Recruitment maneuvers to reduce pulmonary atelectasis after cardiac surgery: A meta-analysis of randomized trials.

BACKGROUND: Pulmonary atelectasis is a common postoperative complication that may lead to intrapulmonary shunt, refractory hypoxemia, and respiratory distress. Recruitment maneuvers may relieve pulmonary atelectasis in patients undergoing cardiac surgery. We conducted a meta-analysis of randomized controlled trials to evaluate the effectiveness of recruitment maneuvers in these patients. METHODS: We conducted a search in PubMed, Embase, Cochrane Library, and the ClinicalTrials.gov registry for trials published before March 2020. Individual effect sizes were standardized, and a meta-analysis was performed to calculate a pooled effect size by using random-effects models. Pulmonary atelectasis was assessed postoperatively. Secondary outcomes included hypoxic events, arterial oxygen tension (Pao2)/inspired oxygen fraction (Fio2) ratio, cardiac index, mean arterial pressure, and postoperative complications including pneumothorax and pneumonia. RESULTS: We reviewed 16 trials involving 1455 patients. Patients receiving recruitment maneuvers had a reduced incidence of pulmonary atelectasis (group with recruited pressure >40 cmH2O: risk ratio [RR], 0.20; 95% confidence interval [CI], 0.07-0.57; group with recruited pressure <40 cmH2O: RR, 0.54; 95% CI, 0.33-0.89), reduced incidence of hypoxic events (RR, 0.23; 95% CI, 0.14-0.37), reduced incidence of pneumonia (RR, 0.42; 95% CI, 0.18-0.95), and improved Pao2/Fio2 ratio (weighted mean difference [WMD]; 58.87, 95% CI, 31.24-86.50) without disturbing the cardiac index (WMD, 0.22; 95% CI, -0.18 to 0.61) or mean arterial pressure (WMD, -0.30, 95% CI, -3.19 to 2.59) as compared with those who received conventional mechanical ventilation. The incidence of pneumothorax was nonsignificant between the groups. CONCLUSIONS: Recruitment maneuvers may reduce postoperative pulmonary atelectasis, hypoxic events, and pneumonia and improve Pao2/Fio2 ratios without hemodynamic disturbance in patients undergoing cardiac surgery.

Recruitment maneuvers in patients undergoing thoracic surgery: a meta-analysis.

OBJECTIVE: Pulmonary atelectasis is a common postoperative complication that may lead to intrapulmonary shunt, refractory hypoxemia, and respiratory distress. Recruitment maneuvers may relieve pulmonary atelectasis in patients undergoing thoracic surgery. This meta-analysis of randomized controlled trials (RCTs) is to evaluate the effectiveness and safety of recruitment maneuvers in patients undergoing thoracic surgery. METHODS: We performed a literature search on the PubMed, Embase, and Cochrane Library databases and the ClinicalTrials.gov registry for trials published before April 2021. We investigated postoperative pulmonary atelectasis incidence, intrapulmonary shunt fraction, static lung compliance, and mean arterial pressure. RESULTS: Six RCTs involving 526 patients were reviewed. Patients receiving a recruitment maneuver exhibited a significant decrease in intrapulmonary shunt fraction [weighted mean difference (WMD) - 0.02, 95% CI - 0.03 to - 0.01], improved static lung compliance (WMD 2.16; 95% CI 1.14-3.18), and PaO2/FIO2 ratio (WMD 31.31; 95% CI 12.11-50.52) without a significant difference in mean arterial pressure (WMD - 0.64; 95% CI - 4.92 to 3.64). The incidence pulmonary atelectasis favored recruitment maneuver group, but was not statistically significant (RR 0.55; 95% CI 0.27-1.12). CONCLUSIONS: Recruitment maneuvers may be a viable treatment for reducing intra-pulmonary shunt and improving static lung compliance and PaO2/FIO2 ratio without the disturbance of hemodynamics in patients undergoing thoracic surgery.

Lung ventilation distribution in patients after traditional full sternotomy and minimally invasive thoracotomy: An observational study.

BACKGROUND: The aim of the study was to examine the post-operative ventilation distribution changes in cardiac surgical patients after traditional full sternotomy (FS) or minimally invasive thoracotomy (MIT). METHODS: A total of 40 patients scheduled for FS with two-lung ventilation or MIT with one-lung ventilation were included. Ventilation distribution was measured with electrical impedance tomography (EIT) at T1, before surgery; T2, after surgery in ICU before weaning; T3, 24 hours after extubation. EIT-based parameters were calculated to assess the ventilation distribution, including the left-to-right lung ratio, ventral-to-dorsal ratio, and the global inhomogeneity index. RESULTS: The global inhomogeneity index increased at T2 and T3 compared to T1 in all patients but only statistically significant in patients with MIT (FS, P = .06; MIT, P < .01). Notable decrease in the dorsal regions (FS) or in the non-ventilated side (MIT) was observed at T2. Ventilation distribution was partially improved at T3 but huge variations of recovery progresses were found in all patients regardless of the surgery types. Subgroup analysis indicated that operation duration was significantly lower in the MIT group (240 ± 40 in FS vs 205 ± 90 minutes in MIT, median ± interquartile range, P < .05) but the incidence of atrial fibrillation/flutter was significantly higher (5% in FS vs 50% in MIT, P < .01). Other exploratory outcomes showed no statistical differences. CONCLUSIONS: Ventilation distribution was impaired after cardiac surgery. The recovery process of ventilation homogeneity was strongly depending on individuals so that MIT was not always superior in this aspect. EIT may help to identify the patients requiring further care after surgery.

Alterations by Air Pollution in Inflammation and Metals in Pleural Effusion of Pneumonia Patients.

Air pollution is known to increase the risk of pneumonia. However, the effects of air pollution on the pleural effusion of patients with pneumonia are unclear. The objective of this study was to investigate alterations in inflammatory⁻immune biomarkers by air pollution in patients with pneumonia by analyzing their pleural effusion. Patients who had undergone thoracentesis to drain their pleural effusion in a hospital were recruited for this study. Patients with pneumonia and those with congestive heart failure respectively served as the case and control groups. We observed that an increase of 1 ppb in one-year NO2 was associated with a decrease of 0.105 ng/mL in cluster of differentiation 62 (CD62) (95% confidence interval (CI) = -0.085, -0.004, p < 0.05) in the pleural effusion. Furthermore, we observed that an increase in one-year 1 ppb of NO2 was associated with a decrease of 0.026 ng/mL in molybdenum (Mo) (95% CI = -0.138, -0.020, p < 0.05). An increase in one-year 1 ppb of SO2 was associated with a decrease of 0.531 ng/mL in zinc (95% CI = -0.164, -0.006, p < 0.05). Also, an increase in one-year 1 ppb of O3 was associated with a decrease of 0.025 ng/mL in Mo (95% CI = -0.372, -0.053, p < 0.05). In conclusion, air pollution exposure, especially gaseous pollution, may be associated with the regulation of immune responses and changes in metal levels in the pleural effusion of pneumonia patients.

MEKK1, JNK, and SMAD3 mediate CXCL12-stimulated connective tissue growth factor expression in human lung fibroblasts.

BACKGROUND: In idiopathic pulmonary fibrosis, the interaction of CXCL12 and CXC receptor 4 (CXCR4) plays a critical role in lung fibrosis. Connective tissue growth factor (CTGF) overexpression underlies the development of pulmonary fibrosis. Our previous report showed that the Rac1-dependent extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein (AP)-1 pathways are involved in CXCL12-generated CTGF expression in human lung fibroblasts (WI-38). In present study, we additionally inspected the involvement of mitogen-activated protein kinase kinase kinase 1 (MEKK1)/JNK-dependent SMAD3 in CXCL12-triggered CTGF expression in WI-38 cells. METHODS: WI-38 cells were stimulated with CXCL12 in the absence or presence of specific inhibitors or small interfering RNAs (siRNAs). CTGF expression and signaling transduction molecules were assessed by Western blot, luciferase activity assay, or ChIP assay. RESULTS: CXCL-12-induced CTGF expression was attenuated by SIS3 (a SMAD3 inhibitor) and SMAD3 siRNA, but not by SB431542 (an activin receptor-like kinase 5, ALK5, inhibitor). CXCL12-stimulated CTGF expression was also attenuated by MEKK1 siRNA. Treatment of cells with CXCL12 caused an increase in SMAD3 phosphorylation at Ser208, translocation to nuclei, SMAD3-luciferase activity, and recruitment of SMAD3 to the CTGF promoter. Stimulation of cells with CXCL12 resulted in increase in JNK phosphorylation at Thr183/Tyr185 and MEKK1 phosphorylation at Thr261. Moreover, CXCL12-mediated SMAD3 phosphorylation or SMAD3-luciferase activity was inhibited by MEKK1 siRNA or SP600125. Finally, CXCL12-mediated JNK phosphorylation was attenuated by MEKK1 siRNA. CONCLUSION: In conclusion, results of this study suggest that CXCL12 activates the MEKK1/JNK signaling pathway, which in turn initiates SMAD3 phosphorylation, its translocation to nuclei, and recruitment of SMAD3 to the CTGF promoter, which ultimately induces CTGF expression in human lung fibroblasts.

Hesperetin-5,7,3'-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice.

BACKGROUND: We recently reported that hesperetin-5,7,3'-O-triacetate (HTA) dually inhibited phosphodiesterase (PDE)3/4 with a therapeutic ratio of 20.8. The application and development of PDE4 inhibitors for treating asthma or COPD are limited by their side effects, such as nausea, vomiting and gastric hypersecretion. PDE4 inhibitors were reported to reverse xylazine/ketamine-induced anesthesia in rats and triggered vomiting in ferrets. Thus the reversing effect of HTA on xylazine/ketamine-induced anesthesia in mice was studied to assess emetic effect of HTA. The aim of this study was to prove the therapeutic effect of HTA without vomiting effect at an effective dose for treating COPD. METHODS: Ten female BALB/c mice in each group were sensitized by ovalbumin (OVA) on days 0 and 14. On day 21, these mice were emphasized the sensitization by Freund's complete adjuvant. Mice were challenged by 1% OVA nebulization on days 28, 29, and 30. Airway hyperresponsiveness (AHR) was assessed on day 32 in each group, using the FlexiVent system to determine airway resistance (RL) and lung dynamic compliance (Cdyn) in anesthetized ovalbumin (OVA)-sensitized and challenged mice. Each group was orally administered HTA (10 ~ 100 µmol/kg), roflumilast (1 and 5 mg/kg) or vehicles (controls) 2 h before and 6 and 24 h after OVA provocation. For comparison, sham-treated mice were challenged with saline instead of 1% OVA. The ability to reverse xylazine/ketamine-induced anesthesia by HTA or roflumilast for 3 h was determined in normal mice. We used roflumilast, a selective PDE4 inhibitor and bronchodilator for severe COPD approved by the US Food and Drug Administration, as a reference drug. RESULTS: In the results, HTA (100 µmol/kg, p.o.) or roflumilast (5 mg/kg, p.o.) significantly suppressed all RL values of MCh at 0.78 ~ 25 mg/mL and enhanced Cdyn values of MCh at 3.125 ~ 25 mg/mL compared to OVA-sensitized and -challenged control mice. Orally administered 1, 3 or 10 mg/kg roflumilast, but not 30 or 100 µmol/kg HTA, significantly reversed xylazine/ketamine-induced anesthesia. CONCLUSIONS: In contrast to roflumilast, HTA may ameliorate COPD but induce few side effects of nausea, vomiting and gastric hypersecretion at an effective dose for treating COPD, because HTA did not reverse xylazine/ketamine-induced anesthesia in mice.

Protein oxidation and degradation caused by particulate matter.

Particulate matter (PM) modulates the expression of autophagy; however, the role of selective autophagy by PM remains unclear. The objective of this study was to determine the underlying mechanisms in protein oxidation and degradation caused by PM. Human epithelial A549 cells were exposed to diesel exhaust particles (DEPs), urban dust (UD), and carbon black (CB; control particles). Cell survival and proliferation were significantly reduced by DEPs and UD in A549 cells. First, benzo(a)pyrene diolepoxide (BPDE) protein adduct was caused by DEPs at 150 µg/ml. Methionine oxidation (MetO) of human albumin proteins was induced by DEPs, UD, and CB; however, the protein repair mechanism that converts MetO back to methionine by methionine sulfoxide reductases A (MSRA) and B3 (MSRB3) was activated by DEPs and inhibited by UD, suggesting that oxidized protein was accumulating in cells. As to the degradation of oxidized proteins, proteasome and autophagy activation was induced by CB with ubiquitin accumulation, whereas proteasome and autophagy activation was induced by DEPs without ubiquitin accumulation. The results suggest that CB-induced protein degradation may be via an ubiquitin-dependent autophagy pathway, whereas DEP-induced protein degradation may be via an ubiquitin-independent autophagy pathway. A distinct proteotoxic effect may depend on the physicochemistry of PM.

Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways.

Colon cancer is the third most common malignancy worldwide. Recently, some interesting associations between ghrelin and cancer were reported, and it may participate in colon cancer development. In the present report, we explored the role of the growth hormone secretagogue receptor (GHS-R), Ras, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) pathways in the ghrelin-induced proliferation of human colon cancer cells. Ghrelin-caused HT-29 proliferation was reduced by [D-Lys3]-GHRP-6 (a GHS-R inhibitor). We also found that a dominant negative mutant of Ras (Ras DN), a PI3K inhibitor (LY 294002), an Akt DN, and an mTOR inhibitor (rapamycin) attenuated ghrelin-caused colon cancer cell proliferation. We found that ghrelin induced time-dependent increases in Ras activity. Moreover, ghrelin-mediated Akt Ser473 phosphorylation was attenuated by a Ras DN and LY 294002. Furthermore, a Ras DN, LY 294002, and an Akt DN all inhibited ghrelin-caused mTOR Ser2448 phosphorylation. These results indicate that the Ras/PI3K/Akt/mTOR cascade plays a critical role in ghrelin-induced colon cancer cell proliferation.

Dysfunction of methionine sulfoxide reductases to repair damaged proteins by nickel nanoparticles.

BACKGROUND: Protein oxidation is considered to be one of the main causes of cell death, and methionine is one of the primary targets of reactive oxygen species (ROS). However, the mechanisms by which nickel nanoparticles (NiNPs) cause oxidative damage to proteins remain unclear. OBJECTIVES: The objective of this study is to investigate the effects of NiNPs on the methionine sulfoxide reductases (MSR) protein repairing system. METHODS: Two physically similar nickel-based nanoparticles, NiNPs and carbon-coated NiNP (C-NiNPs; control particles), were exposed to human epithelial A549 cells. Cell viability, benzo(a)pyrene diolepoxide (BPDE) protein adducts, methionine oxidation, MSRA and B3, microtubule-associated protein 1A/1B-light chain 3 (LC3) and extracellular signal-regulated kinase (ERK) phosphorylation were investigated. RESULTS: Exposure to NiNPs led to a dose-dependent reduction in cell viability and increased BPDE protein adduct production and methionine oxidation. The methionine repairing enzymatic MSRA and MSRB3 production were suppressed in response to NiNP exposure, suggesting the oxidation of methionine to MetO by NiNP was not reversed back to methionine. Additionally, LC3, an autophagy marker, was down-regulated by NiNPs. Both NiNP and C-NiNP caused ERK phosphorylation. LC3 was positively correlated with MSRA (r = 0.929, p < 0.05) and MSRB3 (r = 0.893, p < 0.05). CONCLUSIONS: MSR was made aberrant by NiNP, which could lead to the dysfunction of autophagy and ERK phosphorylation. The toxicological consequences may be dependent on the chemical characteristics of the nanoparticles.

Butylidenephthalide blocks potassium channels and enhances basal tension in isolated guinea-pig trachea.

Butylidenephthalide (Bdph, 30~300 µM), a constituent of Ligusticum chuanxiong Hort., significantly enhanced tension in isolated guinea-pig trachea. In this study, we investigate the mechanism(s) of Bdph-induced contraction in the tissue. Isolated trachea was bathed in 5 mL of Krebs solution containing indomethacin (3 µM), and its tension changes were isometrically recorded. Cromakalim (3 µM), an ATP-dependent K+ channel opener, significantly antagonized the Bdph-induced enhancement of baseline tension. Bdph (300 µM) also significantly antagonized cromakalim-induced relaxation. Bdph (300 µM) did not significantly influence the antagonistic effects of glibenclamide (GBC, 1 µM) and tetraethylammonium (TEA, 8 mM) against the cromakalim-induced relaxation. However, Bdph (300 µM) and 4-aminopiridine (4-AP, 5 mM), a blocker of K v 1 family of K+ channels, in combination significantly rightward shifted the log concentration-relaxation curve of cromakalim. The antagonistic effect of the combination almost equals the sum of the individual effects of Bdph and 4-AP, suggesting that the antagonistic mechanism of Bdph may be similar to that of 4-AP. All calcium channel blockers influenced neither the baseline tension nor antagonistic effect of Bdph against cromakalim. In conclusion, Bdph may be similar to 4-AP, a blocker of K v 1 family of K+ channels, to enhance the baseline tension of guinea-pig trachea.

Comparison of high pressure and ambient pressure aerobic granulation sequential batch reactor processes.

Due to granule size, substrate and oxygen become limited in the core of granules leading to cell lysis at the core. Loss of granule stability is still a major barrier for practical application of AG. Compared to ambient pressure condition (AP), operation of AG under high pressure (HP) is a favorable condition for formation and stability of granules. Experimental results show that granulation was facilitated under HP condition. MLSS and size of granules under AP system are higher than those under HP system. However, SS of effluent in AP is higher than those in HP and is consisted mainly of flocculent sludge. Longer SRT and lower biomass yield are obtained in HP system, indicating that less sludge will be produced in HP system. HP system can operate at high nitrogen loading. Complete nitrification was observed earlier in HP, indicating that the growth of NOB was facilitated under high dissolved oxygen.

Hesperidin-3'-o-methylether is more potent than hesperidin in phosphodiesterase inhibition and suppression of ovalbumin-induced airway hyperresponsiveness.

Hesperidin is present in the traditional Chinese medicine, "Chen Pi," and recently was reported to have anti-inflammatory effects. Therefore, we were interested in comparing the effects of hesperidin and hesperidin-3'-O-methylether on phosphodiesterase inhibition and airway hyperresponsiveness (AHR) in a murine model of asthma. In the present results, hesperidin-3'-O-methylether, but not hesperidin, at 30 µmol/kg (p.o.) significantly attenuated the enhanced pause (P(enh)) value, suppressed the increases in numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, suppressed total and OVA-specific immunoglobulin (Ig)E levels in the serum and BALF, and enhanced the level of total IgG(2a) in the serum of sensitized and challenged mice, suggesting that hesperidin-3'-O-methylether is more potent than hesperidin in suppression of AHR and immunoregulation. The different potency between them may be due to their aglycons, because these two flavanone glycosides should be hydrolyzed by ß-glucosidase after oral administration. Neither influenced xylazine/ketamine-induced anesthesia, suggesting that they may have few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, hesperidin-3'-O-methylether is more potent in phosphodiesterase inhibition and suppression of AHR and has higher therapeutic (PDE4(H)/PDE4(L)) ratio than hesperidin. Thus, hesperidin-3'-O-methylether may have more potential for use in treating allergic asthma and chronic obstructive pulmonary disease.

Systemic human orbital fat-derived stem/stromal cell transplantation ameliorates acute inflammation in lipopolysaccharide-induced acute lung injury.

OBJECTIVE: Acute lung injury results in acute respiratory distress syndrome. There is no standard therapy for acute respiratory distress syndrome but supportive care. Stem cells offer a new therapeutic potential for tissue regeneration as a result of their self-renewal, multipotency, and paracrine capabilities. The objective of this study is to investigate the effects and the mechanisms of systemic human orbital fat-derived stem/stromal cell transplantation on lipopolysaccharide-induced acute lung injury. DESIGN: Prospective, randomized, controlled study. SETTING: University-affiliated research institute. SUBJECTS: Male BALB/c mice. INTERVENTIONS: Twenty-five micrograms lipopolysaccharide in 50 µL sterile saline or 50 µL of sterile saline was delivered through intratracheal injection. Twenty mins later, the animals were further randomized into subgroups that received either a tail vein injection of 3 × 10 orbital fat-derived stem/stromal cells in 50 µL phosphate-buffered saline or 50 µL phosphate-buffered saline. MEASUREMENTS AND MAIN RESULTS: Low immunogenicity and immune-tolerated of orbital fat-derived stem/stromal cells were observed in this xenotransplanted model. Orbital fat-derived stem/stromal cells significantly reduced lipopolysaccharide-induced pulmonary inflammation, which was evidenced by a decrease in total protein concentration and neutrophil counts in alveolar fluid through bronchoalveolar lavage, reduced endothelial and alveolar epithelial permeability as well as neutrophil (Ly6G-expressing cells) and macrophage (CD68-expressing cells) infiltration. Lipopolysaccharide-induced expression of CD14, inducible nitric oxide synthase, and transforming growth factor-ß in lung tissue was significantly inhibited by orbital fat-derived stem/stromal cells. Orbital fat-derived stem/stromal cells not only reduced the circulation numbers of macrophages and neutrophils (CD11b-expressing cells), but also decreased systemic proinflammatory chemokine levels such as macrophage inflammatory protein-1-γ, B-lymphocyte chemoattractant, interleukin-12, and subsequent circulation helper T cell (CD4-expressing cells) numbers. Furthermore, few human orbital fat-derived stem/stromal cells were detectable in the recipient lung after acute inflammation subsided. CONCLUSIONS: Systemic orbital fat-derived stem/stromal cell transplantation was effective in modulating inflammation during acute lung injury. The therapeutic effect was attributed to the inhibition of acute inflammatory responses.

Hesperetin-7,3'-O-dimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio.

BACKGROUND: Hesperetin was reported to selectively inhibit phosphodiesterase 4 (PDE4). While hesperetin-7,3'-O-dimethylether (HDME) is a synthetic liposoluble hesperetin. Therefore, we were interested in investigating its selectivity on PDE4 and binding ability on high-affinity rolipram-binding sites (HARBs) in vitro, and its effects on ovalbumin-induced airway hyperresponsiveness in vivo, and clarifying its potential for treating asthma and chronic obstructive pulmonary disease (COPD). METHODS: PDE1~5 activities were measured using a two-step procedure. The binding of HDME on high-affinity rolipram-binding sites was determined by replacing 2 nM [3H]-rolipram. AHR was assessed using the FlexiVent system and barometric plethysmography. Inflammatory cells were counted using a hemocytometer. Cytokines were determined using mouse T helper (Th)1/Th2 cytokine CBA kits, and total immunoglobulin (Ig)E or IgG2a levels were done using ELISA method. Xylazine (10 mg/kg)/ketamine (70 mg/kg)-induced anesthesia was performed. RESULTS: HDME revealed selective phosphodiesterase 4 (PDE4) inhibition with a therapeutic (PDE4H/PDE4L) ratio of 35.5 in vitro. In vivo, HDME (3~30 µmol/kg, orally (p.o.)) dose-dependently and significantly attenuated the airway resistance (RL) and increased lung dynamic compliance (Cdyn), and decreased enhanced pause (Penh) values induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in the numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF) of these mice. In addition, HDME (3~30 µmol/kg, p.o.) dose-dependently and significantly suppressed total and ovalbumin-specific immunoglobulin (Ig)E levels in the BALF and serum, and enhanced IgG2a level in the serum of these mice. CONCLUSIONS: HDME exerted anti-inflammatory effects, including suppression of AHR, and reduced expressions of inflammatory cells and cytokines in this murine model, which appears to be suitable for studying the effects of drugs on atypical asthma and COPD, and for screening those on typical asthma. However, HDME did not influnce xylazine/ketamine-induced anesthesia. Thus HDME may have the potential for use in treating typical and atypical asthma, and COPD.

Thrombin induces inducible nitric oxide synthase expression via the MAPK, MSK1, and NF-κB signaling pathways in alveolar macrophages.

In this study, we investigated the roles of mitogen activated protein kinase (MAPK), mitogen stress-activated protein kinase 1 (MSK1), and nuclear factor-κB (NF-κB) signaling pathways in thrombin-induced inducible nitric oxide synthase (iNOS) expression in alveolar macrophages (NR8383). Treatment of NR8383 cells with thrombin caused an increase in iNOS expression in a concentration- and time-dependent manner. Treatment of NR8383 cells with SB203580 (4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl)-1H-imidazole, a p38 MAPK inhibitor), PD98059 (2'-amino-3'-methoxyflavone, a MAPK kinase (MEK) inhibitor), and SP600125 (anthra[1-9-cd]pyrazol-6(2H)-one, a JNK inhibitor) all inhibited thrombin-induced iNOS expression. Stimulation of cells with thrombin caused an increase in p38 MAPK, ERK, and JNK phosphorylation. Treatment of cells with Ro 31-8220 (an MSK1 inhibitor) and MSK1 small interfering RNA (MSK1 siRNA) both inhibited thrombin-induced iNOS expression. Thrombin caused time-dependent activation of MSK1 Ser531 phosphorylation, which was inhibited by SB203580 and PD98059, but not by SP600125. Treatment of cells with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) inhibited thrombin-induced iNOS expression in a concentration-dependent manner. Treatment of NR8383 cells with thrombin induced κB-luciferase activity and p65 Ser276 phosphorylation. Thrombin-induced increases in p65 Ser276 phosphorylation and κB-luciferase activity were inhibited by SB203580, PD98059, Ro 31-8220, and MSK1 siRNA. Taken together, these results suggest that the signaling pathways of MAPK, MSK1, and NF-κB play important roles in thrombin-induced iNOS expression in alveolar macrophages.

Comparisons of predictive performance of breathing pattern variability measured during T-piece, automatic tube compensation, and pressure support ventilation for weaning intensive care unit patients from mechanical ventilation.

OBJECTIVE: To investigate the influence of different ventilatory supports on the predictive performance of breathing pattern variability for extubation outcomes in intensive care unit patients. DESIGN AND SETTING: A prospective measurement of retrospectively analyzed breathing pattern variability in a medical center. PATIENTS: Sixty-eight consecutive and ready-for-weaning patients were divided into success (n=45) and failure (n=23) groups based on their extubation outcomes. MEASUREMENTS: Breath-to-breath analyses of peak inspiratory flow, total breath duration, tidal volume, and rapid shallow breathing index were performed for three 30-min periods while patients randomly received T-piece, 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure, and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure trials. Coefficient of variations and data dispersion (standard descriptor values SD1 and SD2 of the Poincaré plot) were analyzed to serve as breathing pattern variability indices. MAIN RESULTS: Under all three trials, breathing pattern variability in extubation failure patients was smaller than in extubation success patients. Compared to the T-piece trial, 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure decreased the ability of certain breathing pattern variability indices to discriminate extubation success from extubation failure. The areas under the receiver operating characteristic curve of these breathing pattern variability indices were: T-piece (0.73-0.87)>100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure (0.60-0.79)>5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure (0.53-0.76). Analysis of the classification and regression tree indicated that during the T-piece trial, a SD1 of peak inspiratory flow>3.36 L/min defined a group including all extubation success patients. Conversely, the combination of a SD1 of peak inspiratory flow ≤3.36 L/min and a coefficient of variations of rapid shallow breathing index ≤0.23 defined a group of all extubation failure patients. The decision strategies using SD1 of peak inspiratory flow and coefficient of variations of rapid shallow breathing index measured during 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure trials achieved a less clear separation of extubation failure from extubation success. CONCLUSIONS: Since 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure reduce the predictive performance of breathing pattern variability, breathing pattern variability measurement during the T-piece trial is the best choice for predicting extubation outcome in intensive care unit patients patients.

Rapid shallow breathing index and its predictive accuracy measured under five different ventilatory strategies in the same patient group.

The rapid shallow breathing index (RSBI) is commonly used clinically for predicting the outcome of weaning from mechanical ventilation. We compared the RSBI and its predictive accuracies measured under 5 ventilatory strategies before weaning trials. Ninety-eight patients were included and divided into successful (n=71) and failed (n=27) groups based on their weaning outcomes. The RSBI was randomly measured when patients spontaneously breathed 21% O2 with no ventilator support (the control strategy) or were connected to ventilator breathing with 21% or 40% O2 and 0 or 5 cm H2O of continuous positive airway pressure (CPAP). We found that the RSBI values did not exhibit significant differences among the 4 ventilator strategies, but all were higher than that of the control; this remained valid in the non-chronic obstructive pulmonary disease (COPD) subgroup, but not in the COPD subgroup. Values of the area under the receiver operating characteristic curve of the RSBI for the 5 strategies were 0.51-0.62 with no significant difference between any 2 strategies. The incidences of adverse reactions (respiratory rate > or =35 breaths/min or oxygen saturation < or =89% for > or =1 min) were relatively high for the 21% O2-0 and 5 cm H2O CPAP groups (20 patients each) and low for the 40% O(2)-5 cmH2O CPAP group (2 patients). We concluded that RSBI values increased with the use of a ventilator, but not with additional applications of 40% 02 and/or 5 cm H2O CPAP. Their accuracies for predicting weaning outcome were unaltered by any of these interventions, but the incidence of adverse reactions increased with the use of the ventilator and decreased with additional 40% O2 supplementation.

Exacerbation of wood smoke-induced acute lung injury by mechanical ventilation using moderately high tidal volume in mice.

We investigated the effects of mechanical ventilation with a moderately high tidal volume (VT) on acute lung injury (ALI) induced by wood smoke inhalation in anesthetized mice. Animals received challenges of air, 30 breaths of smoke (30SM) or 60 breaths of smoke (60SM) and were then ventilated with a VT of 10 ml/kg (10VT) or 16 ml/kg (16VT). After 4-h mechanical ventilation, the bronchoalveolar-capillary permeability, pulmonary infiltration of inflammatory cells, total lung injury score and pulmonary expressions of interleukin-1beta and macrophage inflammatory protein-2 mRNA and proteins in the 30SM+16VT and 60SM+16VT groups were greater than those in the 30SM+10VT and 60SM+10VT groups, respectively. Additionally, the wet/dry weight ratio of lung tissues and lung epithelial cell apoptosis in the 60SM+16VT group were greater than those in the 60SM+10VT group. These differences between the 16VT and 10VT groups were not seen in animals with air challenge. Thus, mechanical ventilation with a moderately high VT in mice exacerbates ALI induced by wood smoke inhalation.

Involvement of tachykinin NK(1) and NK(2) receptors in changes in lung mechanics and airway microvascular leakage during the early phase of endotoxemia in Guinea pigs.

We investigated the role of tachykinins in airway neurogenic responses occurring in the early phase of endotoxemia. Forty-eight anesthetized guinea pigs were evenly divided into six groups pretreated with either saline vehicle, CP-96,345 (a tachykinin NK(1) receptor antagonist), SR-48,968 (a tachykinin NK(2) receptor antagonist) or CP-96,345 and SR-48,968 in combination. Animals then received an intravenous injection of either saline (the vehicle for endotoxin) or endotoxin (30 mg/kg). Total lung resistance (R(L)) and dynamic lung compliance (C(dyn)) were continuously measured before and 30 min after administration of saline or endotoxin. Airway microvascular leakage was assessed at the end of the observation period. Endotoxin significantly increased R(L) and decreased C(dyn) 10 min after intravenous endotoxin injection. Plasma extravasation significantly increased in the trachea, main bronchi and intrapulmonary airways with endotoxin administration. These changes in lung mechanics were abolished by SR-48,968, but were unaffected by CP-96,345. The plasma extravasation was largely attenuated by CP-96,345 and/or SR-48,968. We conclude that (1) endogenous tachykinins play an important role in producing changes in lung mechanics and airway microvascular leakage during the early phase of endotoxemia and (2) activation of tachykinin NK(2) receptors is responsible for the former response, while activation of both tachykinin NK(1) and NK(2) receptors is involved in the latter response.