Plasma Redox Balance in Advanced-Maternal-Age Pregnant Women and Effects of Plasma on Umbilical Cord Mesenchymal Stem Cells.

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal-fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy.

Intraoperative individualization of positive-end-expiratory pressure through electrical impedance tomography or esophageal pressure assessment: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: This systematic review of randomized-controlled trials (RCTs) with meta-analyses aimed to compare the effects on intraoperative arterial oxygen tension to inspired oxygen fraction ratio (PaO2/FiO2), exerted by positive end-expiratory pressure (PEEP) individualized trough electrical impedance tomography (EIT) or esophageal pressure (Pes) assessment (intervention) vs. PEEP not tailored on EIT or Pes (control), in patients undergoing abdominal or pelvic surgery with an open or laparoscopic/robotic approach. METHODS: PUBMED®, EMBASE®, and Cochrane Controlled Clinical trials register were searched for observational studies and RCTs from inception to the end of August 2022. Inclusion criteria were: RCTs comparing PEEP titrated on EIT/Pes assessment vs. PEEP not individualized on EIT/Pes and reporting intraoperative PaO2/FiO2. Two authors independently extracted data from the enrolled investigations. Data are reported as mean difference and 95% confidence interval (CI). RESULTS: Six RCTs were included for a total of 240 patients undergoing general anesthesia for surgery, of whom 117 subjects in the intervention group and 123 subjects in the control group. The intraoperative mean PaO2/FiO2 was 69.6 (95%CI 32.-106.4 ) mmHg higher in the intervention group as compared with the control group with 81.4% between-study heterogeneity (p < 0.01). However, at meta-regression, the between-study heterogeneity diminished to 44.96% when data were moderated for body mass index (estimate 3.45, 95%CI 0.78-6.11, p = 0.011). CONCLUSIONS: In patients undergoing abdominal or pelvic surgery with an open or laparoscopic/robotic approach, PEEP personalized by EIT or Pes allowed the achievement of a better intraoperative oxygenation compared to PEEP not individualized through EIT or Pes. PROSPERO REGISTRATION NUMBER: CRD 42021218306, 30/01/2023.

In-Hospital Predictors of Need for Ventilatory Support and Mortality in Chest Trauma: A Multicenter Retrospective Study.

Chest trauma management often requires the use of invasive and non-invasive ventilation. To date, only a few studies investigated the predictors of the need for ventilatory support. Data on 1080 patients with chest trauma managed in two different centers were retrospectively analyzed. Univariate and multivariate analyses were performed to identify the predictors of tracheal intubation (TI), non-invasive mechanical ventilation (NIMV), and mortality. Rib fractures (p = 0.0001) fracture of the scapula, clavicle, or sternum (p = 0.045), hemothorax (p = 0.0035) pulmonary contusion (p = 0.0241), and a high Injury Severity Score (ISS) (p ≤ 0001) emerged as independent predictors of the need of TI. Rib fractures (p = 0.0009) hemothorax (p = 0.0027), pulmonary contusion (p = 0.0160) and a high ISS (p = 0.0001) were independent predictors of NIMV. The center of trauma care (p = 0.0279), age (p < 0.0001) peripheral oxygen saturation in the emergency department (p = 0.0010), ISS (p < 0.0001), and Revised Trauma Score (RTS) (p < 0.0001) were independent predictors of outcome. In conclusion, patients who do not require TI, while mandating ventilatory support with selected types of injuries and severity scores, are more likely to be subjected to NIMV. Trauma team expertise and the level of the trauma center could influence patient outcomes.

Bronchoscopy during COVID-19 pandemic, ventilatory strategies and procedure measures.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has changed bronchoscopy practices worldwide. Bronchoscopy is a high-risk aerosol-generating procedure with a potential for direct SARS-CoV-2 exposure and hospital-acquired infection. Current guidelines about personal protective equipment and environment considerations represent key competencies to minimize droplets dispersion and reduce the risk of transmission. Different measures should be put in field based on setting, patient's clinical characteristics, urgency and indications of bronchoscopy. The use of this technique in SARS-CoV-2 patients is reported primarily for removal of airway plugs and for obtaining microbiological culture samples. In mechanically ventilated patients with SARS-CoV-2, bronchoscopy is commonly used to manage complications such as hemoptysis, atelectasis or lung collapse when prone positioning, physiotherapy or recruitment maneuvers have failed. Further indications are represented by assistance during percutaneous tracheostomy. Continuous positive airway pressure, non-invasive ventilation support and high flow nasal cannula oxygen are frequently used in patient affected by Coronavirus disease 2019 (COVID-19): management of patients' airways and ventilation strategies differs from bronchoscopy indications, patient's clinical status and in course or required ventilatory support. Sedation is usually administered by the pulmonologist (performing the bronchoscopy) or by the anesthetist depending on the complexity of the procedure and the level of sedation required. Lastly, elective bronchoscopy for diagnostic indications during COVID-19 pandemic should be carried on respecting rigid standards which allow to minimize potential viral transmission, independently from patient's COVID-19 status. This narrative review aims to evaluate the indications, procedural measures and ventilatory strategies of bronchoscopy performed in different settings during COVID-19 pandemic.

Intraoperative protective ventilation in patients undergoing major neurosurgical interventions: a randomized clinical trial.

BACKGROUND: Post-operative pulmonary complications (PPC) can develop in up to 13% of patients undergoing neurosurgical procedures and may adversely affect clinical outcome. The use of intraoperative lung protective ventilation (LPV) strategies, usually including the use of a low Vt, low PEEP and low plateau pressure, seem to reduce the risk of PPC and are strongly recommended in almost all surgical procedures. Nonetheless, feasibility of LPV strategies in neurosurgical patients are still debated because the use of low Vt during LPV might result in hypercapnia with detrimental effects on cerebrovascular physiology. Aim of our study was to determine whether LPV strategies would be feasible compared with a control group in adult patients undergoing cranial or spinal surgery. METHODS: This single-centre, pilot randomized clinical trial was conducted at the University Hospital "Maggiore della Carità" (Novara, Italy). Adult patients undergoing major cerebral or spinal neurosurgical interventions with risk index for pulmonary post-operative complications > 2 and not expected to need post-operative intensive care unit (ICU) admission were considered eligible. Patients were randomly assigned to either LPV (Vt = 6 ml/kg of ideal body weight (IBW), respiratory rate initially set at 16 breaths/min, PEEP at 5 cmH2O and application of a recruitment manoeuvre (RM) immediately after intubation and at every disconnection from the ventilator) or control treatment (Vt = 10 ml/kg of IBW, respiratory rate initially set at 6-8 breaths/min, no PEEP and no RM). Primary outcomes of the study were intraoperative adverse events, the level of cerebral tension at dura opening and the intraoperative control of PaCO2. Secondary outcomes were the rate of pulmonary and extrapulmonary complications, the number of unplanned ICU admissions, ICU and hospital lengths of stay and mortality. RESULTS: A total of 60 patients, 30 for each group, were randomized. During brain surgery, the number of episodes of intraoperative hypercapnia and grade of cerebral tension were similar between patients randomized to receive control or LPV strategies. No difference in the rate of intraoperative adverse events was found between groups. The rate of postoperative pulmonary and extrapulmonary complications and major clinical outcomes were similar between groups. CONCLUSIONS: LPV strategies in patients undergoing major neurosurgical intervention are feasible. Larger clinical trials are needed to assess their role in postoperative clinical outcome improvements. TRIAL REGISTRATION: registered on the Australian New Zealand Clinical Trial Registry ( www.anzctr.org.au ), registration number ACTRN12615000707561.

Esophageal balloon calibration during Sigh: A physiologic, randomized, cross-over study.

PURPOSE: Optimal esophageal balloon filling volume (Vbest) depends on the intrathoracic pressure. During Sigh breath delivered by the ventilator machine, esophageal balloon is surrounded by elevated intrathoracic pressure that might require higher filling volume for accurate measure of tidal changes in esophageal pressure (Pes). The primary aim of our investigation was to evaluate and compare Vbest during volume controlled and pressure support breaths vs. Sigh breath. MATERIALS AND METHODS: Twenty adult patients requiring invasive volume-controlled ventilation (VCV) for hypoxemic acute respiratory failure were enrolled. After the insertion of a naso-gastric catheter equipped with 10 ml esophageal balloon, each patient underwent three 30-min trials as follows: VCV, pressure support ventilation (PSV), and PSV + Sigh. Sigh was added to PSV as 35 cmH2O pressure-controlled breath over 4 s, once per minute. PSV and PSV + Sigh were randomly applied and, at the end of each step, esophageal balloon calibration was performed. RESULTS: Vbest was higher for Sigh breath (4.5 [3.0-6.8] ml) compared to VCV (1.5 [1.0-2.9] ml, P = 0.0004) and PSV tidal breath (1.0 [0.5-2.4] ml, P < 0.0001). CONCLUSIONS: During Sigh breath, applying a calibrated approach for Pes assessment, a higher Vbest was required compared to VCV and PSV tidal breath.

Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia.

We describe a patient affected by Covid-19 acute respiratory distress syndrome with a cerebral nervous system vasculitis triggered by SARS-Cov-2, managed at the University hospital, in Novara, Italy in the area most impacted by the pandemic and where 749 Covid-19 positive patients were admitted from March 1st until April 25th, 2020.

Inferior Vena Cava Filter in a Patient with COVID-19 Pneumonia to Prevent a Massive Pulmonary Embolism.

COVID 19 predispose to deep vein thrombosis. We describe an early placement of inferior vena cava filter added to the therapeutic anticoagulation to prevent a massive pulmonary embolism.

Esophageal Pressure Versus Gas Exchange to Set PEEP During Intraoperative Ventilation.

BACKGROUND: Pneumoperitoneum and Trendelenburg position affect respiratory system mechanics and oxygenation during elective pelvic robotic surgery. The primary aim of this randomized pilot study was to compare the effects of a conventional low tidal volume ventilation with PEEP guided by gas exchange (VGas-guided) versus low tidal volume ventilation tailoring PEEP according to esophageal pressure (VPes-guided) on oxygenation and respiratory mechanics during elective pelvic robotic surgery. METHODS: This study was conducted in a single-center tertiary hospital between September 2017 and January 2019. Forty-nine adult patients scheduled for elective pelvic robotic surgery were screened; 28 subjects completed the full analysis. Exclusion criteria were American Society of Anesthesiologists physical status ≥ 3, contraindications to nasogastric catheter placement, and pregnancy. After dedicated naso/orogastric catheter insertion, subjects were randomly assigned to VGas-guided ([Formula: see text] and PEEP set to achieve [Formula: see text] > 94%) or VPes-guided (PEEP tailored to equalize end-expiratory transpulmonary pressure). Oxygenation ([Formula: see text]/[Formula: see text]) was evaluated (1) at randomization, after pneumoperitoneum and Trendelenburg application; (2) at 60 min; (3) at 120 min following randomization; and (4) at end of surgery. Respiratory mechanics were assessed during the duration of the study. RESULTS: Compared to VGas-guided, oxygenation was higher with VPes-guided at 60 min (388 ± 90 vs 308 ± 95 mm Hg, P = .02), at 120 min after randomization (400 ± 90 vs 308 ± 81 mm Hg, P = .008), and at the end of surgery (402 ± 95 vs 312 ± 95 mm Hg, P = .009). Respiratory system elastance was lower with VPes-guided compared to VGas-guided at 20 min (24.2 ± 7.3 vs 33.4 ± 10.7 cm H2O/L, P = .001) and 60 min (24.1 ± 5.4 vs 31.9 ± 8.5 cm H2O/L, P = .006) from randomization. CONCLUSIONS: Oxygenation and respiratory system mechanics were improved when applying a ventilatory strategy tailoring PEEP to equalize expiratory transpulmonary pressure in subjects undergoing pelvic robotic surgery compared to a VGas-guided approach. (ClinicalTrials.gov registration NCT03153592).

Mechanical Ventilation Guided by Uncalibrated Esophageal Pressure May Be Potentially Harmful.

BACKGROUND: Esophageal balloon calibration was proposed in acute respiratory failure patients to improve esophageal pressure assessment. In a clinical setting characterized by a high variability of abdominal load and intrathoracic pressure (i.e., pelvic robotic surgery), the authors hypothesized that esophageal balloon calibration could improve esophageal pressure measurements. Accordingly, the authors assessed the impact of esophageal balloon calibration compared to conventional uncalibrated approach during pelvic robotic surgery. METHODS: In 30 adult patients, scheduled for elective pelvic robotic surgery, calibrated end-expiratory and end-inspiratory esophageal pressure, and the associated respiratory variations were obtained at baseline, after pneumoperitoneum-Trendelenburg application, and with positive end-expiratory pressure (PEEP) administration and compared to uncalibrated values measured at 4-ml filling volume, as per manufacturer recommendation. Data are expressed as median and [25th, 75th percentile]. RESULTS: Ninety calibrations were successfully performed. Chest wall elastance worsened with pneumoperitoneum-Trendelenburg and PEEP (19.0 [15.5, 24.6] and 16.7 [11.4, 21.7] cm H2O/l) compared to baseline (8.8 [6.3, 9.8] cm H2O/l; P < 0.0001 for both comparisons). End-expiratory and end-inspiratory calibrated esophageal pressure progressively increased from baseline (3.7 [2.2, 6.0] and 7.7 [5.9, 10.2] cm H2O) to pneumoperitoneum-Trendelenburg (6.2 [3.8, 10.2] and 16.1 [13.1, 20.6] cm H2O; P = 0.014 and P < 0.001) and PEEP (8.8 [7.7, 15.6] and 18.9 [16.3, 22.0] cm H2O; P < 0.0001 vs. baseline for both comparison; P < 0.001 and P = 0.002 vs. pneumoperitoneum-Trendelenburg) and, at each study step, they were persistently lower than uncalibrated esophageal pressure (P < 0.0001 for all comparisons). Overall, difference among uncalibrated and calibrated esophageal pressure was 5.1 [3.8, 8.4] cm H2O at end-expiration and 3.8 [3.0, 6.3] cm H2O at end-inspiration. Uncalibrated esophageal pressure swing was always lower than calibrated one (P < 0.0001 for all comparisons) with a difference of -1.0 [-1.8, -0.4] cm H2O. CONCLUSIONS: In a clinical setting with variable chest wall mechanics, uncalibrated measurements substantially overestimated absolute values and underestimated respiratory variations of esophageal pressure. Calibration could substantially improve mechanical ventilation guided by esophageal pressure.

Oesophageal balloon calibration during pressure support ventilation: a proof of concept study.

Oesophageal balloon calibration improves the oesophageal pressure (Pes) assessment during invasive controlled mechanical ventilation. The primary aim of the present investigation was to ascertain the feasibility of oesophageal balloon calibration during pressure support ventilation (PSV). Secondarily, the calibrated Pes (Pescal) was compared to uncalibrated one acquired at 4 ml-filling volume (PesV4), as per manufacturer recommendation. After a naso-gastric tube equipped with oesophageal balloon was correctly positioned in 21 adult patients undergoing invasive volume-controlled ventilation (VCV) for acute hypoxemic respiratory failure, the balloon was progressively inflated, applying a series of end-inspiratory and end-expiratory holds at each filling volume during VCV and PSV. Upon optimal balloon filling volume (Vbest) was identified, Pescal was computed by correcting the Pes measured at Vbest for the oesophageal wall pressure elicited at same filling volume. Finally, end-expiratory and end-inspiratory PesV4 were recorded too. A total of 42 calibrations, 21 per ventilatory mode, were performed. Vbest was 1.9 ± 1.6 ml in VCV and 1.7 ± 1.6 ml in PSV (p = 0.5217). PesV4 was overestimated compared to Pescal at end-expiration and end-inspiration (p <0.0001 for all comparisons) in both VCV (13.4 ± 3.4 cmH2O and 15.4 ± 3 cmH2O vs. 8.5 ± 2.9 cmH2O and 11.4 ± 3 cmH2O) and PSV (14.7 ± 4.2 cmH2O and 17 ± 3.9 cmH2O vs. 8.9 ± 3.4 cmH2O and 12.4 ± 3.9 cmH2O). In PSV, oesophageal balloon calibration is feasible and allows to obtain a reliable Pes assessment compared to uncalibrated approach.

A double blind randomized experimental study on the use of IgM-enriched polyclonal immunoglobulins in an animal model of pneumonia developing shock.

BACKGROUND: Patients with severe pneumonia often develop septic shock. IgM-enriched immunoglobulins have been proposed as a potential adjuvant therapy for septic shock. While in vitro data are available on the possible mechanisms of action of IgM-enriched immunoglobulins, the results of the in vivo experimental studies are non-univocal and, overall, unconvincing. We designed this double blinded randomized controlled study to test whether IgM-enriched immunoglobulins administered as rescue treatment in a pneumonia model developing shock, could either limit lung damage and/or contain systemic inflammatory response. METHODS: Thirty-eight Sprague Dawley rats were ventilated with injurious ventilation for 30min to prime the lung. The rats were subsequently randomized to received intratracheal instillation of either lipopolysaccharide (LPS) (12mg/kg) or placebo followed by 3.5h of protective mechanical ventilation. IgM-enriched immunoglobulins at 25mg/h (0.5mL/h) or saline were intravenously administered in the last hour of mechanical ventilation. During the experiment, gas exchange and hemodynamic measurements were recorded. Thereafter, the animals were sacrificed, and blood and organs were stored for cytokines measurements. RESULTS: Despite similar lung and hemodynamic findings, the administration of IgM-enriched immunoglobulins compared to placebo significantly modulates the inflammatory response by increasing IL-10 levels in the bloodstream and by decreasing TNF-α in bronchoalveolar lavage (BAL) fluid. Furthermore, in vitro data suggest that IgM-enriched immunoglobulins induce monocytes production of IL-10 after LPS stimulation. CONCLUSIONS: In an in vivo model of pneumonia developing shock, IgM-enriched immunoglobulins administered as rescue treatment enhance the anti-inflammatory response by increasing blood levels of IL-10 and reducing TNF-α in BAL fluid.

Osteopontin at the Crossroads of Inflammation and Tumor Progression.

Complex interactions between tumor and host cells regulate systemic tumor dissemination, a process that begins early at the primary tumor site and goes on until tumor cells detach themselves from the tumor mass and start migrating into the blood or lymphatic vessels. Metastatic cells colonize the target organs and are capable of surviving and growing at distant sites. In this context, osteopontin (OPN) appears to be a key determinant of the crosstalk between cancer cells and the host microenvironment, which in turn modulates immune evasion. OPN is overexpressed in several human carcinomas and has been implicated in inflammation, tumor progression, and metastasis. Thus, it represents one of the most attracting targets for cancer therapy. Within the tumor mass, OPN is secreted in various forms either by the tumor itself or by stroma cells, and it can exert either pro- or antitumorigenic effects according to the cell type and tumor microenvironment. Thus, targeting OPN for therapeutic purposes needs to take into account the heterogeneous functions of the multiple OPN forms with regard to cancer formation and progression. In this review, we will describe the role of systemic, tumor-derived, and stroma-derived OPN, highlighting its pivotal role at the crossroads of inflammation and tumor progression.

High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study.

BACKGROUND: To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses. METHODS: Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured. RESULTS: Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed. CONCLUSIONS: During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.

Renal hypoperfusion and impaired endothelium-dependent vasodilation in an animal model of VILI: the role of the peroxynitrite-PARP pathway.

INTRODUCTION: Mechanical ventilation (MV) can injure the lungs and contribute to an overwhelming inflammatory response, leading to acute renal failure (ARF). We previously showed that poly(adenosine diphosphate-ribose) polymerase (PARP) is involved in the development of ventilator-induced lung injury (VILI) and the related ARF, but the mechanisms underneath remain unclear. In the current study we therefore tested the hypothesis that renal blood flow and endothelial, functional and tissue changes in the kidney of rats with lipopolysaccharide (LPS)-induced lung injury aggravated by MV, is caused, in part, by activation of PARP by peroxynitrite. METHODS: Anesthetized Sprague Dawley rats (n = 31), were subjected to intratracheal instillation of lipopolysaccharide at 10 mg/kg followed by 210 min of mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (19 mL/kg) with zero positive end-expiratory pressure in the presence or absence of a peroxynitrite decomposition catalyst, WW85 or a PARP inhibitor, PJ-34. During the experiment, hemodynamics and blood gas variables were monitored. At time (t) t = 0 and t = 180 min, renal blood flow was measured. Blood and urine were collected for creatinine clearance measurement. Arcuate renal arteries were isolated for vasoreactivity experiment and kidneys snap frozen for staining. RESULTS: High tidal volume ventilation resulted in lung injury, hypotension, renal hypoperfusion and impaired renal endothelium-dependent vasodilation, associated with renal dysfunction and tissue changes (leukocyte accumulation and increased expression of neutrophil gelatinase-associated lipocalin). Both WW85 and PJ-34 treatments attenuated lung injury, preserved blood pressure, attenuated renal endothelial dysfunction and maintained renal blood flow. In multivariable analysis, renal blood flow improvement was, independently from each other, associated with both maintained blood pressure and endothelium-dependent vasodilation by drug treatment. Finally, drug treatment improved renal function and reduced tissue changes. CONCLUSIONS: The peroxynitrite-induced PARP activation is involved in renal hypoperfusion, impaired endothelium-dependent vasodilation and resultant dysfunction, and injury, in a model of lung injury.

Production of endothelin-1 and reduced blood flow in the rat kidney during lung-injurious mechanical ventilation.

INTRODUCTION: The mechanisms by which mechanical ventilation (MV) can injure remote organs, such as the kidney, remain poorly understood. We hypothesized that upregulation of systemic inflammation, as reflected by plasma interleukin-6 (IL-6) levels, in response to a lung-injurious ventilatory strategy, ultimately results in kidney dysfunction mediated by local endothelin-1 (ET-1) production and renal vasoconstriction. METHODS: Healthy, male Wistar rats were randomized to 1 of 2 MV settings (n=9 per group) and ventilated for 4 h. One group had a lung-protective setting using peak inspiratory pressure of 14 cm H2O and a positive end-expiratory pressure of 5 cm H2O; the other had a lung-injurious strategy using a peak inspiratory pressure of 20 cm H2O and positive end-expiratory pressure of 2 cm H2O. Nine randomly assigned rats served as nonventilated controls. We measured venous and arterial blood pressure and cardiac output (thermodilution method), renal blood flow (RBF) using fluorescent microspheres, and calculated creatinine clearance, urine flow, and fractional sodium excretion. Histological lung damage was assessed using hematoxylin-eosin staining. Renal ET-1 and plasma ET-1 and IL-6 concentrations were measured using enzyme-linked immunosorbent assays. RESULTS: Lung injury scores were higher after lung-injurious MV than after lung-protective ventilation or in sham controls. Lung-injurious MV resulted in significant production of renal ET-1 compared with the lung-protective and control groups. Simultaneously, RBF in the lung-injurious MV group was approximately 40% lower (P<0.05) than in the control group and 28% lower (P<0.05) than in the lung-protective group. Plasma ET-1 and IL-6 levels did not differ among the groups and systemic hemodynamics, such as cardiac output, were comparable. There was no effect on creatinine clearance, fractional sodium excretion, urine output, or kidney histology. CONCLUSIONS: Lung-injurious MV for 4 h in healthy rats results in significant production of renal ET-1 and in decreased RBF, independent of IL-6. Decreased RBF has no observable effect on kidney function or histology.

Serum levels of osteopontin are increased in SIRS and sepsis.

OBJECTIVE: In sepsis, dysregulation of the immune response leads to rapid multiorgan failure and death. Accurate and timely diagnosis is lifesaving and should discriminate sepsis from the systemic inflammatory response syndrome (SIRS) caused by non-infectious agents. Osteopontin acts as an extracellular matrix component or a soluble cytokine in inflamed tissues. Its exact role in immune response and sepsis remains to be elucidated. Therefore, we investigated the role of osteopontin in SIRS and sepsis. DESIGN: Prospective, observational study. SETTING: Intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: Fifty-six patients with SIRS or sepsis and 56 healthy subjects were enrolled. INTERVENTIONS: We analyzed the serum levels of osteopontin and TH1-TH2 cytokines and investigated the role of osteopontin on interleukin 6 secretion by monocytes. MEASUREMENTS AND MAIN RESULTS: Serum osteopontin levels were strikingly higher in patients than in controls and in sepsis than in SIRS, and decreased during the resolution of both the disorders. Receiver operating characteristic curves showed that osteopontin levels have discriminative power between SIRS and sepsis with an area under the curve of 0.796. Osteopontin levels directly correlated with those of interleukin 6 and in vitro, recombinant osteopontin increased interleukin 6 secretion by monocytes in both the absence and presence of high doses of lipopolysaccharide. CONCLUSION: These data suggest that osteopontin might be a mediator involved in the pathogenesis of SIRS and sepsis, possibly by supporting interleukin 6 secretion. DESCRIPTOR: 45. SIRS/Sepsis: clinical studies.

Inhibition of poly(adenosine diphosphate-ribose) polymerase attenuates ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. METHODS: Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. RESULTS: The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. CONCLUSION: The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

Role of human neutrophil peptides in the initial interaction between lung epithelial cells and CD4+ lymphocytes.

Human neutrophil peptides (HNP) exert immune-modulating effects. We hypothesized that HNP link innate and adaptive immunity through activation of costimulatory molecules. Human lung epithelial cells and CD4+ lymphocytes were treated with HNP separately or in coculture. Stimulation with HNP induced an increase in cell surface expression of CD54 (ICAM-1), CD80, and CD86 on lung epithelial cells and the corresponding major ligands, CD11a (LFA-1), CD152 (CTLA-4), and CD28 on CD4+ lymphocytes. There was an increased nuclear expression of the transcription factor p53 in human alveolar A549 cells and an elevated NF-kappaB (p50) and a degradation of I-kappaB protein in CD4+ lymphocytes following HNP stimulation. HNP enhanced the interaction between A549 cells and CD4+ lymphocytes by increasing cell adhesion and release of IFN-gamma, IL-2, and IL-8. This was attenuated by using an alpha1-proteinase inhibitor to neutralize HNP. We conclude that HNP play an important role in linking innate to acquired immunity by activation of costimulatory molecules in lung epithelial cells and CD4+ lymphocytes.

Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway.

Antimicrobial human neutrophil peptides (HNPs) play a pivotal role in innate host defense against a broad spectrum of prokaryotic pathogens. In addition, HNPs modulate cellular immune responses by producing the chemokine interleukin-8 (IL-8) in myeloid and epithelial cells and by exerting chemotaxis to T cells, immature dendritic cells, and monocytes. However, the mechanisms by which HNPs modulate the immune responses in the eukaryotic cells remain unclear. We demonstrated that, as with adenosine triphosphate (ATP) and uridine diphosphate (UDP), HNP stimulation of human lung epithelial cells selectively induced IL-8 production in 10 pro- and anti-inflammatory cytokines examined. HNP-induced IL-8 release was inhibited by treatment with the nucleotide receptor antagonists suramin and reactive blue. Transfection of lung epithelial cells with antisense oligonucleotides targeting specific purinergic P2Y receptors revealed that the P2Y6 (ligand of UDP) signaling pathway plays a predominant role in mediating HNP-induced IL-8 production.