptosis is involved in acute lung injury (ALI), the mechanism of its regulation remains unclear. The protective effects of Sirtuin 6 (SIRT6), a histone deacetylase, have been demonstrated in multiple diseases; however, further studies are needed to elucidate the role of SIRT6 in ALI. In the present study, we hypothesize that SIRT6 protects against lipopolysaccharide (LPS)-induced ALI by regulating p53-mediated ferroptosis. We observed that the inhibition of ferroptosis prevented LPS-induced ALI. The knockout of p53 blocked LPS-induced ferroptosis and ALI, suggesting that p53 facilitated ALI by promoting ferroptosis. In addition, the inhibition of SIRT6 aggravated LPS-induced ferroptosis and ALI, while the depression of ferroptosis blocked the exacerbation of lung injury induced by SIRT6 inhibition. The results suggest that SIRT6 protects against ALI by regulating ferroptosis. Furthermore, the inhibition of SIRT6 reinforced the p53 acetylation and the deletion of p53 rescued the exacerbation of ferroptosis induced by SIRT6 inhibition. The findings indicate that SIRT6 regulates the acetylation of p53 and prevents p53-mediated ferroptosis. In conclusion, our results indicate that SIRT6 protects against LPS-induced ALI by regulating p53-mediated ferroptosis, thereby demonstrating that SIRT6 holds great promise as a therapeutic target for ALI.

Downregulation of miR-527 alleviates sepsis-induced acute kidney injury via targeting Beclin1.

BACKGROUND: Sepsis-induced acute kidney injury (AKI) is known to result from the inflammatory responses. MiRNAs participate in the development of sepsis-induced AKI. Nevertheless, the function of miR-527 in sepsis-induced AKI remains unclear. METHODS: Cell viability was evaluated by CCK8 assay, and TUNEL staining was applied to assess cell apoptosis. Pro-inflammatory cytokine (TNF-α, IL-6 and IL-1ß) levels were evaluated by ELISA. Meanwhile, the relation among miR-527 and Beclin1 was detected by dual luciferase report assay. Western blot and RT-qPCR were used to examine the protein and mRNA levels, respectively. Furthermore, an in vivo model was constructed to assess the function of miR-527 in sepsis-induced AKI. RESULTS: MiR-527 downregulation significantly alleviated the symptoms of sepsis-induced AKI in mice. MiR-527 level in HK-2 cells was significantly upregulated by LPS, and downregulation of miR-527 notably reversed LPS-induced inhibition of HK-2 cell viability by inhibiting apoptosis. In addition, LPS greatly increased TNF-α, IL-6 and IL-1ß levels in supernatant of HK-2 cells, while miR-527 inhibitor partially restored this phenomenon. Meanwhile, Beclin1 was found to be the downstream mRNA of miR-527, and miR-527 inhibitor notably upregulated the level of LC3. MiR-527 downregulation reversed LPS-induced HK-2 cell injury through suppression of TGF-ß pathway. CONCLUSION: Downregulation of miR-527 alleviated sepsis-induced AKI via targeting Beclin1. Thus, miR-527 might act as a vital mediator in sepsis-induced AKI.

A Better Treatment for Moderate to Severe Hallux Valgus: Scarf + Akin Osteotomy Combined with Lateral Soft Tissue Release in a Single Medial Incision.

OBJECTIVE: Traditional lateral soft tissue release (LSTR) was conducted by an additional dorsal first web incision, as the malformed thick scar and neuritis were common after surgery. A new method of lateral soft tissue release in a single medial incision via dorsal flap over the first metatarsal (LSTR-SMI-DFFM) should be recommended. The objective is to investigate the clinical effectiveness and safety of scarf + Akin osteotomy (SAO) combined with lateral soft tissue release in a single medial incision via dorsal flap over the first metatarsal (LSTR-SMI-DFFM) for moderate to severe hallux valgus. METHODS: Patients who were performed surgery for hallux valgus from April 2014 to June 2020 were retrospectively reviewed. The visual analog scale (VAS) was recorded before surgery and during follow-up, as well as the forefoot score of the American Orthopaedic Foot and Ankle Society (AOFAS). Patient satisfaction was evaluated at the follow-up time. The preoperative and follow-up weightbearing X-ray were conducted in all patients. The radiological parameters of hallux valgus angle (HVA), intermetatarsal angle (IMA), and distal metatarsal articular angle (DMAA) were measured. Tibial sesamoid position (TSP) was also recorded according to seven-part grading system. The quantitative data were performed as mean ± standard deviation or median ± interquartile range. Student's t test was performed in HVA, IMA, and DMAA. The TSP, VAS, and AOFAS were statistical analyzed by Mann-Whitney U test. p value of <0.05 was considered significant. RESULTS: There were 123 feet conducted surgery in 96 patients. The AOFAS score improved a lot which was preoperative 39 to 100 at the follow-up time and VAS was 4 to 0 (p < 0.001). A total of 63 (51.2%) patients were very satisfied, 47 (38.2%) were satisfied, five (4.1%) were undecided and eight (6.5%) were not satisfied. The HVA, IMA, DMAA, and TSP were all decreased after surgery and were statistically significant (p < 0.001). CONCLUSION: The SAO combined with a LSTR-SMI-DFFM for moderate to severe hallux valgus is effective and safe with pretty good clinical and radiographic results, as well as minimal complications. The corrections of AOFAS and VAS conformed to the minimum clinically important difference (MCID).

Spike-specific circulating T follicular helper cell and cross-neutralizing antibody responses in COVID-19-convalescent individuals.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-3 and individuals with COVID-19 have symptoms that can be asymptomatic, mild, moderate or severe4,5. In the early phase of infection, T- and B-cell counts are substantially decreased6,7; however, IgM8-11 and IgG12-14 are detectable within 14 d after symptom onset. In COVID-19-convalescent individuals, spike-specific neutralizing antibodies are variable3,15,16. No specific drug or vaccine is available for COVID-19 at the time of writing; however, patients benefit from treatment with serum from COVID-19-convalescent individuals17,18. Nevertheless, antibody responses and cross-reactivity with other coronaviruses in COVID-19-convalescent individuals are largely unknown. Here, we show that the majority of COVID-19-convalescent individuals maintained SARS-CoV-2 spike S1- and S2-specific antibodies with neutralizing activity against the SARS-CoV-2 pseudotyped virus, and that some of the antibodies cross-neutralized SARS-CoV, Middle East respiratory syndrome coronavirus or both pseudotyped viruses. Convalescent individuals who experienced severe COVID-19 showed higher neutralizing antibody titres, a faster increase in lymphocyte counts and a higher frequency of CXCR3+ T follicular help (TFH) cells compared with COVID-19-convalescent individuals who experienced non-severe disease. Circulating TFH cells were spike specific and functional, and the frequencies of CXCR3+ TFH cells were positively associated with neutralizing antibody titres in COVID-19-convalescent individuals. No individuals had detectable autoantibodies. These findings provide insights into neutralizing antibody responses in COVID-19-convalescent individuals and facilitate the treatment and vaccine development for SARS-CoV-2 infection.

Drp-1 as Potential Therapeutic Target for Lipopolysaccharide-Induced Vascular Hyperpermeability.

Mitochondria-dependent apoptotic signaling has a critical role in the pathogenesis of vascular hyperpermeability (VH). Dynamin-related protein-1- (Drp-1-) mediated mitochondrial fission plays an important role in mitochondrial homeostasis. In the present study, we studied the involvement of Drp-1 in resistance to VH induced by lipopolysaccharide (LPS). To establish the model of LPS-induced VH, LPS at 15 mg/kg was injected into rats in vivo and rat pulmonary microvascular endothelial cells were exposed to 500 ng/ml LPS in vitro. We found that depletion of Drp-1 remarkedly exacerbated the mitochondria-dependent apoptosis induced by LPS, as evidenced by reduced apoptosis, mitochondrial membrane potential (MMP) depolarization, and activation of caspase-3 and caspase-9. Increased FITC-dextran flux indicated endothelial barrier disruption. In addition, overexpression of Drp-1 prevented LPS-induced endothelial hyperpermeability and upregulated mitophagy, as evidenced by the loss of mitochondrial mass and increased PINK1 expression and mitochondrial Parkin. However, the mitophagy inhibitor, 3-Methyladenine, blocked these protective effects of Drp-1. Furthermore, inhibition of Drp-1 using mitochondrial division inhibitor 1 markedly inhibited LPS-induced mitophagy and aggravated LPS-induced VH, as shown by increased FITC-dextran extravasation. These findings implied that Drp-1 strengthens resistance to mitochondria-dependent apoptosis by regulating mitophagy, suggesting Drp-1 as a possible therapeutic target in LPS-induced VH.

Economic variations in patterns of care and outcomes of patients receiving invasive mechanical ventilation in China: a national cross-sectional survey.

BACKGROUND: Ventilation practice may be affected by economic variations, which might result in different outcomes to mechanically ventilated patients. We aimed to investigate the important effect of economic variations in patients with mechanical ventilation (MV) in China. METHODS: We carried out a national prospective multicentre cross-sectional observational study over 1 month of all patients receiving invasive MV for more than 24 hours in 20 intensive care units (ICUs), including patient characteristics, practice of MV, weaning modalities and outcomes, including probability of weaning and survival. Based on the 2012 World Bank classification of counties, patients were divided into high-income and middle-income groups according to gross domestic product per capita in their province of origin. RESULTS: Of the 483 patients enrolled, 291 (60.2%) were from high-income provinces and 192 (39.8%) were from middle-income provinces. Tidal volume, peak pressure, plateau and driving pressure were significantly lower, and the proportion of patients receiving protective ventilation (71.1% vs. 59.9%, P=0.014) was significantly higher in the high-income group than in the middle-income group. The probability of weaning within 28 days was significantly greater in the high-income group than in the middle-income group (P=0.046). Patients in the high-income group had significantly higher median numbers of ventilator-free days within 14 and 28 days than those in the middle-income group (P<0.05). Although the patients did not differ in terms of their demographics, survival within 28 days was significantly higher in the high-income group than in the middle-income group (P=0.025). Driving pressure, positive end-expiratory pressure and spontaneous breathing trial were independently associated with hospital mortality. CONCLUSIONS: Important economic differences exist in the management of MV and patient outcomes. Higher income is associated with a higher proportion of protective ventilation, lower driving pressure, shorter weaning and better survival in mechanically ventilated patients in China.

Practice of diagnosis and management of acute respiratory distress syndrome in mainland China: a cross-sectional study.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) has been recognized for more than 50 years, limited information exists about the incidence and management of ARDS in mainland China. To evaluate the potential for improvement in management of patients with ARDS, this study was designed to describe the incidence and management of ARDS in mainland China. METHODS: National prospective multicenter observational study over one month (August 31st to September 30th, 2012) of all patients who fulfilled the Berlin or American European Consensus Conference (AECC) definition of ARDS in 20 intensive care units, with data collection related to the management of ARDS, patient characteristics and outcomes. RESULTS: Of the 1,814 patients admitted during the enrollment period, 149 (8.2%) and 147 (8.1%) patients were diagnosed by AECC and Berlin definition, respectively. Lung protective strategy with low tidal volume (Vt) (≤8 mL/kg) and limitation of the plateau pressure (Pplat) (≤30 cmH2O) was performed in 75.2% patients. And, 36%, 21.1% and 4.1% patients with severe, moderate and mild ARDS had the driving pressure more than 14 cmH2O (P<0.05). Pplat and driving pressure increased significantly in patients with a higher degree of ARDS severity (P=0.002 and P<0.001, respectively), but Vt were comparable in the three groups (P>0.05). In severe ARDS, patient median positive end expiratory pressure (PEEP) was 10.0 (8.0-11.3) cmH2O and median FiO2 was 90%. A recruitment maneuver was performed in 35.5% of the patients, and 8.7% of patients with severe ARDS received prone position. Overall hospital mortality was 34.0%. Hospital mortality was 21.8% for mild, 31.1% for moderate, and 60.0% for patients with severe ARDS (P=0.004). CONCLUSIONS: Despite general acceptance of low Vt and limited Pplat, high driving pressure, low PEEP and low use of adjunctive measures may still be a concern in mainland China, especially in patients with severe ARDS. TRIAL REGISTRATION: ClinicalTrials.gov NCT01666834; date of registration release: August 14th 2012.

Low plasma leptin level at admission predicts delirium in critically ill patients: A prospective cohort study.

The pathophysiology of delirium remains poorly understood. Low leptin level has been associated with features leading to delirium such as dysregulated immune functions and loss of neuroprotective effects. The purpose of the present study was to investigate the relationship between plasma leptin level at intensive care unit (ICU) entry and subsequent occurrence of delirium in critically ill patients. This single-center prospective cohort study in China allocated 336 critically ill patients admitted to ICU between 05/2015 and 05/2016 into a delirium group (n=102) and non-delirium group (n=234) based on whether delirium occurred during their stay at the ICU. Patients were examined at least twice daily and delirium was diagnosed using the Confusion Assessment Method for the ICU (CAM-ICU). Blood samples were obtained after ICU entry. Plasma leptin concentrations were measured by ELISA. Delirium occurred in 30.4% (102/336) of patients. Patients who developed delirium showed significantly lower leptin level at ICU entry than those who did not (6.1±3.2 vs. 9.2±5.9ng/mL; P<0.001). Low plasma leptin level at ICU entry was independently associated with subsequent occurrence of delirium (OR, 0.865; 95%CI, 0.802-0.934; P<0.001). Other independent risk factors for delirium included increasing age (OR, 1.050; 95%CI, 1.020-1.080; P=0.001) and Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score (OR, 1.148; 95%CI, 1.092-1.208; P<0.001). Patients who developed delirium had a prolonged duration of ICU stay and higher mortality. Low plasma leptin level at ICU entry was associated with the occurrence of delirium in critically ill patients.

Polydatin attenuates ipopolysaccharide-induced acute lung injury in rats.

Anti-inflammatory and anti-apoptotic effects of polydatin (PD) have been demonstrated in our previous studies. Recently, we have found that PD treatment can ameliorate burn-induced acute lung injury (ALI). In the present study, we hypothesized that PD may provide protective effect against LPS-induced ALI through reducing inflammation and apoptosis. Rats were respectively pretreated with PD at doses of 15, 30 and 45 mg/kg weight, followed by intratracheal administration of lipopolysaccharide (LPS). LPS-challenged rats exhibited significant lung injury characterized by the deterioration of histopathology, pulmonary microvascular hyperpermeability, wet-to-dry weight ratio, and oxygenation index, which was attenuated by PD (30 and 45 mg/kg) treatment. Moreover, PD (30 and 45 mg/kg) treatment inhibited LPS-induced inflammatory response, as evidenced by the downregulation of lung myeloperoxidase activity, total cells and PMNs in bronchoalveolar lavage fluid, and the systemic levels of the pro-inflammatory cytokines. Furthermore, PD (30 and 45 mg/kg) treatment remarkably improved LPS-induced increase in TUNEL (deoxynucleotidyl transferase dUTP nick end labeling) staining-positive cells, caspase 3 activity, Bax over-expression and Bcl-2 down-expression. In conclusion, these results demonstrate that PD (30 and 45 mg/kg) treatment attenuates LPS-induced ALI through reducing lung inflammation and apoptosis.

Ulinastatin inhibits oxidant-induced endothelial hyperpermeability and apoptotic signaling.

Oxidants are important signaling molecules known to increase endothelial permeability. Studies implicate reactive oxygen species (ROS) and the intrinsic apoptotic signaling cascades as mediators of vascular hyperpermeability. Here we report the protective effects of ulinastatin, a serine protease inhibitor with antiapoptotic properties, against oxidant-induced endothelial monolayer hyperpermeability. HUVECs were respectively pretreated with 10,000 and 50,000 u/l ulinastatin, followed by stimulation of 0.6 mM H2O2. Monolayer permeability was determined by transendothelial electrical resistance (TER); Mitochondrial release of cytochrome c was determined by enzyme-linked immunosorbent assay; Caspase-3 activity was measured by fluorometric assay; Adherens junction protein ß-catenin was detected by immunofluorescense staining; Ratio of cell apoptosis was evaluated by Annexin-V/PI double stain assay; Mitochondrial membrane potential (Δψm) was determined with JC-1; Intracellular ATP content was assayed by a commercial kit; Bax and Bcl-2 expression were estimated by western blotting; Intracellular reactive oxygen species (ROS) level was measured by DCFH-DA. H2O2 exposure resulted in endothelial hyperpermeability and ROS formation (P < 0.05). The activation of mitochondrial intrinsic apoptotic signaling pathway was evidenced from BAX up-regulation, Bcl-2 down-regulation, mitochondrial depolarization, an increase in cytochrome c release, and activation of caspase-3 (P < 0.05). UTI (50,000 u/l) attenuated endothelial hyperpermeability, ROS formation, mitochondrial dysfunction, cytochrome c release, activation of caspase-3, and disruption of cell adherens junctions (P < 0.05). Together, these results demonstrate that UTI provides protection against vascular hyperpermeability by modulating the intrinsic apoptotic signaling.