Reduce Lung Damage Research Articles

Yeni Koronavirüs (2019-nCoV/COVID-19) ve Vitamin C

For the first time in December 2019, a case of pneumonia of unknown etiology was reported in Wuhan, China. Then, in addition to China and on the basis of increasing incidence and mortality rates in other international countries, the global emergency health status was declared by the World Health Organization Emergency Committee, and a new coronavirus was reported.Due to the very high contagion rate of the new Coronavirus (COVID-19), it has affected and continues to affect quite a lot of people from all age groups in the world. General clinical signs of COVID-19 are high fever, cough, nasal congestion, dyspnea, myalgia, fatigue, upper and lower respiratory tract infection and diarrhea. The most important and fatal clinical sign of the virus has been described as pneumonia. Unfortunately, no vaccine or special antiviral drug has been developed against COVID-19 yet. Therefore, the purpose of this review is to examine whether intravenous vitamin C administration is a promising method for the COVID-19 pandemic in accordance with the most recent evidence. Using vitamin C to prevent or treat diseases is often classified in complementary and alternative medicine. For this reason, it should never prevent the actual treatment. Studies have found that high doses of vitamin C reduce lung damage in COVID-19 and other flu infections. Therefore, intravenous vitamin C administration may be useful in addition to COVID-19 treatment.There is a need for high-level clinical studies on the effect of Vitamin C administration on COVID-19.

Effects of Protective Mechanical Ventilation With Different PEEP Levels on Alveolar Damage and Inflammation in a Model of Open Abdominal Surgery: A Randomized Study in Obese Versus Non-obese Rats.

Intraoperative positive end-expiratory pressure (PEEP) has been proposed to restore lung volumes and improve respiratory function in obesity. However, the biological impact of different PEEP levels on the lungs in obesity remains unknown. We aimed to compare the effects of PEEP = 2 cmH2O versus PEEP = 6 cmH2O during ventilation with low tidal volumes on lung function, histology, and biological markers in obese and non-obese rats undergoing open abdominal surgery. Forty-two Wistar rats (21 obese, 21 non-obese) were anesthetized and tracheotomized, and laparotomy was performed with standardized bowel manipulation. Rats were randomly ventilated with protective tidal volume (7 ml/kg) at PEEP = 2 cmH2O or PEEP = 6 cmH2O for 4 h, after which they were euthanized. Lung mechanics and histology, alveolar epithelial cell integrity, and biological markers associated with pulmonary inflammation, alveolar stretch, extracellular matrix, and epithelial and endothelial cell damage were analyzed. In obese rats, PEEP = 6 cmH2O compared with PEEP = 2 cmH2O was associated with less alveolar collapse (p = 0.02). E-cadherin expression was not different between the two PEEP groups. Gene expressions of interleukin (IL)-6 (p = 0.01) and type III procollagen (p = 0.004), as well as protein levels of tumor necrosis factor-alpha (p = 0.016), were lower at PEEP = 6 cmH2O than at PEEP = 2 cmH2O. In non-obese animals, PEEP = 6 cmH2O compared with PEEP = 2 cmH2O led to increased hyperinflation, reduced e-cadherin (p = 0.04), and increased gene expression of IL-6 (p = 0.004) and protein levels of tumor necrosis factor-alpha (p-0.029), but no changes in fibrogenesis. In conclusion, PEEP = 6 cmH2O reduced lung damage and inflammation in an experimental model of mechanical ventilation for open abdominal surgery, but only in obese animals.

The Modulation of Regulatory T Cells via HMGB1/PTEN/β-Catenin Axis in LPS Induced Acute Lung Injury.

Sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) remains the leading complication for mortality caused by bacterial infection. The regulatory T (Treg) cells appear to be an important modulator in resolving lung injury. Despite the extensive studies, little is known about the role of macrophage HMGB1/PTEN/β-catenin signaling in Treg development during ALI.Objectives: This study was designed to determine the roles and molecular mechanisms of HMGB1/PTEN/β-catenin signaling in mediating CD4+CD25+Foxp3+ Treg development in sepsis-induced lung injury in mice.Setting: University laboratory research of First Affiliated Hospital of Anhui Medical University.Subjects: PTEN/β-catenin Loxp and myeloid-specific knockout mice.Interventions: Groups of PTENloxp/β-cateninloxp and myeloid-specific PTEN/β-catenin knockout (PTENM−KO/β-cateninM−KO) mice were treated with LPS or recombinant HMGB1 (rHMGB1) to induce ALI. The effects of HMGB1-PTEN axis were further analyzed by in vitro co-cultures.Measures and Main Results: In a mouse model of ALI, blocking HMGB1 or myeloid-specific PTEN knockout (PTENM−KO) increased animal survival/body weight, reduced lung damage, increased TGF-β production, inhibited the expression of RORγt and IL-17, while promoting β-catenin signaling and increasing CD4+CD25+Foxp3+ Tregs in LPS- or rHMGB-induced lung injury. Notably, myeloid-specific β-catenin ablation (β-cateninM−KO) resulted in reduced animal survival and increased lung injury, accompanied by reduced CD4+CD25+Foxp3+ Tregs in rHMGB-induced ALI. Furthermore, disruption of macrophage HMGB1/PTEN or activation of β-catenin significantly increased CD4+CD25+Foxp3+ Tregs in vitro.Conclusions: HMGB1/PTEN/β-catenin signaling is a novel pathway that regulates Treg development and provides a potential therapeutic target in sepsis-induced lung injury.

Inhaled corticosteroids for cystic fibrosis.

The reduction of lung inflammation is one of the goals of cystic fibrosis therapy. Inhaled corticosteroids are often used in this respect to treat children and adults with cystic fibrosis. The rationale for this is their potential to reduce lung damage arising from inflammation, as well as their effect on symptomatic wheezing. It is important to establish the current level of evidence for the risks and benefits of inhaled corticosteroids, especially in the light of their known adverse effects on growth. This is an update of a previously published review; however, due to the lack of research in this area, we do not envisage undertaking any further updates. To assess the effectiveness of taking regular inhaled corticosteroids compared to not taking them in children and adults with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We requested information from pharmaceutical companies manufacturing inhaled corticosteroids and authors of identified trials.Date of most recent search of the Group's Trials Register: 19 November 2018. Randomised or quasi-randomised trials, published and unpublished, comparing inhaled corticosteroids to placebo or standard treatment in individuals with cystic fibrosis. Two independent authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro formas. The quality of the evidence was assessed using the GRADE criteria. The searches identified 35 citations, of which 27 (representing 13 trials) were eligible for inclusion. These 13 trials reported the use of inhaled corticosteroids in 525 people with cystic fibrosis aged between 6 and 55 years. One was a withdrawal trial in 171 individuals who were already taking inhaled corticosteroids. Methodological quality and risk of bias were difficult to assess from published information.Objective measures of airway function were reported in most trials but were often incomplete and reported at different time points. We found no difference in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) % predicted in any of the trials, although the quality of the evidence was low due to risks of bias within the included trials and low participant numbers. We are uncertain whether inhaled corticosteroids result in an improvement in exercise tolerance, bronchial hyperreactivity or exacerbations as the quality of the evidence was very low. Data from one trial suggested that inhaled corticosteroids may make little or no difference to quality of life (low-quality evidence).Three trials reported adverse effects, but the quality of the evidence is low and so we are uncertain whether inhaled corticosteroids increase the risk of adverse effects. However, one study did show that growth was adversely affected by high doses of inhaled corticosteroids. Evidence from these trials is of low to very low quality and insufficient to establish whether inhaled corticosteroids are beneficial in cystic fibrosis, but withdrawal in those already taking them has been shown to be safe. There is some evidence they may cause harm in terms of growth. It has not been established whether long-term use is beneficial in reducing lung inflammation, which should improve survival, but it is unlikely this will be proven conclusively in a randomised controlled trial.

Kaempferol reduces K63-linked polyubiquitination to inhibit nuclear factor-κB and inflammatory responses in acute lung injury in mice

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), pose a major clinical challenge. The major driving force in this syndrome is pulmonary inflammation. Recent studies have shown that the naturally occurring flavonoid kaempferol (KPF) reduces endotoxin-induced inflammatory responses in mice. However, the mechanisms of these anti-inflammatory activities are not currently known. Here, we show that enhanced inflammatory cytokine production in response to lipopolysaccharide (LPS) is due to increased TGF-β-activated kinase-1 (TAK1) phosphorylation with subsequent activation of nuclear factor-κB (NF-κB). KPF attenuates LPS-mediated production of cytokines as well as activation of NF-κB. Furthermore, we identified that KPF prevents increased K63-linked polyubiquitination on TNF receptor associated factor-6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1). K63-linked polyubiquitination is a signal leading to enhanced activation of downstream pathways including TAK1. Our study shows that KPF is effective in reducing lung damage induced by LPS by modulating TRAF6 polyubiquitination. Furthermore, our findings may provide novel molecular targets to alleviate acute lung injury.

Mutation S110L of H1N1 Influenza Virus Hemagglutinin: A Potent Determinant of Attenuation in the Mouse Model.

Characterization of a pandemic 2009 H1N1 influenza virus isolated from a fatal case patient (F-IAV), showed the presence of three different mutations; potential determinants of its high pathogenicity that were located in the polymerase subunits (PB2 A221T and PA D529N) and the hemagglutinin (HA S110L). Recombinant viruses containing individually or in combination the polymerase mutations in the backbone of A/California/04/09 (CAL) showed that PA D529N was clearly involved in the increased pathogenicity of the F-IAV virus. Here, we have evaluated the contribution of HA S110L to F-IAV pathogenicity, through introduction of this point mutation in CAL recombinant virus (HA mut). The HA S110L protein has similar pH stability, comparable mobility, and entry properties both in human and mouse cultured cells that wild type HA. The change HA S110L leads to a non-significant trend to reduce the replication capacity of influenza virus in tissue culture, and HA mut is better neutralized than CAL virus by monoclonal and polyclonal antibodies against HA from CAL strain. In addition, recombinant viruses containing HA S110L alone or in combination with polymerase mutations considerably increased the LD50 in infected mice. Characterization of the lungs of HA mut infected animals showed reduced lung damage and inflammation compared with CAL infected mice. Accordingly, lower virus replication, decreased presence in bronchioli and parenchyma and lower leukocytes and epithelial infected cells were found in the lungs of HA mut-infected animals. Our results indicate that, mutation HA S110L constitutes a determinant of attenuation and suggest that its interaction with components of the respiratory tract mucus and lectins, that play an important role on influenza virus outcome, may constitute a physical barrier impeding the infection of the target cells, thus compromising the infection outcome.

The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy.

Impaired lung function is common in people with a history of tuberculosis. Host-directed therapy added to tuberculosis treatment may reduce lung damage and result in improved lung function. An understanding of the pathogenesis of pulmonary damage in TB is fundamental to successfully predicting which interventions could be beneficial. In this review, we describe the different features of TB immunopathology that lead to impaired lung function, namely cavities, bronchiectasis, and fibrosis. We discuss the immunological processes that cause lung damage, focusing on studies performed in humans, and using chest radiograph abnormalities as a marker for pulmonary damage. We highlight the roles of matrix metalloproteinases, neutrophils, eicosanoids and cytokines, like tumor necrosis factor-α and interleukin 1β, as well as the role of HIV co-infection. Finally, we focus on various existing drugs that affect one or more of the immunological mediators of lung damage and could therefore play a role as host-directed therapy.

Anti-inflammatory activities of Aedes aegypti cecropins and their protection against murine endotoxin shock

BackgroundMosquitoes are armed with physiologically active compounds to suppress the host immunity including host inflammatory reaction. However, the specific anti-inflammatory components in mosquitoes remain unknown.ResultsBy searching for the immunomodulatory molecules from the mosquito Aedes aegypti (Diptera: Culicidae) at NCBI for anti-inflammatory function, five cecropins (for short in this study: AeaeCec1, 2, 3, 4 and 5) were selected. AeaeCec1-5 efficiently inhibited the expression of inducible nitric oxide synthase (iNOS), nitrite, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages and human peripheral blood mononuclear cells (PBMCs) with low toxicity to mammalian cells. Among the five analogues, AeaeCec5 had the strongest anti-inflammatory activity, and generated an additive effect with other AeaeCec peptides. In a mouse model of endotoxin shock, AeaeCec1-5 effectively reduced TNF-α, IL-1β and IL-6 expression in lungs, serum and peritoneal lavage and correspondingly reduced lung damage and edema, with AeaeCec5 showing the best protection. In mice infected with Escherichia coli or Pseudomonas aeruginosa, administration of AeaeCec5 reduced the production of TNF-α, IL-1β and IL-6 and correspondingly reduced lung tissue damage. These effects of Ae. aegypti AeaeCec1-5 were attributed to an efficient inhibition of the activation of mitogen-activated protein kinases (MAPKs) and transcriptional nuclear factor-κB (NF-κB) signaling pathways, as well as partial neutralization of LPS.ConclusionsThe current work characterized the specific anti-inflammatory agents in Ae. aegypti and provided AeaeCec5 as a potent anti-endotoxin peptide that could serve as the basis for the development of anti-inflammatory therapy.

The anti-inflammatory effect of hesperetin on lung damage induced by paraquat in rats

Objective: To investigate the anti-inflammatory effect of hesperetin (HSP) on lung damage induced by paraquat (PQ) in rats by detecting the levels of inflammatory makers in rat lung tissues. Methods: 140 Wistar male rats were randomly divided into negative control group, HSP control group, HSP control group, paraquat model group, pirfenidone (PDF) positive control group, and 100, 200, 400 mg/kg HSP treatment groups. All groups were exposed to 50mg/kg paraquat by oral gavage except for the negative control group and HSP control group. After 24 hours, the rats in each group were given drug intervention once daily. 10 rats were randomly sacrificed at 7th day and 28th day after exposure to paraquat respectively. 3 rats were randomly selected from them and HE, Masson staining were used to observe the pathological changes in the lungs of each group. Each group randomly selected 6 rats at two time points to detect the levels of TGF-β(1), TNF-α, IL-4, IL-10, IL-1β and IFN-γ in rat lung tissues. Results: Histopathological examination found that the lung injury were reduced in the rats of PDF positive control group and all HSP treatment groups. Compared with the negative control group, the levels of TGF-β1, IL-1β, TNF-α, IL-4, and IL-10 in rat lung tissues were significantly increased (P<0.05, P<0.01) after PQ exposure at two points in time, and there was no significant difference in the level of IFN-γ in lung tissues compared with the negative control group (P>0.05) . The levels of TGF-β1, IL-1β, IL-4, IL-10 and TNF-α in the lung tissues of rats on the 7th day in different dose treatment groups of HSP were reduced compared with those in the PQ model group with varying degrees (P<0.05, P<0.01) . The level of IFN-γ in lung tissues of rats were not significantly different from that of model group (P>0.05) . The levels of TGF-β(1) and TNF-α in lung tissue of rats on the 28th day in PDF positive control group and different dose treatment groups of HSP were reduced compared with those in the PQ model group with varying degrees (P<0.05, P<0.01). The levels of IFN-γ in the rat lung tissues were increased compared with those in the PQ model group (P<0.05). Besides, there were no significant in the levels of IL-1β, IL-4 and IL-10 in lung tissues compared with PQ model group (P>0.05). Conclusion: HSP can reduce lung damage induced by PQ in rats by inhibiting the release of inflammatory factors and promoting the secretion of anti-inflammatory factors.

Effects of pressure support ventilation on ventilator-induced lung injury in mild acute respiratory distress syndrome depend on level of positive end-expiratory pressure: A randomised animal study.

Harmful effects of spontaneous breathing have been shown in experimental severe acute respiratory distress syndrome (ARDS). However, in the clinical setting, spontaneous respiration has been indicated only in mild ARDS. To date, no study has compared the effects of spontaneous assisted breathing with those of fully controlled mechanical ventilation at different levels of positive end-expiratory pressure (PEEP) on lung injury in ARDS. To compare the effects of assisted pressure support ventilation (PSV) with pressure-controlled ventilation (PCV) on lung function, histology and biological markers at two different PEEP levels in mild ARDS in rats. Randomised controlled experimental study. Basic science laboratory. Thirty-five Wistar rats (weight ± SD, 310 ± 19) g received Escherichia coli lipopolysaccharide (LPS) intratracheally. After 24 h, the animals were anaesthetised and randomly allocated to either PCV (n=14) or PSV (n=14) groups. Each group was further assigned to PEEP = 2 cmH2O or PEEP = 5 cmH2O. Tidal volume was kept constant (≈6 ml kg). Additional nonventilated animals (n=7) were used as a control for postmortem analysis. Ventilatory and mechanical parameters, arterial blood gases, diffuse alveolar damage score, epithelial integrity measured by E-cadherin tissue expression, and biological markers associated with inflammation (IL-6 and cytokine-induced neutrophil chemoattractant, CINC-1) and type II epithelial cell damage (surfactant protein-B) were evaluated. In both PCV and PSV, peak transpulmonary pressure was lower, whereas E-cadherin tissue expression, which is related to epithelial integrity, was higher at PEEP = 5 cmH2O than at PEEP = 2 cmH2O. In PSV, PEEP = 5 cmH2O compared with PEEP = 2 cmH2O was associated with significantly reduced diffuse alveolar damage score [median (interquartile range), 11 (8.5 to 13.5) vs. 23 (19 to 26), P = 0.005] and expressions of IL-6 and CINC-1 (P = 0.02 for both), whereas surfactant protein-B mRNA expression increased (P = 0.03). These changes suggested less type II epithelial cell damage at a PEEP of 5 cmH2O. Peak transpulmonary pressure correlated positively with IL-6 [Spearman's rho (ρ) = 0.62, P = 0.0007] and CINC-1 expressions (ρ = 0.50, P = 0.01) and negatively with E-cadherin expression (ρ = -0.67, P = 0.0002). During PSV, PEEP of 5 cmH2O, but not a PEEP of 2 cmH2O, reduced lung damage and inflammatory markers while maintaining epithelial cell integrity.

Role of the extracellular matrix in the genesis of ventilator-induced lung injury.

The extracellular matrix represents the three-dimensional scaffold of the alveolar wall, which is composed of alayer of epithelial and endothelial cells, their basal membrane, and athin interstitial layer containing fibrous proteins, glycoproteins, glycosaminoglycans, and proteoglycans. Mechanical ventilation with low and high tidal volumes can induce proteoglycan fragmentation, which may cause activation of the inflammatory cascade, leading to the main features of ventilator-induced lung injury (VILI): alveolar edema and collagen deposition. The purpose of this article is to describe VILI pathophysiology with aspecial focus on the effects of mechanical ventilation on the extracellular matrix. Amore complete understanding of the molecular effects induced by physical forces is required to better assess the impact of existing mechanical ventilation strategies, as well as to develop new therapeutic strategies to reduce lung damage.

Volume-targeted versus pressure-limited ventilation in neonates.

Damage caused by lung overdistension (volutrauma) has been implicated in the development of bronchopulmonary dysplasia (BPD). Modern neonatal ventilation modes can target a set tidal volume as an alternative to traditional pressure-limited ventilation (PLV) using a fixed inflation pressure. Volume-targeted ventilation (VTV) aims to produce a more stable tidal volume in order to reduce lung damage and stabilise the partial pressure of carbon dioxide (pCO2). To determine whether VTV compared with PLV leads to reduced rates of death and death or BPD in newborn infants and to determine whether use of VTV affected outcomes including air leak, cranial ultrasound findings and neurodevelopment. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 12), MEDLINE via PubMed (1966 to 13 January 2017), Embase (1980 to 13 January 2017) and CINAHL (1982 to 13 January 2017). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We contacted the principal investigators of studies to obtain supplementary information. Randomised and quasi-randomised trials comparing VTV versus PLV in infants of less than 44 weeks' postmenstrual age and reporting clinically relevant outcomes. We assessed risk of bias for each trial using Cochrane methodology. We evaluated quality of evidence for each outcome using GRADE criteria. We tabulated mortality, rates of BPD, short-term clinical outcomes and long-term developmental outcomes. for categorical outcomes, we calculated typical estimates for risk ratios (RR), risk differences (RD) and number needed to treat for an additional beneficial outcome (NNTB). For continuous variables, we calculated typical estimates for mean differences (MD). We used 95% confidence intervals (CI) and assumed a fixed-effect model for meta-analysis. Twenty randomised trials met our inclusion criteria; 16 parallel trials (977 infants) and four cross-over trials (88 infants). No studies were blinded and the quality of evidence for outcomes assessed varied from moderate to low.We found no difference in the primary outcome, death before hospital discharge, between VTV modes versus PLV modes (typical RR 0.75, 95% CI 0.53 to 1.07; low quality evidence). However, there was moderate quality evidence that the use of VTV modes resulted in a reduction in the primary outcome, death or BPD at 36 weeks' gestation (typical RR 0.73, 95% CI 0.59 to 0.89; typical NNTB 8, 95% CI 5 to 20) and the following secondary outcomes: rates of pneumothorax (typical RR 0.52, 95% CI 0.31 to 0.87; typical NNTB 20, 95% CI 11 to 100), mean days of mechanical ventilation (MD -1.35 days, 95% CI -1.83 to -0.86), rates of hypocarbia (typical RR 0.49, 95% CI 0.33 to 0.72; typical NNTB 3, 95% CI 2 to 5), rates of grade 3 or 4 intraventricular haemorrhage (typical RR 0.53, 95% CI 0.37 to 0.77; typical NNTB 11, 95% CI 7 to 25) and the combined outcome of periventricular leukomalacia with or without grade 3 or 4 intraventricular haemorrhage (typical RR 0.47, 95% CI 0.27 to 0.80; typical NNTB 11, 95% CI 7 to 33). VTV modes were not associated with any increased adverse outcomes. Infants ventilated using VTV modes had reduced rates of death or BPD, pneumothoraces, hypocarbia, severe cranial ultrasound pathologies and duration of ventilation compared with infants ventilated using PLV modes. Further studies are needed to identify whether VTV modes improve neurodevelopmental outcomes and to compare and refine VTV strategies.

Impact of Different Ventilation Strategies on Driving Pressure, Mechanical Power, and Biological Markers During Open Abdominal Surgery in Rats.

Intraoperative mechanical ventilation may yield lung injury. To date, there is no consensus regarding the best ventilator strategy for abdominal surgery. We aimed to investigate the impact of the mechanical ventilation strategies used in 2 recent trials (Intraoperative Protective Ventilation [IMPROVE] trial and Protective Ventilation using High versus Low PEEP [PROVHILO] trial) on driving pressure (ΔPRS), mechanical power, and lung damage in a model of open abdominal surgery. Thirty-five Wistar rats were used, of which 28 were anesthetized, and a laparotomy was performed with standardized bowel manipulation. Postoperatively, animals (n = 7/group) were randomly assigned to 4 hours of ventilation with: (1) tidal volume (VT) = 7 mL/kg and positive end-expiratory pressure (PEEP) = 1 cm H2O without recruitment maneuvers (RMs) (low VT/low PEEP/RM-), mimicking the low-VT/low-PEEP strategy of PROVHILO; (2) VT = 7 mL/kg and PEEP = 3 cm H2O with RMs before laparotomy and hourly thereafter (low VT/moderate PEEP/4 RM+), mimicking the protective ventilation strategy of IMPROVE; (3) VT = 7 mL/kg and PEEP = 6 cm H2O with RMs only before laparotomy (low VT/high PEEP/1 RM+), mimicking the strategy used after intubation and before extubation in PROVHILO; or (4) VT = 14 mL/kg and PEEP = 1 cm H2O without RMs (high VT/low PEEP/RM-), mimicking conventional ventilation used in IMPROVE. Seven rats were not tracheotomized, operated, or mechanically ventilated, and constituted the healthy nonoperated and nonventilated controls. Low VT/moderate PEEP/4 RM+ and low VT/high PEEP/1 RM+, compared to low VT/low PEEP/RM- and high VT/low PEEP/RM-, resulted in lower ΔPRS (7.1 ± 0.8 and 10.2 ± 2.1 cm H2O vs 13.9 ± 0.9 and 16.9 ± 0.8 cm H2O, respectively; P< .001) and less mechanical power (63 ± 7 and 79 ± 20 J/min vs 110 ± 10 and 120 ± 20 J/min, respectively; P = .007). Low VT/high PEEP/1 RM+ was associated with less alveolar collapse than low VT/low PEEP/RM- (P = .03). E-cadherin expression was higher in low VT/moderate PEEP/4 RM+ than in low VT/low PEEP/RM- (P = .013) or high VT/low PEEP/RM- (P = .014). The extent of alveolar collapse, E-cadherin expression, and tumor necrosis factor-alpha correlated with ΔPRS (r = 0.54 [P = .02], r = -0.48 [P = .05], and r = 0.59 [P = .09], respectively) and mechanical power (r = 0.57 [P = .02], r = -0.54 [P = .02], and r = 0.48 [P = .04], respectively). In this model of open abdominal surgery based on the mechanical ventilation strategies used in IMPROVE and PROVHILO trials, lower mechanical power and its surrogate ΔPRS were associated with reduced lung damage.

The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance.

• The Mla pathway regulates outer membrane dynamics in human pathogen Pseudomonas aeruginosa (PA). • Disruption of Mla pathway gene vacJ sensitizes PA to host cathelicidin antimicrobial peptide LL-37. • Loss of vacJ expression renders PA more sensitive to human whole blood and serum killing. • Loss of vacJ expression reduces PA survival and virulence in a murine lung infection model. • The Mla pathway merits exploration as a pharmacologic target to sensitize PA to host innate immunity.

One-lung ventilation for thoracic surgery: current perspectives.

One-lung ventilation (OLV) is an anesthesiological technique that is increasingly being used beyond thoracic surgery. This requires specific skills and knowledge about airway management, maintenance of gas exchange and prevention of acute lung injury. Sometimes maintaining adequate gas exchange and minimizing acute lung injury may be opposing processes. Parameters validated for OLV titration still have not been found, but a multimodal approach based on low tidal volume, end-expiratory pressure application and alveolar recruitment maneuvers is considered the best way to ensure protective ventilation and reduce lung damage. The purpose of this review is to analyze all these factors using the latest scientific evidence and the opinions of the most influential authors.

Effects of pressure support and pressure-controlled ventilation on lung damage in a model of mild extrapulmonary acute lung injury with intra-abdominal hypertension.

Intra-abdominal hypertension (IAH) may co-occur with the acute respiratory distress syndrome (ARDS), with significant impact on morbidity and mortality. Lung-protective controlled mechanical ventilation with low tidal volume and positive end-expiratory pressure (PEEP) has been recommended in ARDS. However, mechanical ventilation with spontaneous breathing activity may be beneficial to lung function and reduce lung damage in mild ARDS. We hypothesized that preserving spontaneous breathing activity during pressure support ventilation (PSV) would improve respiratory function and minimize ventilator-induced lung injury (VILI) compared to pressure-controlled ventilation (PCV) in mild extrapulmonary acute lung injury (ALI) with IAH. Thirty Wistar rats (334±55g) received Escherichia coli lipopolysaccharide intraperitoneally (1000μg) to induce mild extrapulmonary ALI. After 24h, animals were anesthetized and randomized to receive PCV or PSV. They were then further randomized into subgroups without or with IAH (15 mmHg) and ventilated with PCV or PSV (PEEP = 5cmH2O, driving pressure adjusted to achieve tidal volume = 6mL/kg) for 1h. Six of the 30 rats were used for molecular biology analysis and were not mechanically ventilated. The main outcome was the effect of PCV versus PSV on mRNA expression of interleukin (IL)-6 in lung tissue. Regardless of whether IAH was present, PSV resulted in lower mean airway pressure (with no differences in peak airway or peak and mean transpulmonary pressures) and less mRNA expression of biomarkers associated with lung inflammation (IL-6) and fibrogenesis (type III procollagen) than PCV. In the presence of IAH, PSV improved oxygenation; decreased alveolar collapse, interstitial edema, and diffuse alveolar damage; and increased expression of surfactant protein B as compared to PCV. In this experimental model of mild extrapulmonary ALI associated with IAH, PSV compared to PCV improved lung function and morphology and reduced type 2 epithelial cell damage.

Variable Ventilation Improved Respiratory System Mechanics and Ameliorated Pulmonary Damage in a Rat Model of Lung Ischemia-Reperfusion.

Lung ischemia-reperfusion injury remains a major complication after lung transplantation. Variable ventilation (VV) has been shown to improve respiratory function and reduce pulmonary histological damage compared to protective volume-controlled ventilation (VCV) in different models of lung injury induced by endotoxin, surfactant depletion by saline lavage, and hydrochloric acid. However, no study has compared the biological impact of VV vs. VCV in lung ischemia-reperfusion injury, which has a complex pathophysiology different from that of other experimental models. Thirty-six animals were randomly assigned to one of two groups: (1) ischemia-reperfusion (IR), in which the left pulmonary hilum was completely occluded and released after 30 min; and (2) Sham, in which animals underwent the same surgical manipulation but without hilar clamping. Immediately after surgery, the left (IR-injured) and right (contralateral) lungs from 6 animals per group were removed, and served as non-ventilated group (NV) for molecular biology analysis. IR and Sham groups were further randomized to one of two ventilation strategies: VCV (n = 6/group) [tidal volume (VT) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 2 cmH2O, fraction of inspired oxygen (FiO2) = 0.4]; or VV, which was applied on a breath-to-breath basis as a sequence of randomly generated VT values (n = 1200; mean VT = 6 mL/kg), with a 30% coefficient of variation. After 5 min of ventilation and at the end of a 2-h period (Final), respiratory system mechanics and arterial blood gases were measured. At Final, lungs were removed for histological and molecular biology analyses. Respiratory system elastance and alveolar collapse were lower in VCV than VV (mean ± SD, VCV 3.6 ± 1.3 cmH20/ml and 2.0 ± 0.8 cmH20/ml, p = 0.005; median [interquartile range], VCV 20.4% [7.9–33.1] and VV 5.4% [3.1–8.8], p = 0.04, respectively). In left lungs of IR animals, VCV increased the expression of interleukin-6 and intercellular adhesion molecule-1 compared to NV, with no significant differences between VV and NV. Compared to VCV, VV increased the expression of surfactant protein-D, suggesting protection from type II epithelial cell damage. In conclusion, in this experimental lung ischemia-reperfusion model, VV improved respiratory system elastance and reduced lung damage compared to VCV.

Immunization with outer membrane proteins (OprF and OprI) and flagellin Bprotects mice from pulmonary infection with mucoid and nonmucoid Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterium, which considered as a common cause of nosocomial infection and life-threatening complications in immunocompromized and cystic fibrosis patients. Here, we evaluate the protective effect of recombinant vaccines composed of outer membrane proteins OprF and OprI alone or in combination with flagellin B against mucoid and nonmucoid pseudomonas infection. BALB/C mice were immunized subcutaneous using OprF and OprI with or without flagellin B and antibody titers were determined. Serum bactericidal and opsonophagocytosis activities of immunized and control sera were estimated against mucoid and nonmucoid pseudomonas strains. Lung tissue sections from immunized and nonimmunized mice were analyzed and the levels of peripheral neutrophils infiltration into the lung and tissue inflammation were scored. Subcutaneous immunization using OprF and OprI with or without flagellin B elicited higher antibody titers against OprF, OprI, and flagellin B. The produced antibodies successfully opsonized both mucoid and nonmucoid strains with subsequent activation of the terminal pathway of complement that enhances killing of nonmucoid strains via complement-mediated lysis. Furthermore, opsonized mucoid and nonmucoid strains showed enhanced opsonophagocytosis via human peripheral neutrophils, a mechanism that kills P. aeruginosa when complement mediated lysis is not effective especially with mucoid strains. Immunized mice also showed a significant prolonged survival time, lower bacteremia, and reduced lung damage when compared with control nonimmunized mice. Our data showed that mice immunized with OprF/OprI or OprF/OprI and flagellin B are significantly protected from infection caused by mucoid and nonmucoid strains of P. aeruginosa.

Variable ventilation improves pulmonary function and reduces lung damage without increasing bacterial translocation in a rat model of experimental pneumonia.

BackgroundVariable ventilation has been shown to improve pulmonary function and reduce lung damage in different models of acute respiratory distress syndrome. Nevertheless, variable ventilation has not been tested during pneumonia. Theoretically, periodic increases in tidal volume (VT) and airway pressures might worsen the impairment of alveolar barrier function usually seen in pneumonia and could increase bacterial translocation into the bloodstream. We investigated the impact of variable ventilation on lung function and histologic damage, as well as markers of lung inflammation, epithelial and endothelial cell damage, and alveolar stress, and bacterial translocation in experimental pneumonia.MethodsThirty-two Wistar rats were randomly assigned to receive intratracheal of Pseudomonas aeruginosa (PA) or saline (SAL) (n = 16/group). After 24-h, animals were anesthetized and ventilated for 2 h with either conventional volume-controlled (VCV) or variable volume-controlled ventilation (VV), with mean VT = 6 mL/kg, PEEP = 5cmH2O, and FiO2 = 0.4. During VV, tidal volume varied randomly with a coefficient of variation of 30% and a Gaussian distribution. Additional animals assigned to receive either PA or SAL (n = 8/group) were not ventilated (NV) to serve as controls.ResultsIn both SAL and PA, VV improved oxygenation and lung elastance compared to VCV. In SAL, VV decreased interleukin (IL)-6 expression compared to VCV (median [interquartile range]: 1.3 [0.3–2.3] vs. 5.3 [3.6–7.0]; p = 0.02) and increased surfactant protein-D expression compared to NV (2.5 [1.9–3.5] vs. 1.2 [0.8–1.2]; p = 0.0005). In PA, compared to VCV, VV reduced perivascular edema (2.5 [2.0–3.75] vs. 6.0 [4.5–6.0]; p < 0.0001), septum neutrophils (2.0 [1.0–4.0] vs. 5.0 [3.3–6.0]; p = 0.0008), necrotizing vasculitis (3.0 [2.0–5.5] vs. 6.0 [6.0–6.0]; p = 0.0003), and ultrastructural lung damage scores (16 [14–17] vs. 24 [14–27], p < 0.0001). Blood colony-forming-unit (CFU) counts were comparable (7 [0–28] vs. 6 [0–26], p = 0.77). Compared to NV, VCV, but not VV, increased expression amphiregulin, IL-6, and cytokine-induced neutrophil chemoattractant (CINC)-1 (2.1 [1.6–2.5] vs. 0.9 [0.7–1.2], p = 0.025; 12.3 [7.9–22.0] vs. 0.8 [0.6–1.9], p = 0.006; and 4.4 [2.9–5.6] vs. 0.9 [0.8–1.4], p = 0.003, respectively). Angiopoietin-2 expression was lower in VV compared to NV animals (0.5 [0.3–0.8] vs. 1.3 [1.0–1.5], p = 0.01).ConclusionIn this rat model of pneumonia, VV improved pulmonary function and reduced lung damage as compared to VCV, without increasing bacterial translocation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0476-7) contains supplementary material, which is available to authorized users.

Comparison between effects of pressure support and pressure-controlled ventilation on lung and diaphragmatic damage in experimental emphysema.

BackgroundIn patients with emphysema, invasive mechanical ventilation settings should be adjusted to minimize hyperinflation while reducing respiratory effort and providing adequate gas exchange. We evaluated the impact of pressure-controlled ventilation (PCV) and pressure support ventilation (PSV) on pulmonary and diaphragmatic damage, as well as cardiac function, in experimental emphysema.MethodsEmphysema was induced by intratracheal instillation of porcine pancreatic elastase in Wistar rats, once weekly for 4 weeks. Control animals received saline under the same protocol. Eight weeks after first instillation, control and emphysema rats were randomly assigned to PCV (n = 6/each) or PSV (n = 6/each) under protective tidal volume (6 ml/kg) for 4 h. Non-ventilated control and emphysema animals (n = 6/group) were used to characterize the model and for molecular biology analysis. Cardiorespiratory function, lung histology, diaphragm ultrastructure alterations, extracellular matrix organization, diaphragmatic proteolysis, and biological markers associated with pulmonary inflammation, alveolar stretch, and epithelial and endothelial cell damage were assessed.ResultsEmphysema animals exhibited cardiorespiratory changes that resemble human emphysema, such as increased areas of lung hyperinflation, pulmonary amphiregulin expression, and diaphragmatic injury. In emphysema animals, PSV compared to PCV yielded: no changes in gas exchange; decreased mean transpulmonary pressure (Pmean,L), ratio between inspiratory and total time (Ti/Ttot), lung hyperinflation, and amphiregulin expression in lung; increased ratio of pulmonary artery acceleration time to pulmonary artery ejection time, suggesting reduced right ventricular afterload; and increased ultrastructural damage to the diaphragm. Amphiregulin correlated with Pmean,L (r = 0.99, p < 0.0001) and hyperinflation (r = 0.70, p = 0.043), whereas Ti/Ttot correlated with hyperinflation (r = 0.81, p = 0.002) and Pmean,L (r = 0.60, p = 0.04).ConclusionsIn the model of elastase-induced emphysema used herein, PSV reduced lung damage and improved cardiac function when compared to PCV, but worsened diaphragmatic injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-016-0107-0) contains supplementary material, which is available to authorized users.